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Teichman EM, Hu J, Lin HY, Fisher-Foye RL, Blando A, Hu X, Kaniskan HÜ, Montgomery SE, Cai M, Parise LF, Wang J, Russo SJ, Han MH, Jin J, Morel C. Design and validation of novel brain-penetrant HCN channel inhibitors to ameliorate social stress-induced susceptible phenotype. Mol Psychiatry 2025:10.1038/s41380-025-02972-8. [PMID: 40199995 DOI: 10.1038/s41380-025-02972-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 12/16/2024] [Accepted: 03/20/2025] [Indexed: 04/10/2025]
Abstract
Major Depressive Disorder (MDD) is a devastating, multifactorial disease with limited pharmacological treatment options. Patients with MDD exhibit alterations in their dopamine (DA) signaling pathways through the midbrain ventral tegmental area (VTA). A similar observation is also detected in preclinical models of stress - mice exhibit behavioral and physiological impairments following chronic social defeat stress (CSDS). Prior studies demonstrate that CSDS-susceptible mice have increased VTA DA neuronal excitability, in part driven by an upregulation in hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. Inhibiting HCN channels with known inhibitors such as Cilobradine alleviates the negative behavioral effects of CSDS. Here, we aimed to identify Cilobradine analogs with improved neural tropism and inhibitory efficacy. Two compounds, MS7710 and MS7712, differing by their left-hand side moieties, have a similar, potent inhibitory effect on VTA DA Ih currents as compared to Cilobradine, and a greater inhibitory effect than Cilobradine on VTA DA firing rate. We demonstrate that MS7710 and MS7712 have superior brain/plasma concentration ratios as compared to Cilobradine. They were efficacious at inhibiting VTA DA neuron firing rate and bursting activity in CSDS-susceptible male mice at lower doses than Cilobradine, which was recapitulated in female CSDS-susceptible mice with MS7710. Finally, we define that a single intraperitoneal injection of MS7710 ameliorates CSDS-induced social interaction deficits and reward-associated cognitive inflexibility for at least two weeks in male and female mice. These findings yield a novel HCN channel inhibitor with improved neural tropism and stress-alleviating effects that could provide a basis for future antidepressant drug discovery.
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Affiliation(s)
- Emily M Teichman
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jianping Hu
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Hsiao-Yun Lin
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Rachel L Fisher-Foye
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Anthony Blando
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Xiaoping Hu
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - H Ümit Kaniskan
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Sarah E Montgomery
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Modendo Inc., 3415 Colorado Ave, Boulder, Colorado, 80303, USA
| | - Min Cai
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Lyonna F Parise
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jun Wang
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, New York, NY, USA
| | - Scott J Russo
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Brain-Body Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ming-Hu Han
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology; Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
| | - Jian Jin
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Carole Morel
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Copier JS, Verkerk AO, Lodder EM. HCN4 in the atrioventricular node. Heart Rhythm 2025:S1547-5271(25)00200-0. [PMID: 39988103 DOI: 10.1016/j.hrthm.2025.02.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 01/31/2025] [Accepted: 02/11/2025] [Indexed: 02/25/2025]
Abstract
Hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) drives the funny current in cardiac pacemaker regions. Its involvement in sinoatrial node pacemaker generation is well known, but its function in the atrioventricular (AV) node (AVN) has not intensively been studied. HCN4 is expressed in the AVN, and its expression within the AVN seems similar across mammalian species with HCN4 presence in the inferior nodal extensions, compact node, and AV bundle. The main direct regulators of HCN4 are cAMP and protein kinase A. In addition, indirect regulators may affect HCN4 via trafficking and localization. However, these effects are underexplored in the AVN. AVN-specific effects in knockout and knockin mice include reduced funny current density and increased AV block. HCN4 expression in the AVN could be affected by aging, exercise, heart failure, and diabetes. This could underlie changes in PR interval, atria-His interval, Wenckebach cycle length, and AVN effective refractory period. Clinical reports link the HCN4 variant G1097W to AV block. Other clinical data come from studies assessing ivabradine, an HCN4 inhibitor. In animals, ivabradine resulted in prolonged PR and atrial-his intervals. To date, uncertainty regarding the role of HCN4 in the AVN remains. However, AVN-focused studies suggest HCN4's importance for AVN function. This review summarizes recent findings and highlights the involvement of HCN4 in normal and pathological AVN function.
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Affiliation(s)
- Jaël S Copier
- Experimental Cardiology, Amsterdam UMC, Amsterdam, The Netherlands; Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Arie O Verkerk
- Experimental Cardiology, Amsterdam UMC, Amsterdam, The Netherlands; Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; Medical Biology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Elisabeth M Lodder
- Experimental Cardiology, Amsterdam UMC, Amsterdam, The Netherlands; Heart Failure & Arrhythmias, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
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Ohashi N, Ohashi M, Hoshino R, Deguchi H, Baba H. Ivabradine reduces neuropathic pain after spinal cord injury by inhibiting excitatory synaptic transmission in the spinal dorsal horn. Neurosci Lett 2025; 848:138113. [PMID: 39765281 DOI: 10.1016/j.neulet.2025.138113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 12/26/2024] [Accepted: 01/03/2025] [Indexed: 01/12/2025]
Abstract
Spinal cord injuries (SCIs) can lead to severe neuropathic pain and increased risk of myocardial infarction and heart failure; therefore, the use of analgesics against SCI-induced pain should be minimized because of their adverse effects on the cardiovascular system. Ivabradine, a blocker of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels, is used as a bradycardic agent, but recent studies focused on it as an analgesic agent for peripheral neuropathic pain. However, the analgesic effects of ivabradine on central neuropathic pain, such as SCI-induced pain, have not been examined. The aim of this study was to investigate the spinal analgesic effects of ivabradine on central neuropathic pain induced by SCI. Ivabradine induced analgesia in both spontaneous pain-related behavior and mechanical allodynia in SCI-induced pain (6-7 rats/group; p < 0.01). In immunohistochemical staining analyses, ivabradine suppressed phosphorylation of extracellular signal-regulated kinases activated by SCI-induced pain in the superficial spinal dorsal horn (6 rats/group; p < 0.01). In in vitro whole-cell patch-clamp analysis, ivabradine decreased the frequency of miniature excitatory postsynaptic currents in substantia gelatinosa neurons (11-12 rats/group; p < 0.01). We concluded that ivabradine reduces SCI-induced pain by inhibiting excitatory synaptic transmission in the spinal dorsal horn.
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Affiliation(s)
- Nobuko Ohashi
- Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, Niigata 951-8510, Japan.
| | - Masayuki Ohashi
- Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, Niigata 951-8510, Japan.
| | - Rintaro Hoshino
- Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, Niigata 951-8510, Japan
| | - Hiroyuki Deguchi
- Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, Niigata 951-8510, Japan
| | - Hiroshi Baba
- Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City, Niigata 951-8510, Japan.
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Alijanzadeh D, Moghim S, Zarand P, Akbarzadeh MA, Zarinfar Y, Khaheshi I. Reassessing Ivabradine: Potential Benefits and Risks in Atrial Fibrillation Therapy. Cardiovasc Drugs Ther 2024. [DOI: 10.1007/s10557-024-07652-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/12/2024] [Indexed: 01/03/2025]
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Yin Z, Torre E, Marrot M, Peters CH, Feather A, Nichols WG, Logantha SJRJ, Arshad A, Martis SA, Ozturk NT, Chen W, Liu J, Qu J, Zi M, Cartwright EJ, Proenza C, Torrente A, Mangoni ME, Dobrzynski H, Atkinson AJ. Identifying sex similarities and differences in structure and function of the sinoatrial node in the mouse heart. Front Med (Lausanne) 2024; 11:1488478. [PMID: 39703520 PMCID: PMC11655232 DOI: 10.3389/fmed.2024.1488478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 11/26/2024] [Indexed: 12/21/2024] Open
Abstract
Background The sinoatrial node (SN) generates the heart rate (HR). Its spontaneous activity is regulated by a complex interplay between the modulation by the autonomic nervous system (ANS) and intrinsic factors including ion channels in SN cells. However, the systemic and intrinsic regulatory mechanisms are still poorly understood. This study aimed to elucidate the sex-specific differences in heart morphology and SN function, particularly focusing on basal HR, expression and function of hyperpolarization-activated HCN4 and HCN1 channels and mRNA abundance of ion channels and mRNA abundance of ion channels contributing to diastolic depolarization (DD) and spontaneous action potentials (APs). Methods Body weight, heart weight and tibia length of 2- to 3-month-old male and female mice were measured. Conscious in-vivo HR of male and female mice was recorded via electrocardiography (ECG). Unconscious ex-vivo HR, stroke volume (SV) and ejection fraction (EF) were recorded via echocardiography. Ex-vivo HR was measured via Langendorff apparatus. Volume of atria, ventricles and whole hearts were measured from the ex-vivo hearts by microcomputed tomography (micro-CT). Immunohistochemistry targeting HCN4 and HCN1 was conducted in the SN and RA tissues from both male and female hearts. The funny current (I f) of SN cells in 1 nM and following wash-on of 1 μM isoproterenol (ISO) were recorded via whole cell patch clamp. The APs of SN tissue were recorded via sharp microelectrode and optical mapping of membrane voltage. The relative abundance of mRNAs was measured in male and female mice by qPCR. Results Heart weight to tibia length ratio and heart volume of females were significantly smaller than males. Unconscious in-vivo HR in male mice was higher than that in females. Conscious in-vivo HR, ex-vivo HR, SV, and EF showed no notable difference between male and female mice. Immunohistochemistry revealed HCN4, HCN1, and the sum of HCN4 and HCN1, expression in the SN was notably elevated compared with the RA in both male and females, but there was no sex difference in these channels expression. There were also no significant sex differences in the V 0.5 of I f in SN cells in the presence of 1 nM ISO, however wash-on 1 μM ISO in the same cells induced a significantly increased shift of V 0.5 to more positive voltages in males than in females. The expression of mRNA coding for adrenergic receptor beta-1 (Adrb1) and cholinergic receptors muscarinic 2 (chrm2) in male mice was higher compared with that in female mice. Early diastolic depolarization (EDD) rate in APs from peripheral SN (pSN) from male mice were higher than these in female mice. Mice of both sexes showed equivalent frequency of SN APs and spatial localization of the leading site in control, and similar significant response to ISO 100 nM superfusion. Conclusion Males display faster in-vivo HR, but not ex-vivo HR, than females associated with increased expression of Adrb1 in male versus female. This suggests a possible difference in the β-adrenergic modulation in males and females, possibly related to the greater ISO response of I f observed in cells from males. The role of hormonal influences or differential expression of other ion channels may explain these sex-specific variations in HR dynamics. Further investigations are necessary to pinpoint the precise molecular substrates responsible for these differences.
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Affiliation(s)
- Zeyuan Yin
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Eleonora Torre
- Institut de Génomique Fonctionnelle, Université de Montpellier CNRS, INSERM, Montpellier, France
| | - Manon Marrot
- Institut de Génomique Fonctionnelle, Université de Montpellier CNRS, INSERM, Montpellier, France
- Laboratory of Excellence Ion Channels Science and Therapeutics (ICST), Valbonne, France
| | - Colin H. Peters
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Amy Feather
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - William G. Nichols
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Sunil Jit R. J. Logantha
- Department of Cardiovascular and Metabolic Medicine and Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, United Kingdom
| | - Areej Arshad
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Simran Agnes Martis
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Nilay Tugba Ozturk
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Weixuan Chen
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Jiaxuan Liu
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Jingmo Qu
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Min Zi
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Elizabeth J. Cartwright
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Catherine Proenza
- Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Angelo Torrente
- Institut de Génomique Fonctionnelle, Université de Montpellier CNRS, INSERM, Montpellier, France
| | - Matteo E. Mangoni
- Institut de Génomique Fonctionnelle, Université de Montpellier CNRS, INSERM, Montpellier, France
| | - Halina Dobrzynski
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
- Department of Anatomy, Jagiellonian University Medical College, Kraków, Poland
| | - Andrew J. Atkinson
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
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Jean Jacques A, D’Avanzo N. Inhibition of HCN1 currents by norquetiapine, an active metabolite of the atypical anti-psychotic drug quetiapine. Front Pharmacol 2024; 15:1445509. [PMID: 39434909 PMCID: PMC11491390 DOI: 10.3389/fphar.2024.1445509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 09/23/2024] [Indexed: 10/23/2024] Open
Abstract
Quetiapine is a second-generation atypical antipsychotic drug that has been commonly prescribed for the treatment of schizophrenia, major depressive disorder (depression), and other psychological disorders. Targeted inhibition of hyperpolarization-activated cyclic-nucleotide gated (HCN) channels, which generate Ih, may provide effective resistance against schizophrenia and depression. We investigated if HCN channels could contribute to the therapeutic effect of quetiapine, and its major active metabolite norquetiapine. Two-electrode voltage clamp recordings were used to assess the effects of quetiapine and its active metabolites 7-hydroxyquetiapine and norquetiapine on currents from HCN1 channels expressed in Xenopus laevis oocytes. Norquetiapine, but not quetiapine nor 7-hydroxyquetiapine, has an inhibitory effect on HCN1 channels. Norquetiapine selectively inhibited HCN1 currents by shifting the voltage-dependence of activation to more hyperpolarized potentials in a concentration-dependent manner with an IC50 of 13.9 ± 0.8 μM for HCN1 and slowing channel opening, without changing the kinetics of closing. Inhibition by norquetiapine primarily occurs from in the closed state. Norquetiapine inhibition is not sensitive to the external potassium concentration, and therefore, likely does not block the pore. Norquetiapine inhibition also does not dependent on the cyclic-nucleotide binding domain. Norquetiapine also inhibited HCN4 channels with reduced efficacy than HCN1 and had no effect on HCN2 channels. Therefore, HCN channels are key targets of norquetiapine, the primary active metabolite of quetiapine. These data help to explain the therapeutic mechanisms by which quetiapine aids in the treatment of anxiety, major depressive disorder, bipolar disorder, and schizophrenia, and may represent a novel structure for future drug design of HCN inhibitors.
