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Bo Y, Zhao X, Li L. Cardiotoxic effects of common and emerging drugs: role of cannabinoid receptors. Clin Sci (Lond) 2024; 138:413-434. [PMID: 38505994 DOI: 10.1042/cs20231156] [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: 09/21/2023] [Revised: 02/23/2024] [Accepted: 03/12/2024] [Indexed: 03/21/2024]
Abstract
Drug-induced cardiotoxicity has become one of the most common and detrimental health concerns, which causes significant loss to public health and drug resources. Cannabinoid receptors (CBRs) have recently achieved great attention for their vital roles in the regulation of heart health and disease, with mounting evidence linking CBRs with the pathogenesis and progression of drug-induced cardiotoxicity. This review aims to summarize fundamental characteristics of two well-documented CBRs (CB1R and CB2R) from aspects of molecular structure, signaling and their functions in cardiovascular physiology and pathophysiology. Moreover, we describe the roles of CB1R and CB2R in the occurrence of cardiotoxicity induced by common drugs such as antipsychotics, anti-cancer drugs, marijuana, and some emerging synthetic cannabinoids. We highlight the 'yin-yang' relationship between CB1R and CB2R in drug-induced cardiotoxicity and propose future perspectives for CBR-based translational medicine toward cardiotoxicity curation and clinical monitoring.
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Affiliation(s)
- Yiming Bo
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xin Zhao
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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Why Do Marijuana and Synthetic Cannabimimetics Induce Acute Myocardial Infarction in Healthy Young People? Cells 2022; 11:cells11071142. [PMID: 35406706 PMCID: PMC8997492 DOI: 10.3390/cells11071142] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/18/2022] [Accepted: 03/23/2022] [Indexed: 12/19/2022] Open
Abstract
The use of cannabis preparations has steadily increased. Although cannabis was traditionally assumed to only have mild vegetative side effects, it has become evident in recent years that severe cardiovascular complications can occur. Cannabis use has recently even been added to the risk factors for myocardial infarction. This review is dedicated to pathogenetic factors contributing to cannabis-related myocardial infarction. Tachycardia is highly important in this respect, and we provide evidence that activation of CB1 receptors in brain regions important for cardiovascular regulation and of presynaptic CB1 receptors on sympathetic and/or parasympathetic nerve fibers are involved. The prototypical factors for myocardial infarction, i.e., thrombus formation and coronary constriction, have also been considered, but there is little evidence that they play a decisive role. On the other hand, an increase in the formation of carboxyhemoglobin, impaired mitochondrial respiration, cardiotoxic reactions and tachyarrhythmias associated with the increased sympathetic tone are factors possibly intensifying myocardial infarction. A particularly important factor is that cannabis use is frequently accompanied by tobacco smoking. In conclusion, additional research is warranted to decipher the mechanisms involved, since cannabis use is being legalized increasingly and Δ9-tetrahydrocannabinol and its synthetic analogue nabilone are indicated for the treatment of various disease states.
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Miklós Z, Wafa D, Nádasy GL, Tóth ZE, Besztercei B, Dörnyei G, Laska Z, Benyó Z, Ivanics T, Hunyady L, Szekeres M. Angiotensin II-Induced Cardiac Effects Are Modulated by Endocannabinoid-Mediated CB 1 Receptor Activation. Cells 2021; 10:724. [PMID: 33805075 PMCID: PMC8064086 DOI: 10.3390/cells10040724] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/13/2021] [Accepted: 03/21/2021] [Indexed: 12/02/2022] Open
Abstract
Angiotensin II (Ang II) has various cardiac effects and causes vasoconstriction. Ang II activates the type-1 angiotensin receptor-Gq/11 signaling pathway resulting in the release of 2-arachidonoylglycerol (2-AG). We aimed to investigate whether cardiac Ang II effects are modulated by 2-AG-release and to identify the role of type-1 cannabinoid receptors (CB1R) in these effects. Expression of CB1R in rat cardiac tissue was confirmed by immunohistochemistry. To characterize short-term Ang II effects, increasing concentrations of Ang II (10-9-10-7 M); whereas to assess tachyphylaxis, repeated infusions of Ang II (10-7 M) were administered to isolated Langendorff-perfused rat hearts. Ang II infusions caused a decrease in coronary flow and ventricular inotropy, which was more pronounced during the first administration. CB agonist 2-AG and WIN55,212-2 administration to the perfusate enhanced coronary flow. The flow-reducing effect of Ang II was moderated in the presence of CB1R blocker O2050 and diacylglycerol-lipase inhibitor Orlistat. Our findings indicate that Ang II-induced cardiac effects are modulated by simultaneous CB1R-activation, most likely due to 2-AG-release during Ang II signalling. In this combined effect, the response to 2-AG via cardiac CB1R may counteract the positive inotropic effect of Ang II, which may decrease metabolic demand and augment Ang II-induced coronary vasoconstriction.
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Affiliation(s)
- Zsuzsanna Miklós
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (D.W.); (B.B.); (Z.L.); (Z.B.); (T.I.)
| | - Dina Wafa
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (D.W.); (B.B.); (Z.L.); (Z.B.); (T.I.)
| | - György L. Nádasy
- Department of Physiology, Semmelweis University, 1094 Budapest, Hungary; (G.L.N.); (L.H.)
| | - Zsuzsanna E. Tóth
- Department of Anatomy, Histology and Embryology, Semmelweis University, 1094 Budapest, Hungary;
| | - Balázs Besztercei
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (D.W.); (B.B.); (Z.L.); (Z.B.); (T.I.)
| | - Gabriella Dörnyei
- Department of Morphology and Physiology, Semmelweis University, 1088 Budapest, Hungary;
| | - Zsófia Laska
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (D.W.); (B.B.); (Z.L.); (Z.B.); (T.I.)
| | - Zoltán Benyó
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (D.W.); (B.B.); (Z.L.); (Z.B.); (T.I.)
| | - Tamás Ivanics
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (D.W.); (B.B.); (Z.L.); (Z.B.); (T.I.)
| | - László Hunyady
- Department of Physiology, Semmelweis University, 1094 Budapest, Hungary; (G.L.N.); (L.H.)
- Laboratory of Molecular Physiology, Semmelweis University and Hungarian Academy of Sciences, 1094 Budapest, Hungary
| | - Mária Szekeres
- Department of Physiology, Semmelweis University, 1094 Budapest, Hungary; (G.L.N.); (L.H.)
- Department of Morphology and Physiology, Semmelweis University, 1088 Budapest, Hungary;
- Laboratory of Molecular Physiology, Semmelweis University and Hungarian Academy of Sciences, 1094 Budapest, Hungary
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Walker OS, Ragos R, Gurm H, Lapierre M, May LL, Raha S. Delta-9-tetrahydrocannabinol disrupts mitochondrial function and attenuates syncytialization in human placental BeWo cells. Physiol Rep 2020; 8:e14476. [PMID: 32628362 PMCID: PMC7336740 DOI: 10.14814/phy2.14476] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/20/2022] Open
Abstract
The psychoactive component in cannabis, delta-9-tetrahydrocannabinol, can restrict fetal growth and development. Delta-9-tetrahydrocannabinol has been shown to negatively impact cellular proliferation and target organelles like the mitochondria resulting in reduced cellular respiration. In the placenta, mitochondrial dysfunction leading to oxidative stress prevents proper placental development and function. A key element of placental development is the proliferation and fusion of cytotrophoblasts to form the syncytium that comprises the materno-fetal interface. The impact of delta-9-tetrahydrocannabinol on this process is not well understood. To elucidate the nature of the mitochondrial dysfunction and its consequences on trophoblast fusion, we treated undifferentiated and differentiated BeWo human trophoblast cells, with 20 µM delta-9-tetrahydrocannabinol for 48 hr. At this concentration, delta-9-tetrahydrocannabinol on BeWo cells reduced the expression of markers involved in syncytialization and mitochondrial dynamics, but had no effect on cell viability. Delta-9-tetrahydrocannabinol significantly attenuated the process of syncytialization and induced oxidative stress responses in BeWo cells. Importantly, delta-9-tetrahydrocannabinol also caused a reduction in the secretion of human chorionic gonadotropin and the production of human placental lactogen and insulin growth factor 2, three hormones known to be important in facilitating fetal growth. Furthermore, we also demonstrate that delta-9-tetrahydrocannabinol attenuated mitochondrial respiration, depleted adenosine triphosphate, and reduced mitochondrial membrane potential. These changes were also associated with an increase in cellular reactive oxygen species, and the expression of stress responsive chaperones, HSP60 and HSP70. These findings have important implications for understanding the role of delta-9-tetrahydrocannabinol-induced mitochondrial injury and the role this might play in compromising human pregnancies.