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Affiliation(s)
| | - Nazzareno D’Avanzo
- Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, QC, Canada
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Porro A, Armano E, Brandalise F, Appiani R, Beltrame M, Saponaro A, Dallanoce C, Nakajo K, Ryu K, Leone R, Thiel G, Pallavicini M, Moroni A, Bolchi C. A Photoactivatable Version of Ivabradine Enables Light-Induced Block of HCN Current In Vivo. J Med Chem 2024; 67:16209-16221. [PMID: 39238314 DOI: 10.1021/acs.jmedchem.4c01047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2024]
Abstract
Therapeutic drugs, whose bioactivity is hindered by a photoremovable cage, offer the advantage of spatiotemporal confinement of their action to the target diseased tissue with improved bioavailability and efficacy. Here, we have applied such an approach to ivabradine (IVA), a bradycardic agent indicated for angina pectoris and heart failure, acting as a specific HCN channel blocker. To overcome the side effects due to its poor discrimination among HCN channel subtypes (HCN1-4), we prepared a caged version of IVA linked to a photocleavable bromoquinolinylmethyl group (BHQ-IVA). We show that upon illumination with blue light (440 nm), BHQ-IVA releases active IVA that blocks HCN channel currents in vitro and exerts a bradycardic effect in vivo. Both BHQ-IVA and the cage are inactive. Caging is stable in aqueous medium and in the dark, and it does not impair aqueous solubility and cell permeation, indispensable for IVA activity. This approach allows for bypassing the poor subtype-specificity of IVA, expanding its prescription to HCN-related diseases besides cardiac.
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Affiliation(s)
- Alessandro Porro
- Department of Biosciences, University of Milan, Milano 20133, Italy
| | - Edoardo Armano
- Department of Pharmaceutical Sciences, University of Milan, Milano 20133, Italy
| | | | - Rebecca Appiani
- Department of Pharmaceutical Sciences, University of Milan, Milano 20133, Italy
| | - Monica Beltrame
- Department of Biosciences, University of Milan, Milano 20133, Italy
| | - Andrea Saponaro
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milano 20133, Italy
| | - Clelia Dallanoce
- Department of Pharmaceutical Sciences, University of Milan, Milano 20133, Italy
| | - Koichi Nakajo
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Kawachi District, Shimotsuke 329-0498, Japan
| | - Kaei Ryu
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Kawachi District, Shimotsuke 329-0498, Japan
| | - Roberta Leone
- Department of Biosciences, University of Milan, Milano 20133, Italy
| | - Gerhard Thiel
- Department of Biology, TU-Darmstadt, Darmstadt 64287, Germany
| | - Marco Pallavicini
- Department of Pharmaceutical Sciences, University of Milan, Milano 20133, Italy
| | - Anna Moroni
- Department of Biosciences, University of Milan, Milano 20133, Italy
| | - Cristiano Bolchi
- Department of Pharmaceutical Sciences, University of Milan, Milano 20133, Italy
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Che T, Zhang W, Cheng X, Lv S, Zhang M, Zhang Y, Yang T, Nan W, Wan S, Zeng B, Li J, Xiong B, Zhang J. Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine. J Biol Chem 2024; 300:107798. [PMID: 39307309 PMCID: PMC11530593 DOI: 10.1016/j.jbc.2024.107798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/15/2024] [Accepted: 09/13/2024] [Indexed: 10/19/2024] Open
Abstract
The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role in regulating neuronal excitability. Despite growing evidence supporting the therapeutic potential of HCN1 inhibition in treating neurological disorders, the structural basis of channel inhibition by inhibitor has remained elusive. Here, we present the cryo-electron microscopy structure of human HCN1 channel in complex with inhibitor ivabradine, the drug on the market that acts on HCN channels. Combining electrophysiology, mutagenesis, and molecular dynamics simulations, our findings reveal that ivabradine binds to a previously unidentified pocket formed between the S4, S1, and HCN domain. Furthermore, through structure-based virtual screening, we identify two Food and Drug Administration-approved drugs that can inhibit the HCN1 channel by interacting with the ivabradine-binding site. Our results not only provide insights into the structural intricacies of ivabradine-mediated inhibition, but also offer a potential pharmacological framework for developing novel drugs targeting the HCN1 channel. The elucidation of these molecular interactions serves as a foundational step in advancing therapeutic strategies for modulating HCN1 activity, contributing to the broader landscape of drug discovery and development in this area.
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Affiliation(s)
- Tong Che
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Wei Zhang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xinyu Cheng
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Sijia Lv
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Minqing Zhang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yuting Zhang
- Shenzhen Crystalo Biopharmaceutical Co, Ltd, Shenzhen, Guangdong, China
| | - Tingting Yang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Weiwei Nan
- Shenzhen Crystalo Biopharmaceutical Co, Ltd, Shenzhen, Guangdong, China
| | - Shuangyan Wan
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Bo Zeng
- Key Laboratory of Medical Electrophysiology, Ministry of Education and Sichuan Province and Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China; Department of Endocrinology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jian Li
- College of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi, China.
| | - Bing Xiong
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
| | - Jin Zhang
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
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Iness AN, Shah KM, Kukreja RC. Physiological effects of ivabradine in heart failure and beyond. Mol Cell Biochem 2024; 479:2405-2414. [PMID: 37768496 DOI: 10.1007/s11010-023-04862-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023]
Abstract
Ivabradine is a pharmacologic agent that inhibits the funny current responsible for determining heart rate in the sinoatrial node. Ivabradine's clinical potential has been investigated in the context of heart failure since it is associated with reduced myocardial oxygen demand, enhanced diastolic filling, stroke volume, and coronary perfusion time; however, it is yet to demonstrate definitive mortality benefit. Alternative effects of ivabradine include modulation of the renin-angiotensin-aldosterone system, sympathetic activation, and endothelial function. Here, we review key clinical trials informing the clinical use of ivabradine and explore opportunities for leveraging its potential pleiotropic effects in other diseases, including treatment of hyperadrenergic states and mitigating complications of COVID-19 infection.
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Affiliation(s)
- Audra N Iness
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Keyur M Shah
- Division of Cardiology, Pauley Heart Center, Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Rakesh C Kukreja
- Division of Cardiology, Pauley Heart Center, Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.
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10
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Wulkan F, Romagnuolo R, Qiang B, Valdman Sadikov T, Kim KP, Quesnel E, Jiang W, Andharia N, Weyers JJ, Ghugre NR, Ozcan B, Alibhai FJ, Laflamme MA. Stem cell-derived cardiomyocytes expressing a dominant negative pacemaker HCN4 channel do not reduce the risk of graft-related arrhythmias. Front Cardiovasc Med 2024; 11:1374881. [PMID: 39045008 PMCID: PMC11263024 DOI: 10.3389/fcvm.2024.1374881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 06/11/2024] [Indexed: 07/25/2024] Open
Abstract
Background Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) show tremendous promise for cardiac regeneration following myocardial infarction (MI), but their transplantation gives rise to transient ventricular tachycardia (VT) in large-animal MI models, representing a major hurdle to translation. Our group previously reported that these arrhythmias arise from a focal mechanism whereby graft tissue functions as an ectopic pacemaker; therefore, we hypothesized that hPSC-CMs engineered with a dominant negative form of the pacemaker ion channel HCN4 (dnHCN4) would exhibit reduced automaticity and arrhythmogenic risk following transplantation. Methods We used CRISPR/Cas9-mediated gene-editing to create transgenic dnHCN4 hPSC-CMs, and their electrophysiological behavior was evaluated in vitro by patch-clamp recordings and optical mapping. Next, we transplanted WT and homozygous dnHCN4 hPSC-CMs in a pig MI model and compared post-transplantation outcomes including the incidence of spontaneous arrhythmias and graft structure by immunohistochemistry. Results In vitro dnHCN4 hPSC-CMs exhibited significantly reduced automaticity and pacemaker funny current (I f ) density relative to wildtype (WT) cardiomyocytes. Following transplantation with either dnHCN4 or WT hPSC-CMs, all recipient hearts showed transmural infarct scar that was partially remuscularized by scattered islands of human myocardium. However, in contrast to our hypothesis, both dnHCN4 and WT hPSC-CM recipients exhibited frequent episodes of ventricular tachycardia (VT). Conclusions While genetic silencing of the pacemaker ion channel HCN4 suppresses the automaticity of hPSC-CMs in vitro, this intervention is insufficient to reduce VT risk post-transplantation in the pig MI model, implying more complex mechanism(s) are operational in vivo.
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Affiliation(s)
- Fanny Wulkan
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
| | - Rocco Romagnuolo
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
| | - Beiping Qiang
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
| | | | | | - Elya Quesnel
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
| | - Wenlei Jiang
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
| | - Naaz Andharia
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
| | - Jill J. Weyers
- Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada
| | - Nilesh R. Ghugre
- Physical Sciences Platform, Sunnybrook Research Institute, Toronto, ON, Canada
- Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Bilgehan Ozcan
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
| | - Faisal J. Alibhai
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
| | - Michael A. Laflamme
- McEwen Stem Cell Institute, University Health Network, Toronto, ON, Canada
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada
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11
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Saponaro A, Krumbach JH, Chaves-Sanjuan A, Sharifzadeh AS, Porro A, Castelli R, Hamacher K, Bolognesi M, DiFrancesco D, Clarke OB, Thiel G, Moroni A. Structural determinants of ivabradine block of the open pore of HCN4. Proc Natl Acad Sci U S A 2024; 121:e2402259121. [PMID: 38917012 PMCID: PMC11228525 DOI: 10.1073/pnas.2402259121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 05/26/2024] [Indexed: 06/27/2024] Open
Abstract
HCN1-4 channels are the molecular determinants of the If/Ih current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial block (HCN4), epilepsy (HCN1), and chronic pain (HCN2), widespread medical conditions awaiting subtype-specific treatments. Here, we address the problem by solving the cryo-EM structure of HCN4 in complex with ivabradine, to date the only HCN-specific drug on the market. Our data show ivabradine bound inside the open pore at 3 Å resolution. The structure unambiguously proves that Y507 and I511 on S6 are the molecular determinants of ivabradine binding to the inner cavity, while F510, pointing outside the pore, indirectly contributes to the block by controlling Y507. Cysteine 479, unique to the HCN selectivity filter (SF), accelerates the kinetics of block. Molecular dynamics simulations further reveal that ivabradine blocks the permeating ion inside the SF by electrostatic repulsion, a mechanism previously proposed for quaternary ammonium ions.
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Affiliation(s)
- Andrea Saponaro
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy
| | - Jan H Krumbach
- Department of Physics, Technische Universität Darmstadt, Darmstadt 64289, Germany
- Department of Biology and Centre for Synthetic Biology, Technische Universität Darmstadt, Darmstadt 64287, Germany
| | | | | | - Alessandro Porro
- Department of Biosciences, University of Milan, Milan 20133, Italy
| | - Roberta Castelli
- Department of Biosciences, University of Milan, Milan 20133, Italy
| | - Kay Hamacher
- Department of Physics, Technische Universität Darmstadt, Darmstadt 64289, Germany
- Department of Biology and Centre for Synthetic Biology, Technische Universität Darmstadt, Darmstadt 64287, Germany
| | | | - Dario DiFrancesco
- Department of Biosciences, University of Milan, Milan 20133, Italy
- Institute of Biophysics-Milan, Consiglio Nazionale delle Ricerche, Milan 20133, Italy
| | - Oliver B Clarke
- Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032
- Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY 10032
- Irving Institute for Clinical and Translational Research, Columbia University, New York, NY 10032
| | - Gerhard Thiel
- Department of Biology and Centre for Synthetic Biology, Technische Universität Darmstadt, Darmstadt 64287, Germany
- Department of Biosciences, University of Milan, Milan 20133, Italy
| | - Anna Moroni
- Department of Biosciences, University of Milan, Milan 20133, Italy
- Institute of Biophysics-Milan, Consiglio Nazionale delle Ricerche, Milan 20133, Italy
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12
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Hennis K, Piantoni C, Biel M, Fenske S, Wahl-Schott C. Pacemaker Channels and the Chronotropic Response in Health and Disease. Circ Res 2024; 134:1348-1378. [PMID: 38723033 PMCID: PMC11081487 DOI: 10.1161/circresaha.123.323250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/13/2024]
Abstract
Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease-including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating β-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate-sensitive hyperpolarization-activated current (If) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate-dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.
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Affiliation(s)
- Konstantin Hennis
- Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center Munich, Walter Brendel Centre of Experimental Medicine, Faculty of Medicine (K.H., C.P., C.W.-S.), Ludwig-Maximilians-Universität München, Germany
| | - Chiara Piantoni
- Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center Munich, Walter Brendel Centre of Experimental Medicine, Faculty of Medicine (K.H., C.P., C.W.-S.), Ludwig-Maximilians-Universität München, Germany
| | - Martin Biel
- Department of Pharmacy, Center for Drug Research (M.B., S.F.), Ludwig-Maximilians-Universität München, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Germany (M.B., S.F.)
| | - Stefanie Fenske
- Department of Pharmacy, Center for Drug Research (M.B., S.F.), Ludwig-Maximilians-Universität München, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Germany (M.B., S.F.)
| | - Christian Wahl-Schott
- Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center Munich, Walter Brendel Centre of Experimental Medicine, Faculty of Medicine (K.H., C.P., C.W.-S.), Ludwig-Maximilians-Universität München, Germany
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13
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Harde E, Hierl M, Weber M, Waiz D, Wyler R, Wach JY, Haab R, Gundlfinger A, He W, Schnider P, Paina M, Rolland JF, Greiter-Wilke A, Gasser R, Reutlinger M, Dupont A, Roberts S, O'Connor EC, Bartels B, Hall BJ. Selective and brain-penetrant HCN1 inhibitors reveal links between synaptic integration, cortical function, and working memory. Cell Chem Biol 2024; 31:577-592.e23. [PMID: 38042151 DOI: 10.1016/j.chembiol.2023.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 09/28/2023] [Accepted: 11/07/2023] [Indexed: 12/04/2023]
Abstract
Hyperpolarization-activated and cyclic-nucleotide-gated 1 (HCN1) ion channels are proposed to be critical for cognitive function through regulation of synaptic integration. However, resolving the precise role of HCN1 in neurophysiology and exploiting its therapeutic potential has been hampered by minimally selective antagonists with poor potency and limited in vivo efficiency. Using automated electrophysiology in a small-molecule library screen and chemical optimization, we identified a primary carboxamide series of potent and selective HCN1 inhibitors with a distinct mode of action. In cognition-relevant brain circuits, selective inhibition of native HCN1 produced on-target effects, including enhanced excitatory postsynaptic potential summation, while administration of a selective HCN1 inhibitor to rats recovered decrement working memory. Unlike prior non-selective HCN antagonists, selective HCN1 inhibition did not alter cardiac physiology in human atrial cardiomyocytes or in rats. Collectively, selective HCN1 inhibitors described herein unmask HCN1 as a potential target for the treatment of cognitive dysfunction in brain disorders.
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Affiliation(s)
- Eva Harde
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
| | - Markus Hierl
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Michael Weber
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - David Waiz
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Roger Wyler
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Jean-Yves Wach
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Rachel Haab
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Anja Gundlfinger
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Weiping He
- WuXi AppTec (Wuhan) Co., Ltd, 666 Gaoxin Road, Wuhan East Lake High-Tech Development Zone, Wuhan, Huibei, China
| | - Patrick Schnider
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | | | - Andrea Greiter-Wilke
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Rodolfo Gasser
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Michael Reutlinger
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Amanda Dupont
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Sonia Roberts
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Eoin C O'Connor
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
| | - Björn Bartels
- Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
| | - Benjamin J Hall
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
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14
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Cámara-Checa A, Perin F, Rubio-Alarcón M, Dago M, Crespo-García T, Rapún J, Marín M, Cebrián J, Gómez R, Bermúdez-Jiménez F, Monserrat L, Tamargo J, Caballero R, Jiménez-Jáimez J, Delpón E. A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family. Proc Natl Acad Sci U S A 2023; 120:e2305135120. [PMID: 38032931 PMCID: PMC10710060 DOI: 10.1073/pnas.2305135120] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 10/12/2023] [Indexed: 12/02/2023] Open
Abstract
In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. IHCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases If and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.
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Affiliation(s)
- Anabel Cámara-Checa
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
| | - Francesca Perin
- Department of Pediatric Cardiology, Virgen de las Nieves University Hospital, Granada18014, Spain
- Instituto de Investigación Biosanitaria de Granada, Granada18014, Spain
| | - Marcos Rubio-Alarcón
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
| | - María Dago
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
| | - Teresa Crespo-García
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
| | - Josu Rapún
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
| | - María Marín
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
| | - Jorge Cebrián
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
| | - Ricardo Gómez
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
| | - Francisco Bermúdez-Jiménez
- Department of Pediatric Cardiology, Virgen de las Nieves University Hospital, Granada18014, Spain
- Instituto de Investigación Biosanitaria de Granada, Granada18014, Spain
- Centro Nacional de Investigaciones Cardiovasculares, Madrid28029, Spain
| | - Lorenzo Monserrat
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
- Health in Code Sociedad Limitada, A Coruña15008, Spain
| | - Juan Tamargo
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
| | - Ricardo Caballero
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
| | - Juan Jiménez-Jáimez
- Department of Pediatric Cardiology, Virgen de las Nieves University Hospital, Granada18014, Spain
- Instituto de Investigación Biosanitaria de Granada, Granada18014, Spain
| | - Eva Delpón
- Department of Pharmacology and Toxicology, School of Medicine, Universidad Complutense de Madrid, Instituto de Investigación Gregorio Marañón, 28040Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid28029, Spain
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15
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Mu L, Liu X, Yu H, Vickstrom CR, Friedman V, Kelly TJ, Hu Y, Su W, Liu S, Mantsch JR, Liu QS. cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement. Mol Psychiatry 2023; 28:3930-3942. [PMID: 37845497 PMCID: PMC10730389 DOI: 10.1038/s41380-023-02290-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 09/25/2023] [Accepted: 10/03/2023] [Indexed: 10/18/2023]
Abstract
Chronic cocaine exposure induces enduring neuroadaptations that facilitate motivated drug taking. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to modulate neuronal firing and pacemaker activity in ventral tegmental area (VTA) dopamine neurons. However, it remained unknown whether cocaine self-administration affects HCN channel function and whether HCN channel activity modulates motivated drug taking. We report that rat VTA dopamine neurons predominantly express Hcn3-4 mRNA, while VTA GABA neurons express Hcn1-4 mRNA. Both neuronal types display similar hyperpolarization-activated currents (Ih), which are facilitated by acute increases in cAMP. Acute cocaine application decreases voltage-dependent activation of Ih in VTA dopamine neurons, but not in GABA neurons. Unexpectedly, chronic cocaine self-administration results in enhanced Ih selectively in VTA dopamine neurons. This differential modulation of Ih currents is likely mediated by a D2 autoreceptor-induced decrease in cAMP as D2 (Drd2) mRNA is predominantly expressed in dopamine neurons, whereas D1 (Drd1) mRNA is barely detectable in the VTA. Moreover, chronically decreased cAMP via Gi-DREADD stimulation leads to an increase in Ih in VTA dopamine neurons and enhanced binding of HCN3/HCN4 with tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit that is known to facilitate HCN channel surface trafficking. Finally, we show that systemic injection and intra-VTA infusion of the HCN blocker ivabradine reduces cocaine self-administration under a progressive ratio schedule and produces a downward shift of the cocaine dose-response curve. Our results suggest that cocaine self-administration induces an upregulation of Ih in VTA dopamine neurons, while HCN inhibition reduces the motivation for cocaine intake.
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Affiliation(s)
- Lianwei Mu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Xiaojie Liu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Hao Yu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Casey R Vickstrom
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Vladislav Friedman
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Thomas J Kelly
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Ying Hu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Wantang Su
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
- Department of Exercise Physiology, Beijing Sport University, Beijing, 100084, China
| | - Shuai Liu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - John R Mantsch
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Qing-Song Liu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
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16
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Mangmool S, Duangrat R, Parichatikanond W, Kurose H. New Therapeutics for Heart Failure: Focusing on cGMP Signaling. Int J Mol Sci 2023; 24:12866. [PMID: 37629047 PMCID: PMC10454066 DOI: 10.3390/ijms241612866] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/30/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Current drugs for treating heart failure (HF), for example, angiotensin II receptor blockers and β-blockers, possess specific target molecules involved in the regulation of the cardiac circulatory system. However, most clinically approved drugs are effective in the treatment of HF with reduced ejection fraction (HFrEF). Novel drug classes, including angiotensin receptor blocker/neprilysin inhibitor (ARNI), sodium-glucose co-transporter-2 (SGLT2) inhibitor, hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, soluble guanylyl cyclase (sGC) stimulator/activator, and cardiac myosin activator, have recently been introduced for HF intervention based on their proposed novel mechanisms. SGLT2 inhibitors have been shown to be effective not only for HFrEF but also for HF with preserved ejection fraction (HFpEF). In the myocardium, excess cyclic adenosine monophosphate (cAMP) stimulation has detrimental effects on HFrEF, whereas cyclic guanosine monophosphate (cGMP) signaling inhibits cAMP-mediated responses. Thus, molecules participating in cGMP signaling are promising targets of novel drugs for HF. In this review, we summarize molecular pathways of cGMP signaling and clinical trials of emerging drug classes targeting cGMP signaling in the treatment of HF.
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Affiliation(s)
- Supachoke Mangmool
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (S.M.); (R.D.)
| | - Ratchanee Duangrat
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand; (S.M.); (R.D.)
| | | | - Hitoshi Kurose
- Pharmacology for Life Sciences, Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima 770-8505, Japan
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McKenzie CE, Hung A, Phillips AM, Soh MS, Reid CA, Forster IC. The Potential Antidepressant Compound Org 34167 Modulates HCN Channels Via a Novel Mode of Action. Mol Pharmacol 2023; 104:62-72. [PMID: 37280099 DOI: 10.1124/molpharm.123.000676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 04/19/2023] [Accepted: 05/19/2023] [Indexed: 06/08/2023] Open
Abstract
Org 34167 is a small molecule hyperpolarization-activated cyclic nucleotide-gated (HCN) channel modulator that has been trialed in humans for its potential antidepressant activity. The precise action of Org 34167 is not fully understood. Here we use two-electrode voltage clamp recordings and an allosteric model to explore the interaction of Org 34167 with human HCN1 channels. The impact of Org 34167 on channel function included a hyperpolarizing shift in activation voltage dependence and a slowing of activation kinetics. Furthermore, a reduction in the maximum open probability at extreme hyperpolarization argued for an additional voltage-independent mechanism. Org 34167 had a similar impact on a truncated HCN1 channel lacking the C-terminal nucleotide binding domain, thus ruling out an interaction with this domain. Fitting a gating model, derived from a 10-state allosteric scheme, predicted that Org 34167 strongly reduced the equilibrium constant for the voltage-independent pore domain to favor a closed pore, as well as reducing the voltage sensing domain-pore domain coupling and shifting the zero voltage equilibrium constant of the voltage sensing domain to favor the inactive state. SIGNIFICANCE STATEMENT: The brain penetrant small molecule Org 34167 has been reported to have an antidepressant action by targeting HCN channels; however, its mode of action is unknown. We used heterologously expressed human HCN1 channels to show that Org 34167 inhibits channel activity by modulating kinetic parameters associated with the channel pore domain, voltage sensing domain, and interdomain coupling.