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Affiliation(s)
- O’Llenecia S. Walker
- Department of PediatricsMcMaster UniversityHamiltonONCanada
- The Graduate Program in Medical SciencesMcMaster UniversityHamiltonONCanada
| | | | - Harmeet Gurm
- Department of PediatricsMcMaster UniversityHamiltonONCanada
| | | | - Linda L. May
- Department of PediatricsMcMaster UniversityHamiltonONCanada
| | - Sandeep Raha
- Department of PediatricsMcMaster UniversityHamiltonONCanada
- The Graduate Program in Medical SciencesMcMaster UniversityHamiltonONCanada
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Hauer D, Toth R, Schelling G. Endocannabinoids, “New-Old” Mediators of Stress Homeostasis. STRESS CHALLENGES AND IMMUNITY IN SPACE 2020:181-204. [DOI: 10.1007/978-3-030-16996-1_10] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Role of Nitric Oxide in the Cardiovascular and Renal Systems. Int J Mol Sci 2018; 19:ijms19092605. [PMID: 30177600 PMCID: PMC6164974 DOI: 10.3390/ijms19092605] [Citation(s) in RCA: 154] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 08/30/2018] [Accepted: 08/31/2018] [Indexed: 12/17/2022] Open
Abstract
The gasotransmitters are a family of gaseous signaling molecules which are produced endogenously and act at specific receptors to play imperative roles in physiologic and pathophysiologic processes. As a well-known gasotransmitter along with hydrogen sulfide and carbon monoxide, nitric oxide (NO) has earned repute as a potent vasodilator also known as endothelium-derived vasorelaxant factor (EDRF). NO has been studied in greater detail, from its synthesis and mechanism of action to its physiologic, pathologic, and pharmacologic roles in different disease states. Different animal models have been applied to investigate the beneficial effects of NO as an antihypertensive, renoprotective, and antihypertrophic agent. NO and its interaction with different systems like the renin–angiotensin system, sympathetic nervous system, and other gaseous transmitters like hydrogen sulfide are also well studied. However, links that appear to exist between the endocannabinoid (EC) and NO systems remain to be fully explored. Experimental approaches using modulators of its synthesis including substrate, donors, and inhibitors of the synthesis of NO will be useful for establishing the relationship between the NO and EC systems in the cardiovascular and renal systems. Being a potent vasodilator, NO may be unique among therapeutic options for management of hypertension and resulting renal disease and left ventricular hypertrophy. Inclusion of NO modulators in clinical practice may be useful not only as curatives for particular diseases but also for arresting disease prognoses through its interactions with other systems.
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Pędzińska-Betiuk A, Weresa J, Toczek M, Baranowska-Kuczko M, Kasacka I, Harasim-Symbor E, Malinowska B. Chronic inhibition of fatty acid amide hydrolase by URB597 produces differential effects on cardiac performance in normotensive and hypertensive rats. Br J Pharmacol 2017; 174:2114-2129. [PMID: 28437860 DOI: 10.1111/bph.13830] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 03/27/2017] [Accepted: 04/12/2017] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND AND PURPOSE Fatty acid amide hydrolase (FAAH) inhibitors are postulated to possess anti-hypertensive potential, because their acute injection decreases BP in spontaneously hypertensive rats (SHR), partly through normalization of cardiac contractile function. Here, we examined whether the potential hypotensive effect of chronic FAAH inhibition by URB597 in hypertensive rats correlated with changes in cardiac performance. EXPERIMENTAL APPROACH Experiments were performed using perfused hearts and left atria isolated from 8- to 10-week-old SHR, age-matched deoxycorticosterone acetate (DOCA)-salt rats and normotensive controls chronically treated with URB597 (1 mg·kg-1 ) or vehicle. KEY RESULTS URB597 decreased BP only in the DOCA-salt rats, along with a reduction of ventricular hypertrophy and diastolic stiffness, determined in hypertension. We also observed normalization of the negative inotropic atrial response to the cannabinoid receptor agonist CP55940. In the SHR model, URB597 normalized (atria) and enhanced (hearts) the positive ino- and chronotropic effects of the β-adrenoceptor agonist isoprenaline respectively. Ventricular CB1 and CB2 receptor expression was decreased only in the DOCA-salt model, whereas FAAH expression was reduced in both models. URB597 caused translocation of CB1 receptor immunoreactivity to the intercalated discs in the hearts of SHR. URB597 increased cardiac diastolic stiffness and modified the ino- and lusitropic effects of isoprenaline in normotensive rats. CONCLUSION AND IMPLICATIONS Hypotensive effect of chronic FAAH inhibition depend on the model of hypertension and partly correlate with improved cardiac performance. In normotensive rats, chronic FAAH inhibition produced several side-effects. Thus, the therapeutic potential of these agents should be interpreted cautiously.
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Affiliation(s)
- Anna Pędzińska-Betiuk
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Bialystok, Poland
| | - Jolanta Weresa
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Bialystok, Poland
| | - Marek Toczek
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Bialystok, Poland
| | - Marta Baranowska-Kuczko
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Bialystok, Poland
| | - Irena Kasacka
- Department of Histology and Cytophysiology, Medical University of Białystok, Bialystok, Poland
| | - Ewa Harasim-Symbor
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | - Barbara Malinowska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Bialystok, Poland
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Effekte des Endocannabinoidrezeptors CB2 auf die myokardiale Protektion. ZEITSCHRIFT FUR HERZ THORAX UND GEFASSCHIRURGIE 2016. [DOI: 10.1007/s00398-016-0087-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Jeng XJ, Daye ZJ, Lu W, Tzeng JY. Rare Variants Association Analysis in Large-Scale Sequencing Studies at the Single Locus Level. PLoS Comput Biol 2016; 12:e1004993. [PMID: 27355347 PMCID: PMC4927097 DOI: 10.1371/journal.pcbi.1004993] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 05/21/2016] [Indexed: 11/24/2022] Open
Abstract
Genetic association analyses of rare variants in next-generation sequencing (NGS) studies are fundamentally challenging due to the presence of a very large number of candidate variants at extremely low minor allele frequencies. Recent developments often focus on pooling multiple variants to provide association analysis at the gene instead of the locus level. Nonetheless, pinpointing individual variants is a critical goal for genomic researches as such information can facilitate the precise delineation of molecular mechanisms and functions of genetic factors on diseases. Due to the extreme rarity of mutations and high-dimensionality, significances of causal variants cannot easily stand out from those of noncausal ones. Consequently, standard false-positive control procedures, such as the Bonferroni and false discovery rate (FDR), are often impractical to apply, as a majority of the causal variants can only be identified along with a few but unknown number of noncausal variants. To provide informative analysis of individual variants in large-scale sequencing studies, we propose the Adaptive False-Negative Control (AFNC) procedure that can include a large proportion of causal variants with high confidence by introducing a novel statistical inquiry to determine those variants that can be confidently dispatched as noncausal. The AFNC provides a general framework that can accommodate for a variety of models and significance tests. The procedure is computationally efficient and can adapt to the underlying proportion of causal variants and quality of significance rankings. Extensive simulation studies across a plethora of scenarios demonstrate that the AFNC is advantageous for identifying individual rare variants, whereas the Bonferroni and FDR are exceedingly over-conservative for rare variants association studies. In the analyses of the CoLaus dataset, AFNC has identified individual variants most responsible for gene-level significances. Moreover, single-variant results using the AFNC have been successfully applied to infer related genes with annotation information. Next-generation sequencing technologies have allowed genetic association studies of complex traits at the single base-pair resolution, where most genetic variants have extremely low mutation frequencies. These rare variants have been the focus of modern statistical-computational genomics due to their potential to explain missing disease heritability. The identification of individual rare variants associated with diseases can provide new biological insights and enable the precise delineation of disease mechanisms. However, due to the extreme rarity of mutations and large numbers of variants, significances of causative variants tend to be mixed inseparably with a few noncausative ones, and standard multiple testing procedures controlling for false positives fail to provide a meaningful way to include a large proportion of the causative variants. To address the challenge of detecting weak biological signals, we propose a novel statistical procedure, based on false-negative control, to provide a practical approach for variant inclusion in large-scale sequencing studies. By determining those variants that can be confidently dispatched as noncausative, the proposed procedure offers an objective selection of a modest number of potentially causative variants at the single-locus level. Results can be further prioritized or used to infer disease-associated genes with annotation information.
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Affiliation(s)
- Xinge Jessie Jeng
- Department of Statistics, North Carolina State University, Raleigh, North Carolina, United States of America
| | - Zhongyin John Daye
- Epidemiology and Biostatistics, University of Arizona, Tucson, Arizona, United States of America
| | - Wenbin Lu
- Department of Statistics, North Carolina State University, Raleigh, North Carolina, United States of America
| | - Jung-Ying Tzeng
- Department of Statistics, North Carolina State University, Raleigh, North Carolina, United States of America
- Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, United States of America
- Department of Statistics, National Cheng-Kung University, Tainan, Taiwan
- * E-mail:
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10
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Abstract
The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.