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Affiliation(s)
- Chaseley E McKenzie
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia (C.E.M., A.M.P., M.S.S., C.A.R, I.C.F.); School of Science, STEM College, RMIT University, Melbourne, VIC, Australia (A.H.); and School of Biosciences, The University of Melbourne, Parkville, VIC, Australia (A.M.P.)
| | - Andrew Hung
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia (C.E.M., A.M.P., M.S.S., C.A.R, I.C.F.); School of Science, STEM College, RMIT University, Melbourne, VIC, Australia (A.H.); and School of Biosciences, The University of Melbourne, Parkville, VIC, Australia (A.M.P.)
| | - A Marie Phillips
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia (C.E.M., A.M.P., M.S.S., C.A.R, I.C.F.); School of Science, STEM College, RMIT University, Melbourne, VIC, Australia (A.H.); and School of Biosciences, The University of Melbourne, Parkville, VIC, Australia (A.M.P.)
| | - Ming S Soh
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia (C.E.M., A.M.P., M.S.S., C.A.R, I.C.F.); School of Science, STEM College, RMIT University, Melbourne, VIC, Australia (A.H.); and School of Biosciences, The University of Melbourne, Parkville, VIC, Australia (A.M.P.)
| | - Christopher A Reid
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia (C.E.M., A.M.P., M.S.S., C.A.R, I.C.F.); School of Science, STEM College, RMIT University, Melbourne, VIC, Australia (A.H.); and School of Biosciences, The University of Melbourne, Parkville, VIC, Australia (A.M.P.)
| | - Ian C Forster
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia (C.E.M., A.M.P., M.S.S., C.A.R, I.C.F.); School of Science, STEM College, RMIT University, Melbourne, VIC, Australia (A.H.); and School of Biosciences, The University of Melbourne, Parkville, VIC, Australia (A.M.P.)
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Yamaguchi S, Nadoyama N, Kinjo K, Yagi N, Ishimori H, Shimabukuro M. The Usefulness of Prioritization of Ivabradine Before Beta-Blockers in a Heart Failure Patient Suffering From Intra-hemodialysis Hypotension. Cureus 2023; 15:e40609. [PMID: 37342295 PMCID: PMC10277751 DOI: 10.7759/cureus.40609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2023] [Indexed: 06/22/2023] Open
Abstract
Depressed cardiac systolic function in hemodialysis patients occurs for a variety of reasons and is a clinical problem. Beta-blockers are a key drug in the treatment of heart failure; however, hypotension may occur, particularly in dialysis patients, thereby complicating dialysis. Ivabradine has the unique property of a negative chronotropic effect only, without the negative inotropic effect. A 55-year-old woman who underwent dialysis presented with dyspnea and fatigue even at rest due to low cardiac systolic function. The left ventricular ejection fraction (LVEF) was 30%. Medications for heart failure, such as carvedilol and enalapril, were initiated; however, they were discontinued owing to intradialytic hypotension. Subsequently, her heart rate increased to over 100 beats per minute (bpm); therefore, we administered 2.5 mg of ivabradine before beta-blockers, which reduced her heart rate by approximately 30 bpm without a significant blood pressure decrease. Moreover, her blood pressure stabilized during dialysis. After two weeks, we added 1.25 mg of bisoprolol and adjusted the dose to 0.625 mg. After seven months of treatment with 2.5 mg ivabradine and 0.625 mg bisoprolol, systolic cardiac function significantly improved to 70% of LVEF. Prioritizing ivabradine over beta-blockers may not cause intradialytic hypotension; even low doses of ivabradine and bisoprolol were considered effective heart failure therapies.
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Affiliation(s)
- Satoshi Yamaguchi
- Department of Diabetes, Endocrinology and Metabolism, School of Medicine, Fukushima Medical University, Fukushima, JPN
- Department of Cardiology, Nakagami Hospital, Okinawa, JPN
| | | | - Kazushi Kinjo
- Department of Nephrology, Nakagami Hospital, Okinawa, JPN
| | - Nobumori Yagi
- Department of Cardiology, Nakagami Hospital, Okinawa, JPN
| | | | - Michio Shimabukuro
- Department of Diabetes, Endocrinology and Metabolism, School of Medicine, Fukushima Medical University, Fukushima, JPN
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Barbuti A, Baruscotti M, Bucchi A. The “Funny” Pacemaker Current. HEART RATE AND RHYTHM 2023:63-87. [DOI: 10.1007/978-3-031-33588-4_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Analgesic effect of ivabradine against inflammatory pain mediated by hyperpolarization-activated cyclic nucleotide–gated cation channels expressed on primary afferent terminals in the spinal dorsal horn. Pain 2022; 163:1356-1369. [DOI: 10.1097/j.pain.0000000000002523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 10/14/2021] [Indexed: 11/25/2022]
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Liu J, Kasuya G, Zempo B, Nakajo K. Two HCN4 Channels Play Functional Roles in the Zebrafish Heart. Front Physiol 2022; 13:901571. [PMID: 35846012 PMCID: PMC9281569 DOI: 10.3389/fphys.2022.901571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
The HCN4 channel is essential for heart rate regulation in vertebrates by generating pacemaker potentials in the sinoatrial node. HCN4 channel abnormality may cause bradycardia and sick sinus syndrome, making it an important target for clinical research and drug discovery. The zebrafish is a popular animal model for cardiovascular research. They are potentially suitable for studying inherited heart diseases, including cardiac arrhythmia. However, it has not been determined how similar the ion channels that underlie cardiac automaticity are in zebrafish and humans. In the case of HCN4, humans have one gene, whereas zebrafish have two ortholog genes (DrHCN4 and DrHCN4L; ‘Dr’ referring to Danio rerio). However, it is not known whether the two HCN4 channels have different physiological functions and roles in heart rate regulation. In this study, we characterized the biophysical properties of the two zebrafish HCN4 channels in Xenopus oocytes and compared them to those of the human HCN4 channel. We found that they showed different gating properties: DrHCN4L currents showed faster activation kinetics and a more positively shifted G-V curve than did DrHCN4 and human HCN4 currents. We made chimeric channels of DrHCN4 and DrHCN4L and found that cytoplasmic domains were determinants for the faster activation and the positively shifted G-V relationship in DrHCN4L. The use of a dominant-negative HCN4 mutant confirmed that DrHCN4 and DrHCN4L can form a heteromultimeric channel in Xenopus oocytes. Next, we confirmed that both are sensitive to common HCN channel inhibitors/blockers including Cs+, ivabradine, and ZD7288. These HCN inhibitors successfully lowered zebrafish heart rate during early embryonic stages. Finally, we knocked down the HCN4 genes using antisense morpholino and found that knocking down either or both of the HCN4 channels caused a temporal decrease in heart rate and tended to cause pericardial edema. These findings suggest that both DrHCN4 and DrHCN4L play a significant role in zebrafish heart rate regulation.
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22
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Kessi M, Peng J, Duan H, He H, Chen B, Xiong J, Wang Y, Yang L, Wang G, Kiprotich K, Bamgbade OA, He F, Yin F. The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review. Front Mol Neurosci 2022; 15:807202. [PMID: 35663267 PMCID: PMC9161305 DOI: 10.3389/fnmol.2022.807202] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 04/06/2022] [Indexed: 12/04/2022] Open
Abstract
Background Hyperpolarization-activated cyclic nucleotide-gated (HCN) current reduces dendritic summation, suppresses dendritic calcium spikes, and enables inhibitory GABA-mediated postsynaptic potentials, thereby suppressing epilepsy. However, it is unclear whether increased HCN current can produce epilepsy. We hypothesized that gain-of-function (GOF) and loss-of-function (LOF) variants of HCN channel genes may cause epilepsy. Objectives This systematic review aims to summarize the role of HCN channelopathies in epilepsy, update genetic findings in patients, create genotype–phenotype correlations, and discuss animal models, GOF and LOF mechanisms, and potential treatment targets. Methods The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, for all years until August 2021. Results We identified pathogenic variants of HCN1 (n = 24), HCN2 (n = 8), HCN3 (n = 2), and HCN4 (n = 6) that were associated with epilepsy in 74 cases (43 HCN1, 20 HCN2, 2 HCN3, and 9 HCN4). Epilepsy was associated with GOF and LOF variants, and the mechanisms were indeterminate. Less than half of the cases became seizure-free and some developed drug-resistant epilepsy. Of the 74 cases, 12 (16.2%) died, comprising HCN1 (n = 4), HCN2 (n = 2), HCN3 (n = 2), and HCN4 (n = 4). Of the deceased cases, 10 (83%) had a sudden unexpected death in epilepsy (SUDEP) and 2 (16.7%) due to cardiopulmonary failure. SUDEP affected more adults (n = 10) than children (n = 2). HCN1 variants p.M234R, p.C329S, p.V414M, p.M153I, and p.M305L, as well as HCN2 variants p.S632W and delPPP (p.719–721), were associated with different phenotypes. HCN1 p.L157V and HCN4 p.R550C were associated with genetic generalized epilepsy. There are several HCN animal models, pharmacological targets, and modulators, but precise drugs have not been developed. Currently, there are no HCN channel openers. Conclusion We recommend clinicians to include HCN genes in epilepsy gene panels. Researchers should explore the possible underlying mechanisms for GOF and LOF variants by identifying the specific neuronal subtypes and neuroanatomical locations of each identified pathogenic variant. Researchers should identify specific HCN channel openers and blockers with high binding affinity. Such information will give clarity to the involvement of HCN channelopathies in epilepsy and provide the opportunity to develop targeted treatments.
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Affiliation(s)
- Miriam Kessi
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
- Department of Pediatrics, Kilimanjaro Christian Medical University College, Moshi, Tanzania
| | - Jing Peng
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
| | - Haolin Duan
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
| | - Hailan He
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
| | - Baiyu Chen
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
| | - Juan Xiong
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
| | - Ying Wang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
| | - Lifen Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
| | - Guoli Wang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
| | - Karlmax Kiprotich
- Department of Epidemiology and Medical Statistics, School of Public Health, Moi University, Eldoret, Kenya
| | - Olumuyiwa A. Bamgbade
- Department of Anesthesiology and Pharmacology, University of British Columbia, Vancouver, BC, Canada
| | - Fang He
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
| | - Fei Yin
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, China
- *Correspondence: Fei Yin
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23
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Hackl B, Lukacs P, Ebner J, Pesti K, Haechl N, Földi MC, Lilliu E, Schicker K, Kubista H, Stary-Weinzinger A, Hilber K, Mike A, Todt H, Koenig X. The Bradycardic Agent Ivabradine Acts as an Atypical Inhibitor of Voltage-Gated Sodium Channels. Front Pharmacol 2022; 13:809802. [PMID: 35586063 PMCID: PMC9108390 DOI: 10.3389/fphar.2022.809802] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 02/24/2022] [Indexed: 12/19/2022] Open
Abstract
Background and purpose: Ivabradine is clinically administered to lower the heart rate, proposedly by inhibiting hyperpolarization-activated cyclic nucleotide-gated cation channels in the sinoatrial node. Recent evidence suggests that voltage-gated sodium channels (VGSC) are inhibited within the same concentration range. VGSCs are expressed within the sinoatrial node and throughout the conduction system of the heart. A block of these channels thus likely contributes to the established and newly raised clinical indications of ivabradine. We, therefore, investigated the pharmacological action of ivabradine on VGSCs in sufficient detail in order to gain a better understanding of the pro- and anti-arrhythmic effects associated with the administration of this drug. Experimental Approach: Ivabradine was tested on VGSCs in native cardiomyocytes isolated from mouse ventricles and the His-Purkinje system and on human Nav1.5 in a heterologous expression system. We investigated the mechanism of channel inhibition by determining its voltage-, frequency-, state-, and temperature-dependence, complemented by a molecular drug docking to the recent Nav1.5 cryoEM structure. Automated patch-clamp experiments were used to investigate ivabradine-mediated changes in Nav1.5 inactivation parameters and inhibition of different VGSC isoforms. Key results: Ivabradine inhibited VGSCs in a voltage- and frequency-dependent manner, but did not alter voltage-dependence of activation and fast inactivation, nor recovery from fast inactivation. Cardiac (Nav1.5), neuronal (Nav1.2), and skeletal muscle (Nav1.4) VGSC isoforms were inhibited by ivabradine within the same concentration range, as were sodium currents in native cardiomyocytes isolated from the ventricles and the His-Purkinje system. Molecular drug docking suggested an interaction of ivabradine with the classical local anesthetic binding site. Conclusion and Implications: Ivabradine acts as an atypical inhibitor of VGSCs. Inhibition of VGSCs likely contributes to the heart rate lowering effect of ivabradine, in particular at higher stimulation frequencies and depolarized membrane potentials, and to the observed slowing of intra-cardiac conduction. Inhibition of VGSCs in native cardiomyocytes and across channel isoforms may provide a potential basis for the anti-arrhythmic potential as observed upon administration of ivabradine.
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Affiliation(s)
- Benjamin Hackl
- Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria
| | - Peter Lukacs
- ELKH, Plant Protection Institute, Centre for Agricultural Research, Martonvásár, Hungary
| | - Janine Ebner
- Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria
| | - Krisztina Pesti
- Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary
- Semmelweis University, School of Ph.D. Studies, Budapest, Hungary
| | - Nicholas Haechl
- Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria
| | - Mátyás C Földi
- ELKH, Plant Protection Institute, Centre for Agricultural Research, Martonvásár, Hungary
- Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Elena Lilliu
- Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria
| | - Klaus Schicker
- Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria
| | - Helmut Kubista
- Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria
| | | | - Karlheinz Hilber
- Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria
| | - Arpad Mike
- ELKH, Plant Protection Institute, Centre for Agricultural Research, Martonvásár, Hungary
- Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Hannes Todt
- Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria
| | - Xaver Koenig
- Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Vienna, Austria
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24
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Solari E, Marcozzi C, Ottaviani C, Negrini D, Moriondo A. Draining the Pleural Space: Lymphatic Vessels Facing the Most Challenging Task. BIOLOGY 2022; 11:419. [PMID: 35336793 PMCID: PMC8945018 DOI: 10.3390/biology11030419] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/25/2022] [Accepted: 03/08/2022] [Indexed: 01/06/2023]
Abstract
Lymphatic vessels exploit the mechanical stresses of their surroundings together with intrinsic rhythmic contractions to drain lymph from interstitial spaces and serosal cavities to eventually empty into the blood venous stream. This task is more difficult when the liquid to be drained has a very subatmospheric pressure, as it occurs in the pleural cavity. This peculiar space must maintain a very low fluid volume at negative hydraulic pressure in order to guarantee a proper mechanical coupling between the chest wall and lungs. To better understand the potential for liquid drainage, the key parameter to be considered is the difference in hydraulic pressure between the pleural space and the lymphatic lumen. In this review we collected old and new findings from in vivo direct measurements of hydraulic pressures in anaesthetized animals with the aim to better frame the complex physiology of diaphragmatic and intercostal lymphatics which drain liquid from the pleural cavity.
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Affiliation(s)
| | | | | | | | - Andrea Moriondo
- Department of Medicine and Surgery, School of Medicine, University of Insubria, 21100 Varese, Italy; (E.S.); (C.M.); (C.O.); (D.N.)
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Singh N, Zabbarova I, Ikeda Y, Kanai A, Chermansky C, Yoshimura N, Tyagi P. Role of hyperpolarization-activated cyclic nucleotide-gated channels in aging bladder phenotype. Life Sci 2022; 289:120203. [PMID: 34875252 PMCID: PMC8724453 DOI: 10.1016/j.lfs.2021.120203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/22/2021] [Accepted: 11/29/2021] [Indexed: 01/17/2023]
Abstract
OBJECTIVE To assess the functional role of Hyperpolarization-activated cyclic nucleotide-gated gated channel (HCN) subtypes in the aging bladder phenotype characterized by diminished bladder volume sensation (BVS) with or without the detrusor instability (DI). METHODS Expression of HCN subtypes was examined by quantitative RT-PCR and Western blot in aged male Fisher 344 rats (n = 15) and young rats (n = 15). Nocturnal urination and awake cystometry (CMG) were assessed in presence and absence of a steady state HCN channel blockade achieved with daily oral gavage of vehicle or Ivabradine (HCN blocker) 6 mg/kg for 7 days. RESULTS The association of BVS with the age-related downregulation (~30%) of cAMP sensitive HCN1, HCN2 subtypes, and (~50%) upregulation of cAMP insensitive HCN3 subtype is evinced by the doubling in the mean urine volume of nocturnal voids (0.82 ± 0.22 mL vs 0.41 ± 0.12 mL; n = 10; p < 0.05) predicting an age-related rise in the micturition volume threshold (p < 0.0001) in CMG, which is raised further by Ivabradine treatment (p < 0.0005). Ivabradine also doubled non-voiding contractions (NVC) and maximum voiding pressure (MVP) in young and aged rats, respectively (p < 0.0001) to abolish the age-related, innate two -fold elevation in NVC not accompanied with MVP rise in untreated aged rats (p < 0.005). CONCLUSION The age-related HCN downregulation is mechanistically linked to the exhibition of aging bladder phenotype with the manifestation of DI following steady state blockade of HCN channels in Ivabradine treated young rats. The amplification of MVP in aged rats mediated by FDA approved Ivabradine hints at potential repurposing opportunity in detrusor underactivity.
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Affiliation(s)
- Nishant Singh
- Department of Urology, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Irina Zabbarova
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Youko Ikeda
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Anthony Kanai
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Christopher Chermansky
- Department of Urology, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Naoki Yoshimura
- Department of Urology, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Pradeep Tyagi
- Department of Urology, University of Pittsburgh, Pittsburgh, PA, United States of America
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Depuydt AS, Peigneur S, Tytgat J. Review: HCN Channels in the Heart. Curr Cardiol Rev 2022; 18:e040222200836. [PMID: 35125083 PMCID: PMC9893134 DOI: 10.2174/1573403x18666220204142436] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 12/13/2021] [Accepted: 12/23/2021] [Indexed: 11/22/2022] Open
Abstract
Pacemaker cells are the basis of rhythm in the heart. Cardiovascular diseases, and in particular, arrhythmias are a leading cause of hospital admissions and have been implicated as a cause of sudden death. The prevalence of people with arrhythmias will increase in the next years due to an increase in the ageing population and risk factors. The current therapies are limited, have a lot of side effects, and thus, are not ideal. Pacemaker channels, also called hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels, are the molecular correlate of the hyperpolarization- activated current, called Ih (from hyperpolarization) or If (from funny), that contribute crucially to the pacemaker activity in cardiac nodal cells and impulse generation and transmission in neurons. HCN channels have emerged as interesting targets for the development of drugs, in particular, to lower the heart rate. Nonetheless, their pharmacology is still rather poorly explored in comparison to many other voltage-gated ion channels or ligand-gated ion channels. Ivabradine is the first and currently the only clinically approved compound that specifically targets HCN channels. The therapeutic indication of ivabradine is the symptomatic treatment of chronic stable angina pectoris in patients with coronary artery disease with a normal sinus rhythm. Several other pharmacological agents have been shown to exert an effect on heart rate, although this effect is not always desired. This review is focused on the pacemaking process taking place in the heart and summarizes the current knowledge on HCN channels.
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Affiliation(s)
- Anne-Sophie Depuydt
- Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N2, PO Box 922, Herestraat 49, 3000Leuven, Belgium
| | - Steve Peigneur
- Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N2, PO Box 922, Herestraat 49, 3000Leuven, Belgium
| | - Jan Tytgat
- Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N2, PO Box 922, Herestraat 49, 3000Leuven, Belgium
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Greenberg B. Medical Management of Patients With Heart Failure and Reduced Ejection Fraction. Korean Circ J 2022; 52:173-197. [PMID: 35257531 PMCID: PMC8907986 DOI: 10.4070/kcj.2021.0401] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 12/28/2021] [Indexed: 11/23/2022] Open
Abstract
The options for treating heart failure with reduced ejection fraction (HFrEF) have expanded considerably over the past decade. While neurohormonal modulation using angiotensin converting enzyme inhibitors and angiotensin receptor blockers, beta blockers and mineralocorticoid receptor antagonists remain the cornerstone of therapy, additional novel approaches including angiotensin receptor neprilysin inhibitors, sodium glucose cotransporter 2 inhibitors, ivrabradine, vericiguat and omecamtiv mecarbil have been shown to improve outcomes in patients with HFrEF. This reviews summarizes currently available approaches as well as promising additional strategies that may be used in the future. Treatment options for patients with heart failure (HF) with reduced ejection fraction (HFrEF) have expanded considerably over the past few decades. Whereas neurohormonal modulation remains central to the management of patients with HFrEF, other pathways have been targeted with drugs that have novel mechanisms of action. The angiotensin receptor-neprilysin inhibitors (ARNIs) which enhance levels of compensatory molecules such as the natriuretic peptides while simultaneously providing angiotensin receptor blockade have emerged as the preferred strategy for inhibiting the renin angiotensin system. Sodium glucose cotransporter 2 (SGLT2) inhibitors which were developed as hypoglycemic agents have been shown to improve outcomes in patients with HF regardless of their diabetic status. These agents along with beta blockers and mineralocorticoid receptor antagonists are the core medical therapies for patients with HFrEF. Additional approaches using ivabradine to slow heart rate in patients with sinus rhythm, the hydralazine/isosorbide dinitrate combination to unload the heart, digoxin to provide inotropic support and vericiguat to augment cyclic guanosine monophosphate production have been shown in well-designed trials to have beneficial effects in the HFrEF population and are used as adjuncts to the core therapies in selected patients. This review provides an overview of the medical management of patients with HFrEF with focus on the major developments that have taken place in the field. It offers prospective of how these drugs should be employed in clinical practice and also a glimpse into some strategies that may prove to be useful in the future.
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Oknińska M, Paterek A, Zambrowska Z, Mackiewicz U, Mączewski M. Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe? J Clin Med 2021; 10:4732. [PMID: 34682854 PMCID: PMC8537674 DOI: 10.3390/jcm10204732] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/24/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Life-threatening ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation remain an ongoing clinical problem and their prevention and treatment require optimization. Conventional antiarrhythmic drugs are associated with significant proarrhythmic effects that often outweigh their benefits. Another option, the implantable cardioverter defibrillator, though clearly the primary therapy for patients at high risk of ventricular arrhythmias, is costly, invasive, and requires regular monitoring. Thus there is a clear need for new antiarrhythmic treatment strategies. Ivabradine, a heartrate-reducing agent, an inhibitor of HCN channels, may be one of such options. In this review we discuss emerging data from experimental studies that indicate new mechanism of action of this drug and further areas of investigation and potential use of ivabradine as an antiarrhythmic agent. However, clinical evidence is limited, and the jury is still out on effects of ivabradine on cardiac ventricular arrhythmias in the clinical setting.
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Affiliation(s)
| | | | | | | | - Michał Mączewski
- Centre of Postgraduate Medical Education, Department of Clinical Physiology, ul. Marymoncka 99/103, 01-813 Warsaw, Poland; (M.O.); (A.P.); (Z.Z.); (U.M.)
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29
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Janson CM, Clancy CE. Ivabradine for Postoperative JET: Clear for Take-Off? JACC Clin Electrophysiol 2021; 7:1061-1063. [PMID: 34412869 DOI: 10.1016/j.jacep.2021.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 03/17/2021] [Indexed: 11/18/2022]
Affiliation(s)
- Christopher M Janson
- Division of Cardiology, The Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
| | - Colleen E Clancy
- Department of Physiology and Membrane Biology and Department of Pharmacology, School of Medicine, University of California-Davis, Davis, California, USA
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30
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Bai X, Wang K, Boyett MR, Hancox JC, Zhang H. The Functional Role of Hyperpolarization Activated Current ( I f) on Cardiac Pacemaking in Human vs. in the Rabbit Sinoatrial Node: A Simulation and Theoretical Study. Front Physiol 2021; 12:582037. [PMID: 34489716 PMCID: PMC8417414 DOI: 10.3389/fphys.2021.582037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 07/23/2021] [Indexed: 01/01/2023] Open
Abstract
The cardiac hyperpolarization-activated "funny" current (I f), which contributes to sinoatrial node (SAN) pacemaking, has a more negative half-maximal activation voltage and smaller fully-activated macroscopic conductance in human than in rabbit SAN cells. The consequences of these differences for the relative roles of I f in the two species, and for their responses to the specific bradycardic agent ivabradine at clinical doses have not been systematically explored. This study aims to address these issues, through incorporating rabbit and human I f formulations developed by Fabbri et al. into the Severi et al. model of rabbit SAN cells. A theory was developed to correlate the effect of I f reduction with the total inward depolarising current (I total) during diastolic depolarization. Replacing the rabbit I f formulation with the human one increased the pacemaking cycle length (CL) from 355 to 1,139 ms. With up to 20% I f reduction (a level close to the inhibition of I f by ivabradine at clinical concentrations), a modest increase (~5%) in the pacemaking CL was observed with the rabbit I f formulation; however, the effect was doubled (~12.4%) for the human I f formulation, even though the latter has smaller I f density. When the action of acetylcholine (ACh, 0.1 nM) was considered, a 20% I f reduction markedly increased the pacemaking CL by 37.5% (~27.3% reduction in the pacing rate), which is similar to the ivabradine effect at clinical concentrations. Theoretical analysis showed that the resultant increase of the pacemaking CL is inversely proportional to the magnitude of I total during diastolic depolarization phase: a smaller I f in the model resulted in a smaller I total amplitude, resulting in a slower pacemaking rate; and the same reduction in I f resulted in a more significant change of CL in the cell model with a smaller I total. This explained the mechanism by which a low dose of ivabradine slows pacemaking rate more in humans than in the rabbit. Similar results were seen in the Fabbri et al. model of human SAN cells, suggesting our observations are model-independent. Collectively, the results of study explain why low dose ivabradine at clinically relevant concentrations acts as an effective bradycardic agent in modulating human SAN pacemaking.