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Affiliation(s)
- Saoirse Elizabeth O'Sullivan
- Faculty of Medicine and Health Sciences, Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, Royal Derby Hospital Centre, University of Nottingham, Room 4107, Uttoxeter Road, Derby, DE22 3DT, UK.
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Walsh SK, Hepburn CY, Keown O, Åstrand A, Lindblom A, Ryberg E, Hjorth S, Leslie SJ, Greasley PJ, Wainwright CL. Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach. Pharmacol Res Perspect 2015; 3:e00143. [PMID: 26236485 PMCID: PMC4492759 DOI: 10.1002/prp2.143] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 03/14/2015] [Indexed: 11/24/2022] Open
Abstract
The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPγS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1−/− and GPR55−/−) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPγS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55−/− mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55−/− mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control.
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Affiliation(s)
- Sarah K Walsh
- Institute for Health & Wellbeing Research, Robert Gordon University Riverside East, Aberdeen, AB10 7GJ, United Kingdom
| | - Claire Y Hepburn
- Institute for Health & Wellbeing Research, Robert Gordon University Riverside East, Aberdeen, AB10 7GJ, United Kingdom
| | - Oliver Keown
- Institute for Health & Wellbeing Research, Robert Gordon University Riverside East, Aberdeen, AB10 7GJ, United Kingdom ; Cardiac Unit, Raigmore Hospital Old Perth Road, Inverness, IV2 3UJ, United Kingdom
| | - Annika Åstrand
- Cardiovascular & Metabolic Disease IMED, AstraZeneca R&D Mölndal, Sweden
| | - Anna Lindblom
- Cardiovascular & Metabolic Disease IMED, AstraZeneca R&D Mölndal, Sweden
| | - Erik Ryberg
- Cardiovascular & Metabolic Disease IMED, AstraZeneca R&D Mölndal, Sweden
| | - Stephan Hjorth
- Cardiovascular & Metabolic Disease IMED, AstraZeneca R&D Mölndal, Sweden
| | - Stephan J Leslie
- Cardiac Unit, Raigmore Hospital Old Perth Road, Inverness, IV2 3UJ, United Kingdom
| | - Peter J Greasley
- Cardiovascular & Metabolic Disease IMED, AstraZeneca R&D Mölndal, Sweden
| | - Cherry L Wainwright
- Institute for Health & Wellbeing Research, Robert Gordon University Riverside East, Aberdeen, AB10 7GJ, United Kingdom
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Al Kury LT, Voitychuk OI, Yang KHS, Thayyullathil FT, Doroshenko P, Ramez AM, Shuba YM, Galadari S, Howarth FC, Oz M. Effects of the endogenous cannabinoid anandamide on voltage-dependent sodium and calcium channels in rat ventricular myocytes. Br J Pharmacol 2015; 171:3485-98. [PMID: 24758718 DOI: 10.1111/bph.12734] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 02/17/2014] [Accepted: 03/14/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND AND PURPOSE The endocannabinoid anandamide (N-arachidonoyl ethanolamide; AEA) exerts negative inotropic and antiarrhythmic effects in ventricular myocytes. EXPERIMENTAL APPROACH Whole-cell patch-clamp technique and radioligand-binding methods were used to analyse the effects of anandamide in rat ventricular myocytes. KEY RESULTS In the presence of 1-10 μM AEA, suppression of both Na(+) and L-type Ca(2+) channels was observed. Inhibition of Na(+) channels was voltage and Pertussis toxin (PTX) - independent. Radioligand-binding studies indicated that specific binding of [(3) H] batrachotoxin (BTX) to ventricular muscle membranes was also inhibited significantly by 10 μM metAEA, a non-metabolized AEA analogue, with a marked decrease in Bmax values but no change in Kd . Further studies on L-type Ca(2+) channels indicated that AEA potently inhibited these channels (IC50 0.1 μM) in a voltage- and PTX-independent manner. AEA inhibited maximal amplitudes without affecting the kinetics of Ba(2+) currents. MetAEA also inhibited Na(+) and L-type Ca(2+) currents. Radioligand studies indicated that specific binding of [(3) H]isradipine, was inhibited significantly by metAEA. (10 μM), changing Bmax but not Kd . CONCLUSION AND IMPLICATIONS Results indicate that AEA inhibited the function of voltage-dependent Na(+) and L-type Ca(2+) channels in rat ventricular myocytes, independent of CB1 and CB2 receptor activation.