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Affiliation(s)
- Xiangyun Bai
- Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester, United Kingdom
- School of Computer Science and Technology, Xi'an University of Posts and Telecommunications, Xi'an, China
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Kuanquan Wang
- School of Computer Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Mark R. Boyett
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, København, Denmark
| | - Jules C. Hancox
- Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester, United Kingdom
- School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences Building, University Walk, Bristol, United Kingdom
| | - Henggui Zhang
- Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester, United Kingdom
- Peng Cheng Laboratory, Shenzhen, China
- Key Laboratory of Medical Electrophysiology of Ministry of Education, Medical Electrophysiological Key Laboratory of Sichuan, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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31
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The HCN channel as a pharmacological target: Why, where, and how to block it. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2021; 166:173-181. [PMID: 34303730 DOI: 10.1016/j.pbiomolbio.2021.07.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/22/2021] [Accepted: 07/20/2021] [Indexed: 12/19/2022]
Abstract
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, expressed in a variety of cell types and in all tissues, control excitation and rhythm. Since their discovery in neurons and cardiac pacemaker cells, they attracted the attention of medicinal chemistry and pharmacology as novel targets to shape (patho)physiological mechanisms. To date, ivabradine represents the first-in-class drug as specific bradycardic agent in cardiac diseases; however, new applications are emerging in parallel with the demonstration of the involvement of different HCN isoforms in central and peripheral nervous system. Hence, the possibility to target specific isoforms represents an attractive development in this field; indeed, HCN1, HCN2 or HCN4 specific blockers have shown promising features in vitro and in vivo, with remarkable pharmacological differences likely depending on the diverse functional role and tissue distribution. Here, we show a recently developed compound with high potency as HCN2-HCN4 blocker; because of its unique profile, this compound may deserve further investigation.
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32
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Abstract
Heart rate modulation therapy using ivabradine improves mortality and morbidity in patients with systolic dysfunction. However, a target heart rate remains uncertain. Echocardiography-guided ivabradine therapy, in which we attempt to approach zero overlap between two diastolic filling inflow waves, has recently been proposed to maximize cardiac output, facilitate reverse remodeling, and reduce mortality and morbidity, instead of using an absolute value for the target heart rate. Prospective studies are needed to validate the clinical implication of these therapeutic strategies. Also, this concept should be expanded to other clinical scenarios.
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Affiliation(s)
- Teruhiko Imamura
- The Second Department of Internal Medicine, University of Toyama
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33
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Saponaro A, Bauer D, Giese MH, Swuec P, Porro A, Gasparri F, Sharifzadeh AS, Chaves-Sanjuan A, Alberio L, Parisi G, Cerutti G, Clarke OB, Hamacher K, Colecraft HM, Mancia F, Hendrickson WA, Siegelbaum SA, DiFrancesco D, Bolognesi M, Thiel G, Santoro B, Moroni A. Gating movements and ion permeation in HCN4 pacemaker channels. Mol Cell 2021; 81:2929-2943.e6. [PMID: 34166608 PMCID: PMC8294335 DOI: 10.1016/j.molcel.2021.05.033] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 04/12/2021] [Accepted: 05/27/2021] [Indexed: 10/31/2022]
Abstract
The HCN1-4 channel family is responsible for the hyperpolarization-activated cation current If/Ih that controls automaticity in cardiac and neuronal pacemaker cells. We present cryoelectron microscopy (cryo-EM) structures of HCN4 in the presence or absence of bound cAMP, displaying the pore domain in closed and open conformations. Analysis of cAMP-bound and -unbound structures sheds light on how ligand-induced transitions in the channel cytosolic portion mediate the effect of cAMP on channel gating and highlights the regulatory role of a Mg2+ coordination site formed between the C-linker and the S4-S5 linker. Comparison of open/closed pore states shows that the cytosolic gate opens through concerted movements of the S5 and S6 transmembrane helices. Furthermore, in combination with molecular dynamics analyses, the open pore structures provide insights into the mechanisms of K+/Na+ permeation. Our results contribute mechanistic understanding on HCN channel gating, cyclic nucleotide-dependent modulation, and ion permeation.
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Affiliation(s)
- Andrea Saponaro
- Department of Biosciences, University of Milan, Milan, Italy
| | - Daniel Bauer
- Department of Biology, TU-Darmstadt, Darmstadt, Germany
| | - M Hunter Giese
- Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA
| | - Paolo Swuec
- Department of Biosciences, University of Milan, Milan, Italy; Pediatric Research Center "Romeo ed Enrica Invernizzi," University of Milan, Milan, Italy
| | | | | | | | - Antonio Chaves-Sanjuan
- Department of Biosciences, University of Milan, Milan, Italy; Pediatric Research Center "Romeo ed Enrica Invernizzi," University of Milan, Milan, Italy
| | - Laura Alberio
- Department of Biosciences, University of Milan, Milan, Italy; Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Giacomo Parisi
- Center for Life Nano Science, Istituto Italiano di Tecnologia, Rome, Italy
| | - Gabriele Cerutti
- Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy
| | - Oliver B Clarke
- Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA; Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Kay Hamacher
- Department of Biology, TU-Darmstadt, Darmstadt, Germany
| | - Henry M Colecraft
- Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA
| | - Filippo Mancia
- Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA
| | - Wayne A Hendrickson
- Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA
| | - Steven A Siegelbaum
- Department of Neuroscience, Zuckerman Institute, Columbia University, New York, NY, USA
| | - Dario DiFrancesco
- Department of Biosciences, University of Milan, Milan, Italy; Institute of Biophysics-Milano, Consiglio Nazionale delle Ricerche, Rome, Italy
| | - Martino Bolognesi
- Department of Biosciences, University of Milan, Milan, Italy; Pediatric Research Center "Romeo ed Enrica Invernizzi," University of Milan, Milan, Italy
| | - Gerhard Thiel
- Department of Biology, TU-Darmstadt, Darmstadt, Germany
| | - Bina Santoro
- Department of Neuroscience, Zuckerman Institute, Columbia University, New York, NY, USA.
| | - Anna Moroni
- Department of Biosciences, University of Milan, Milan, Italy; Institute of Biophysics-Milano, Consiglio Nazionale delle Ricerche, Rome, Italy.
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34
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Nakashima K, Nakao K, Matsui H. Discovery of Novel HCN4 Blockers with Unique Blocking Kinetics and Binding Properties. SLAS DISCOVERY 2021; 26:896-908. [PMID: 34041946 PMCID: PMC8293762 DOI: 10.1177/24725552211013824] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) channel underlies the pacemaker currents, called “If,” in sinoatrial nodes (SANs), which regulate heart rhythm. Some HCN4 blockers such as ivabradine have been extensively studied for treating various heart diseases. Studies have shown that these blockers have diverse state dependencies and binding sites, suggesting the existence of potential chemical and functional diversity among HCN4 blockers. Here we report approaches for the identification of novel HCN4 blockers through a random screening campaign among 16,000 small-molecule compounds using an automated patch-clamp system. These molecules exhibited various blockade profiles, and their blocking kinetics and associating amino acids were determined by electrophysiological studies and site-directed mutagenesis analysis, respectively. The profiles of these blockers were distinct from those of the previously reported HCN channel blockers ivabradine and ZD7288. Notably, the mutagenesis analysis showed that blockers with potencies that were increased when the channel was open involved a C478 residue, located at the pore cavity region near the cellular surface of the plasma membrane, while those with potencies that were decreased when the channel was open involved residues Y506 and I510, located at the intracellular region of the pore gate. Thus, this study reported for the first time the discovery of novel HCN4 blockers by screening, and their profiling analysis using an automated patch-clamp system provided chemical tools that will be useful to obtain unique molecular insights into the drug-binding modes of HCN4 and may contribute to the expansion of therapeutic options in the future.
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Affiliation(s)
- Kosuke Nakashima
- Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
| | - Kenji Nakao
- Biomolecular Research Laboratories, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.,Seedsupply Inc., Fujisawa, Kanagawa, Japan
| | - Hideki Matsui
- Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
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35
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Kawada T, Yamamoto H, Uemura K, Hayama Y, Nishikawa T, Zheng C, Li M, Miyamoto T, Sugimachi M. Ivabradine augments high-frequency dynamic gain of the heart rate response to low- and moderate-intensity vagal nerve stimulation under β-blockade. Am J Physiol Heart Circ Physiol 2021; 320:H2201-H2210. [PMID: 33891515 DOI: 10.1152/ajpheart.00057.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Our previous study indicated that intravenously administered ivabradine (IVA) augmented the dynamic heart rate (HR) response to moderate-intensity vagal nerve stimulation (VNS). Considering an accentuated antagonism, the results were somewhat paradoxical; i.e., the accentuated antagonism indicates that an activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels via the accumulation of intracellular cyclic adenosine monophosphate (cAMP) augments the HR response to VNS, whereas the inhibition of HCN channels by IVA also augmented the HR response to VNS. To remove the possible influence from the accentuated antagonism, we examined the effects of IVA on the dynamic vagal control of HR under β-blockade. In anesthetized rats (n = 7), the right vagal nerve was stimulated for 10 min according to binary white noise signals between 0 and 10 Hz (V0-10), between 0 and 20 Hz (V0-20), and between 0 and 40 Hz (V0-40). The transfer function from VNS to HR was estimated. Under β-blockade (propranolol, 2 mg/kg iv), IVA (2 mg/kg iv) did not augment the asymptotic low-frequency gain but increased the asymptotic high-frequency gain in V0-10 (0.53 ± 0.10 vs. 1.74 ± 0.40 beats/min/Hz, P < 0.01) and V0-20 (0.79 ± 0.14 vs. 2.06 ± 0.47 beats/min/Hz, P < 0.001). These changes, which were observed under a minimal influence from sympathetic background tone, may reflect an increased contribution of the acetylcholine-sensitive potassium channel (IK,ACh) pathway after IVA, because the HR control via the IK,ACh pathway is faster and acts in the frequency range higher than the cAMP-mediated pathway.NEW & NOTEWORTHY Since ivabradine (IVA) inhibits hyperpolarization-activated cyclic nucleotide-gated channels, interactions among the sympathetic effect, vagal effect, and IVA can occur in the control of heart rate (HR). To remove the sympathetic effect, we estimated the transfer function from vagal nerve stimulation to HR under β-blockade in anesthetized rats. IVA augmented the high-frequency dynamic gain during low- and moderate-intensity vagal nerve stimulation. Untethering the hyperpolarizing effect of acetylcholine-sensitive potassium channels after IVA may be a possible underlying mechanism.
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Affiliation(s)
- Toru Kawada
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Hiromi Yamamoto
- Department of Cardiology, Kurashiki Central Hospital, Ohara HealthCare Foundation, Okayama, Japan.,Division of Clinical Research, Kurashiki Clinical Research Institute, Ohara HealthCare Foundation, Okayama, Japan
| | - Kazunori Uemura
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Yohsuke Hayama
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Takuya Nishikawa
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Can Zheng
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Meihua Li
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Tadayoshi Miyamoto
- Department of Sport and Health Sciences, Faculty of Sport and Health Science, Osaka Sangyo University, Osaka, Japan
| | - Masaru Sugimachi
- Department of Cardiovascular Dynamics, National Cerebral and Cardiovascular Center, Osaka, Japan
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36
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Saponaro A, Sharifzadeh AS, Moroni A. Detection of ligand binding to purified HCN channels using fluorescence-based size exclusion chromatography. Methods Enzymol 2021; 652:105-123. [PMID: 34059279 DOI: 10.1016/bs.mie.2021.01.043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Biochemical measurements of ligand binding to eukaryotic membrane proteins are challenging because they can require large amounts of purified protein. For this reason, ligand binding is preferentially evaluated on soluble domains rather than on the full length proteins. In this chapter, we describe the use of fluorescence size exclusion chromatography-based thermostability (FSEC-TS) as an assay to monitor ligand binding to the full length mammalian ion channel HCN4. FSEC-TS monitors the effect of the ligand on the thermal denaturation curve of the protein by following the fluorescence of a fused GFP protein. Changes in the melting temperature (Tm) provide a quantitative value for measuring ligand-protein interaction. As a proof of concept, we describe here the protocol for monitoring the binding of the second messenger cAMP and of the known HCN drug Ivabradine to the purified GFP-HCN4 channel. cTMP, a known non-binder of HCN channels, is used as a control. Due to the small amount of protein required, the assay represents a high-throughput screening system for evaluating binding of small molecules to full length proteins.
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Affiliation(s)
- Andrea Saponaro
- Department of Biosciences, University of Milan, Milan, Italy
| | | | - Anna Moroni
- Department of Biosciences, University of Milan, Milan, Italy.
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37
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Jæger KH, Wall S, Tveito A. Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes. PLoS Comput Biol 2021; 17:e1008089. [PMID: 33591962 PMCID: PMC7909705 DOI: 10.1371/journal.pcbi.1008089] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 02/26/2021] [Accepted: 12/20/2020] [Indexed: 12/20/2022] Open
Abstract
Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient's electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effect in vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSC-CMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC50 values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from pure in vitro measurements of patient derived cell lines.
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MESH Headings
- Action Potentials/drug effects
- Adult
- Ajmaline/pharmacology
- Algorithms
- Anti-Arrhythmia Agents/pharmacology
- Arrhythmias, Cardiac/drug therapy
- Arrhythmias, Cardiac/genetics
- Arrhythmias, Cardiac/physiopathology
- Cell Line
- Computational Biology
- Drug Evaluation, Preclinical/methods
- Drug Evaluation, Preclinical/statistics & numerical data
- ERG1 Potassium Channel/genetics
- Electrocardiography
- Heart Conduction System/abnormalities
- Heart Conduction System/physiopathology
- Heart Defects, Congenital/drug therapy
- Heart Defects, Congenital/genetics
- Heart Defects, Congenital/physiopathology
- Humans
- In Vitro Techniques
- Induced Pluripotent Stem Cells/drug effects
- Induced Pluripotent Stem Cells/physiology
- Ivabradine/pharmacology
- Mexiletine/pharmacology
- Models, Cardiovascular
- Mutation
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/physiology
- Quinidine/pharmacology
- Translational Research, Biomedical
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Affiliation(s)
| | | | - Aslak Tveito
- Simula Research Laboratory, Oslo, Norway
- Department of Informatics, University of Oslo, Oslo, Norway
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38
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Hemodynamic effects of ivabradine use in combination with intravenous inotropic therapy in advanced heart failure. Heart Fail Rev 2020; 26:355-361. [PMID: 32997214 DOI: 10.1007/s10741-020-10029-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/15/2020] [Indexed: 12/28/2022]
Abstract
Intravenous inotropic therapy can be used in patients with advanced heart failure, as palliative therapy or as a bridge to cardiac transplantation or mechanical circulatory support, as well as in cardiogenic shock. Their use is limited to increasing cardiac output in low cardiac output states and reducing ventricular filling pressures to alleviate patient symptoms and improve functional class. Many advanced heart failure patients have sinus tachycardia as a compensatory mechanism to maintain cardiac output. However, excessive sinus tachycardia caused by intravenous inotropes can increase myocardial oxygen consumption, decrease coronary perfusion, and at extreme heart rates decrease ventricular filling and stroke volume. The limited available hemodynamic studies support the hypothesis that adding ivabradine, a rate control agent without negative inotropic effect, may blunt inotrope-induced tachycardia and its associated deleterious effects, while optimizing cardiac output by increasing stroke volume. This review analyzes the intriguing pathophysiology of combined intravenous inotropes and ivabradine to optimize the hemodynamic profile of patients in advanced heart failure. Graphical abstract Illustration of the beneficial and deleterious hemodynamic effects of intravenous inotropes in advanced heart failure, and the positive effects of adding ivabradine.
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39
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Popova E, Kupenova P. Effects of HCN channel blockade on the intensity-response function of electroretinographic ON and OFF responses in dark adapted frogs. Acta Neurobiol Exp (Wars) 2020. [DOI: 10.21307/ane-2020-018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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40
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Zhong LY, Fan XR, Shi ZJ, Fan ZC, Luo J, Lin N, Liu YC, Wu L, Zeng XR, Cao JM, Wei Y. Hyperpolarization-Activated Cyclic Nucleotide-Gated Ion (HCN) Channels Regulate PC12 Cell Differentiation Toward Sympathetic Neuron. Front Cell Neurosci 2019; 13:415. [PMID: 31616252 PMCID: PMC6763607 DOI: 10.3389/fncel.2019.00415] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 08/28/2019] [Indexed: 12/15/2022] Open
Abstract
Hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN channels) are widely expressed in the central and peripheral nervous systems and organs, while their functions are not well elucidated especially in the sympathetic nerve. The present study aimed to investigate the roles of HCN channel isoforms in the differentiation of sympathetic neurons using PC12 cell as a model. PC12 cells derived from rat pheochromocytoma were cultured and induced by nerve growth factor (NGF) (25 ng/ml) to differentiate to sympathetic neuron-like cells. Sympathetic directional differentiation of PC12 cells were evaluated by expressions of growth-associated protein 43 (GAP-43) (a growth cone marker), tyrosine hydroxylase (TH) (a sympathetic neuron marker) and neurite outgrowth. Results show that the HCN channel isoforms (HCN1-4) were all expressed in PC12 cells; blocking HCN channels with ivabradine suppressed NGF-induced GAP-43 expression and neurite outgrowth; silencing the expression of HCN2 and HCN4 using silenced using small interfering RNAs (siRNA), rather than HCN1 and HCN3, restrained GAP-43 expression and neurite outgrowth, while overexpression of HCN2 and HCN4 channels with gene transfer promoted GAP-43 expression and neurite outgrowth. Patch clamp experiments show that PC12 cells exhibited resting potentials (RP) of about −65 to −70 mV, and also presented inward HCN channel currents and outward (K+) currents, but no inward voltage-gated Na+ current was induced; NGF did not significantly affect the RP but promoted the establishment of excitability as indicated by the increased ability to depolarize and repolarize in the evoked suspicious action potentials (AP). We conclude that HCN2 and HCN4 channel isoforms, but not HCN1 and HCN3, promote the differentiation of PC12 cells toward sympathetic neurons. NGF potentiates the establishment of excitability during PC12 cell differentiation.
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Affiliation(s)
- Li-Ying Zhong
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Xin-Rong Fan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Zhang-Jing Shi
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.,Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Zhong-Cai Fan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jian Luo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Na Lin
- Department of Respiratory Medicine, Rongcheng People's Hospital, Rongcheng, China
| | - Ying-Cai Liu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lin Wu
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.,Department of Cardiology, Peking University First Hospital, Beijing, China
| | - Xiao-Rong Zeng
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Ji-Min Cao
- Key Laboratory of Cellular Physiology of Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, China
| | - Yan Wei
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
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Kumar SA, Bhaskar BL. Computational and spectral studies of 3,3'-(propane-1,3-diyl)bis(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one). Heliyon 2019; 5:e02420. [PMID: 31687545 PMCID: PMC6819847 DOI: 10.1016/j.heliyon.2019.e02420] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/19/2019] [Accepted: 09/02/2019] [Indexed: 11/24/2022] Open
Abstract
Detection and qualification of unknown impurities during commercial drug synthesis have been mandated by the regulatory authorities. 3,3'-(propane-1,3-diyl)bis(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-benzo [d]azepin-2-one) in short IVA-9, is one such process-related impurity formed during the synthesis of cardiotonic drug Ivabradine. The structure and properties of this molecule have not been explored yet. A suggestive reaction route for the chance formation of IVA-9 during the commercial synthesis of parent drug molecule has been reported in this article. Further, the optimized geometry and vibrational studies have been computed using Gaussian 09. Experimental FTIR scan has also been performed and values show satisfactory consilience with the computational data. The frontier orbital energies and energy band gaps of the reaction fragments and products were computed. The evaluation of ADME parameters such as absorption, distribution, metabolism, and excretion are performed using SwissADME tool to assess the drug-likeness and medicinal chemistry friendliness. Six physiochemical parameters namely flexibility, lipophilicity, size, polarity, solubility and saturation and their critical limits are depicted using the bioavailability radar of the programme to provide insights into pharmacokinetic properties such as human gastrointestinal absorption (HIA), blood-brain-barrier (BBB) permeability, total polar surface area (TPSA) and inhibitor action to important cytochromes etc.
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Affiliation(s)
- S Anil Kumar
- Department of Chemistry, Amrita School of Engineering, Bengaluru, Amrita Vishwa Vidyapeetham, India
| | - B L Bhaskar
- Department of Chemistry, Amrita School of Engineering, Bengaluru, Amrita Vishwa Vidyapeetham, India
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Banavalikar B, Shenthar J, Padmanabhan D, Valappil SP, Singha SI, Kottayan A, Ghadei M, Ali M. Clinical and Electrophysiological Correlates of Incessant Ivabradine-Sensitive Atrial Tachycardia. Circ Arrhythm Electrophysiol 2019; 12:e007387. [DOI: 10.1161/circep.119.007387] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background:
Incessant focal atrial tachycardia (FAT), if untreated, can lead to ventricular dysfunction and heart failure (tachycardia-induced cardiomyopathy). Drug therapy of FAT is often difficult and ineffective. The efficacy of ivabradine has not been systematically evaluated in the treatment of FAT.
Methods:
The study group consisted of patients with incessant FAT (lasting >24 hours) and structurally normal hearts. Patients with ventricular dysfunction as a consequence of FAT were not excluded. All antiarrhythmic drugs were discontinued at least 5 half-lives before the initiation of ivabradine. Oral ivabradine (adults, 10 mg twice 12 hours apart; pediatric patients: 0.28 mg/kg in 2 divided doses) was initiated in the intensive care unit under continuous electrocardiographic monitoring. A positive response was defined as the termination of tachycardia with the restoration of sinus rhythm or suppression of the tachycardia to <100 beats per minute without termination within 12 hours of initiating ivabradine.
Results:
Twenty-eight patients (mean age, 34.6±21.5 years; women, 60.7%) were included in the study. The most common symptom was palpitation (85.7%) followed by shortness of breath (25%). The mean atrial rate during tachycardia was 170±21 beats per minute, and the mean left ventricular ejection fraction was 54.7±14.3%. Overall, 18 (64.3%) patients responded within 6 hours of the first dose of ivabradine. Thirteen of 18 ivabradine responders subsequently underwent successful catheter ablation. FAT originating in the atrial appendages was a predictor of ivabradine response compared with those arising from other atrial sites (
P
=0.046).
Conclusions:
Ivabradine-sensitive atrial tachycardia constitutes 64% of incessant FAT in patients without structural heart disease. Incessant FAT originating in the atrial appendages is more likely to respond to ivabradine than that arising from other atrial sites. Our findings implicate the funny current in the pathogenesis of FAT.
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Affiliation(s)
- Bharatraj Banavalikar
- Cardiac Electrophysiology Unit, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India
| | - Jayaprakash Shenthar
- Cardiac Electrophysiology Unit, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India
| | - Deepak Padmanabhan
- Cardiac Electrophysiology Unit, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India
| | - Sanjai Pattu Valappil
- Cardiac Electrophysiology Unit, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India
| | - Sinam Inaoton Singha
- Cardiac Electrophysiology Unit, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India
| | - Anju Kottayan
- Cardiac Electrophysiology Unit, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India
| | - Milan Ghadei
- Cardiac Electrophysiology Unit, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India
| | - Muzaffar Ali
- Cardiac Electrophysiology Unit, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India
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Chen SJ, Xu Y, Liang YM, Cao Y, Lv JY, Pang JX, Zhou PZ. Identification and characterization of a series of novel HCN channel inhibitors. Acta Pharmacol Sin 2019; 40:746-754. [PMID: 30315249 DOI: 10.1038/s41401-018-0162-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 08/13/2018] [Indexed: 11/09/2022]
Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in controlling pacemaker activity in both heart and nervous system. Developing HCN channel inhibitors has been proposed to be an important strategy for the treatment of pain, heart failure, arrhythmias, and epilepsy. One HCN channel inhibitor, ivabradine, has been clinically approved for the treatment of angina pectoris and heart failure. In this study, we designed and synthesized eight alkanol amine derivatives, and assessed their effects on HCN channels expressed in COS7 cells using a whole-cell patch clamp method. Among them, compound 4e displayed the most potent inhibitory activity with an IC50 of 2.9 ± 1.2 µM at - 120 mV on HCN2 channel expressed in COS7 cells. Further analysis revealed that application of compound 4e (10 μM) caused a slowing of activation and a hyperpolarizing shift (ΔV1/2 = - 30.2 ± 2.9 mV, n = 5) in the voltage dependence of HCN2 channel activation. The inhibitory effect of compound 4e on HCN1 and HCN4 channel expressed in COS7 cells was less potent with IC50 of 17.2 ± 1.3 and 7.3 ± 1.2 μM, respectively. Besides, we showed that application of compound 4e (10 μM) inhibited Ih and action potential firing in acutely dissociated mouse small dorsal root ganglion neurons. Our study provides a new strategy for the design and development of potent HCN channel inhibitors.
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NPY 2 Receptors Reduce Tonic Action Potential-Independent GABA B Currents in the Basolateral Amygdala. J Neurosci 2019; 39:4909-4930. [PMID: 30971438 DOI: 10.1523/jneurosci.2226-18.2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 03/29/2019] [Accepted: 04/01/2019] [Indexed: 01/17/2023] Open
Abstract
Although NPY has potent anxiolytic actions within the BLA, selective activation of BLA NPY Y2 receptors (Y2Rs) acutely increases anxiety by an unknown mechanism. Using ex vivo male rat brain slice electrophysiology, we show that the selective Y2R agonist, [ahx5-24]NPY, reduced the frequency of GABAA-mediated mIPSCs in BLA principal neurons (PNs). [ahx5-24]NPY also reduced tonic activation of GABAB receptors (GABABR), which increased PN excitability through inhibition of a tonic, inwardly rectifying potassium current (KIR ). Surprisingly, Y2R-sensitive GABABR currents were action potential-independent, persisting after treatment with TTX. Additionally, the Ca2+-dependent, slow afterhyperpolarizing K+ current (IsAHP ) was enhanced in approximately half of the Y2R-sensitive PNs, possibly from enhanced Ca2+ influx, permitted by reduced GABABR tone. In male and female mice expressing tdTomato in Y2R-mRNA cells (tdT-Y2R mice), immunohistochemistry revealed that BLA somatostatin interneurons express Y2Rs, as do a significant subset of BLA PNs. In tdT-Y2R mice, [ahx5-24]NPY increased excitability and suppressed the KIR in nearly all BLA PNs independent of tdT-Y2R fluorescence, consistent with presynaptic Y2Rs on somatostatin interneurons mediating the above effects. However, only tdT-Y2R-expressing PNs responded to [ahx5-24]NPY with an enhancement of the IsAHP Ultimately, increased PN excitability via acute Y2R activation likely correlates with enhanced BLA output, consistent with reported Y2R-mediated anxiogenesis. Furthermore, we demonstrate the following: (1) a novel mechanism whereby activity-independent GABA release can powerfully dampen BLA neuronal excitability via postsynaptic GABABRs; and (2) that this tonic inhibition can be interrupted by neuromodulation, here by NPY via Y2Rs.SIGNIFICANCE STATEMENT Within the BLA, NPY is potently anxiolytic. However, selective activation of NPY2 receptors (Y2Rs) increases anxiety by an unknown mechanism. We show that activation of BLA Y2Rs decreases tonic GABA release onto BLA principal neurons, probably from Y2R-expressing somatostatin interneurons, some of which coexpress NPY. This increases principal neuron excitability by reducing GABAB receptor (GABABR)-mediated activation of G-protein-coupled, inwardly rectifying K+ currents. Tonic, Y2R-sensitive GABABR currents unexpectedly persisted in the absence of action potential firing, revealing, to our knowledge, the first report of substantial, activity-independent GABABR activation. Ultimately, we provide a plausible explanation for Y2R-mediated anxiogenesis in vivo and describe a novel and modulatable means of damping neuronal excitability.
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45
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Fragasso G, Margonato A, Spoladore R, Lopaschuk GD. Metabolic effects of cardiovascular drugs. Trends Cardiovasc Med 2019; 29:176-187. [DOI: 10.1016/j.tcm.2018.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 07/12/2018] [Accepted: 08/03/2018] [Indexed: 01/04/2023]
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Tanguay J, Callahan KM, D'Avanzo N. Characterization of drug binding within the HCN1 channel pore. Sci Rep 2019; 9:465. [PMID: 30679654 PMCID: PMC6345760 DOI: 10.1038/s41598-018-37116-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 11/29/2018] [Indexed: 11/09/2022] Open
Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate rhythmic electrical activity of cardiac pacemaker cells, and in neurons play important roles in setting resting membrane potentials, dendritic integration, neuronal pacemaking, and establishing action potential threshold. Block of HCN channels slows the heart rate and is currently used to treat angina. However, HCN block also provides a promising approach to the treatment of neuronal disorders including epilepsy and neuropathic pain. While several molecules that block HCN channels have been identified, including clonidine and its derivative alinidine, lidocaine, mepivacaine, bupivacaine, ZD7288, ivabradine, zatebradine, and cilobradine, their low affinity and lack of specificity prevents wide-spread use. Different studies suggest that the binding sites of these inhibitors are located in the inner vestibule of HCN channels, but the molecular details of their binding remain unknown. We used computational docking experiments to assess the binding sites and mode of binding of these inhibitors against the recently solved atomic structure of human HCN1 channels, and a homology model of the open pore derived from a closely related CNG channel. We identify a possible hydrophobic groove in the pore cavity that plays an important role in conformationally restricting the location and orientation of drugs bound to the inner vestibule. Our results also help explain the molecular basis of the low-affinity binding of these inhibitors, paving the way for the development of higher affinity molecules.
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Affiliation(s)
- Jérémie Tanguay
- Department of Physics, Université de Montréal, Montréal, Canada
| | - Karen M Callahan
- Department of Pharmacology and Physiology, Université de Montréal, Montréal, Canada
| | - Nazzareno D'Avanzo
- Department of Pharmacology and Physiology, Université de Montréal, Montréal, Canada.
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Zhang H, Kashihara T, Nakada T, Tanaka S, Ishida K, Fuseya S, Kawagishi H, Kiyosawa K, Kawamata M, Yamada M. Prostanoid EP4 Receptor-Mediated Augmentation of I h Currents in A β Dorsal Root Ganglion Neurons Underlies Neuropathic Pain. J Pharmacol Exp Ther 2019; 368:50-58. [PMID: 30409832 DOI: 10.1124/jpet.118.252767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 11/05/2018] [Indexed: 11/22/2022] Open
Abstract
An injury of the somatosensory system causes neuropathic pain, which is usually refractory to conventional analgesics, thus warranting the development of novel drugs against this kind of pain. The mechanism of neuropathic pain in rats that had undergone left L5 spinal nerve transection was analyzed. Ten days after surgery, these rats acquired neuropathic pain. The patch-clamp technique was used on the isolated bilateral L5 dorsal root ganglion neurons. The current-clamped neurons on the ipsilateral side exhibited significantly higher excitability than those on the contralateral side. However, only neurons with diameters of 40-50 μm on the ipsilateral side exhibited significantly larger voltage sags in response to hyperpolarizing current pulses than those on the contralateral side. Under the voltage clamp, only these neurons on the ipsilateral side showed a significantly larger density of an inward current at < -80 mV [hyperpolarization-activated nonselective cation (I h) current] with a rightward-shifted activation curve than that on the contralateral side. Ivabradine-an I h current inhibitor-inhibited I h currents in these neurons on both sides in a similar concentration-dependent manner, with an IC50 value of ∼3 μM. Moreover, the oral administration of ivabradine significantly alleviated the neuropathic pain on the ipsilateral side. An inhibitor of adenylyl cyclase or an antagonist of prostanoid EP4 receptors (CJ-023423) inhibited ipsilateral, but not contralateral I h, currents in these neurons. Furthermore, the intrathecal administration of CJ-023423 significantly attenuated neuropathic pain on the ipsilateral side. Thus, ivabradine and/or CJ-023423 may be a lead compound for the development of novel therapeutics against neuropathic pain.
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Affiliation(s)
- Hao Zhang
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Toshihide Kashihara
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Tsutomu Nakada
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Satoshi Tanaka
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Kumiko Ishida
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Satoshi Fuseya
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Hiroyuki Kawagishi
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Kenkichi Kiyosawa
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Mikito Kawamata
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Mitsuhiko Yamada
- Departments of Molecular Pharmacology (H.Z., T.K., T.N., H.K., K.K., M.Y.) and Anesthesiology and Resuscitology (H.Z., S.T., K.I., S.F., K.K., M.K.), Shinshu University School of Medicine, Matsumoto, Nagano, Japan
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Rivera-Meza M. The Hyperpolarization-Activated Cyclic Nucleotide-Gated Ion Channels in the Rewarding Effects of Ethanol. NEUROSCIENCE OF ALCOHOL 2019:171-178. [DOI: 10.1016/b978-0-12-813125-1.00018-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Ide T, Ohtani K, Higo T, Tanaka M, Kawasaki Y, Tsutsui H. Ivabradine for the Treatment of Cardiovascular Diseases. Circ J 2018; 83:252-260. [PMID: 30606942 DOI: 10.1253/circj.cj-18-1184] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Higher heart rate (HR) is independently related to worse outcomes in various cardiac diseases, including hypertension, coronary artery disease, and heart failure (HF). HR is determined by the pacemaker activity of cells within the sinoatrial node. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 4 channel, one of 4 HCN isoforms, generates the If current and plays an important role in the regulation of pacemaker activity in the sinoatrial node. Ivabradine is a novel and only available HCN inhibitor, which can reduce HR and has been approved for stable angina and chronic HF in many countries other than Japan. In this review, we summarize the current knowledge of the HCN4 channel and ivabradine, including the function of HCN4 in cardiac pacemaking, the mechanism of action of If inhibition by ivabradine, and the pharmacological and clinical effects of ivabradine in cardiac diseases as HF, coronary artery disease, and atrial fibrillation.
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Affiliation(s)
- Tomomi Ide
- Department of Experimental and Clinical Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
| | - Kisho Ohtani
- Department of Experimental and Clinical Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
| | - Taiki Higo
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
| | | | | | - Hiroyuki Tsutsui
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University
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Canine and human sinoatrial node: differences and similarities in the structure, function, molecular profiles, and arrhythmia. J Vet Cardiol 2018; 22:2-19. [PMID: 30559056 DOI: 10.1016/j.jvc.2018.10.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 10/02/2018] [Accepted: 10/02/2018] [Indexed: 12/17/2022]
Abstract
The sinoatrial node (SAN) is the primary pacemaker in canine and human hearts. The SAN in both species has a unique three-dimensional heterogeneous structure characterized by small pacemaker myocytes enmeshed within fibrotic strands, which partially insulate the cells from aberrant atrial activation. The SAN pacemaker tissue expresses a unique signature of proteins and receptors that mediate SAN automaticity, ion channel currents, and cell-to-cell communication, which are predominantly similar in both species. Recent intramural optical mapping, integrated with structural and molecular studies, has revealed the existence of up to five specialized SAN conduction pathways that preferentially conduct electrical activation to atrial tissues. The intrinsic heart rate, intranodal leading pacemaker shifts, and changes in conduction in response to physiological and pathophysiological stimuli are similar. Structural and/or functional impairments due to cardiac diseases including heart failure cause SAN dysfunctions (SNDs) in both species. These dysfunctions are usually manifested as severe bradycardia, tachy-brady arrhythmias, and conduction abnormalities including exit block and SAN reentry, which could lead to atrial tachycardia and fibrillation, cardiac arrest, and heart failure. Pharmaceutical drugs and implantable pacemakers are only partially successful in managing SNDs, emphasizing a critical need to develop targeted mechanism-based therapies to treat SNDs. Because several structural and functional characteristics are similar between the canine and human SAN, research in these species may be mutually beneficial for developing novel treatment approaches. This review describes structural, functional, and molecular similarities and differences between the canine and human SAN, with special emphasis on arrhythmias and unique causal mechanisms of SND in diseased hearts.
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