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Affiliation(s)
- Lina T Al Kury
- Laboratory of Functional Lipidomics, Department of Pharmacology, UAE University, Al Ain, UAE
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Fede G, Privitera G, Tomaselli T, Spadaro L, Purrello F. Cardiovascular dysfunction in patients with liver cirrhosis. Ann Gastroenterol 2015; 28:31-40. [PMID: 25608575 PMCID: PMC4290002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Accepted: 09/03/2014] [Indexed: 11/19/2022] Open
Abstract
Hyperdynamic syndrome is a well-known clinical condition found in patients with cirrhosis and portal hypertension, characterized by increased heart rate and cardiac output, and reduced systemic vascular resistance and arterial blood pressure. The leading cause of hyperdynamic circulation in cirrhotic patients is peripheral and splanchnic vasodilatation, due to an increased production/activity of vasodilator factors and decreased vascular reactivity to vasoconstrictors. The term "cirrhotic cardiomyopathy" describes impaired contractile responsiveness to stress, diastolic dysfunction and electrophysiological abnormalities in patients with cirrhosis without known cardiac disease. Underlying circulatory and cardiac dysfunctions are the main determinant in the development of hepatorenal syndrome in advanced cirrhosis. Moreover, the clinical consequences of cirrhosis-related cardiovascular dysfunction are evident during and after liver transplantation, and after transjugular intrahepatic portosystemic shunt insertion. Cardiovascular complications following these procedures are common, with pulmonary edema being the most common complication. Other complications include overt heart failure, arrhythmia, pulmonary hypertension, pericardial effusion, and cardiac thrombus formation. This review discusses the circulatory and cardiovascular dysfunctions in cirrhosis, examining the pathophysiologic and clinical implications in light of the most recent published literature.
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Affiliation(s)
- Giuseppe Fede
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
| | - Graziella Privitera
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
| | - Tania Tomaselli
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
| | - Luisa Spadaro
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
| | - Francesco Purrello
- Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi Hospital, Catania, Italy
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Gassanov N, Caglayan E, Semmo N, Massenkeil G, Er F. Cirrhotic cardiomyopathy: A cardiologist’s perspective. World J Gastroenterol 2014; 20:15492-15498. [PMID: 25400434 PMCID: PMC4229515 DOI: 10.3748/wjg.v20.i42.15492] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 04/01/2014] [Accepted: 06/13/2014] [Indexed: 02/06/2023] Open
Abstract
Cardiac dysfunction is frequently observed in patients with cirrhosis, and has long been linked to the direct toxic effect of alcohol. Cirrhotic cardiomyopathy (CCM) has recently been identified as an entity regardless of the cirrhosis etiology. Increased cardiac output due to hyperdynamic circulation is a pathophysiological hallmark of the disease. The underlying mechanisms involved in pathogenesis of CCM are complex and involve various neurohumoral and cellular pathways, including the impaired β-receptor and calcium signaling, altered cardiomyocyte membrane physiology, elevated sympathetic nervous tone and increased activity of vasodilatory pathways predominantly through the actions of nitric oxide, carbon monoxide and endocannabinoids. The main clinical features of CCM include attenuated systolic contractility in response to physiologic or pharmacologic strain, diastolic dysfunction, electrical conductance abnormalities and chronotropic incompetence. Particularly the diastolic dysfunction with impaired ventricular relaxation and ventricular filling is a prominent feature of CCM. The underlying mechanism of diastolic dysfunction in cirrhosis is likely due to the increased myocardial wall stiffness caused by myocardial hypertrophy, fibrosis and subendothelial edema, subsequently resulting in high filling pressures of the left ventricle and atrium. Currently, no specific treatment exists for CCM. The liver transplantation is the only established effective therapy for patients with end-stage liver disease and associated cardiac failure. Liver transplantation has been shown to reverse systolic and diastolic dysfunction and the prolonged QT interval after transplantation. Here, we review the pathophysiological basis and clinical features of cirrhotic cardiomyopathy, and discuss currently available limited therapeutic options.
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Al Kury LT, Yang KHS, Thayyullathil FT, Rajesh M, Ali RM, Shuba YM, Howarth FC, Galadari S, Oz M. Effects of endogenous cannabinoid anandamide on cardiac Na⁺/Ca²⁺ exchanger. Cell Calcium 2014; 55:231-7. [PMID: 24674601 DOI: 10.1016/j.ceca.2014.02.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 02/17/2014] [Accepted: 02/23/2014] [Indexed: 10/25/2022]
Abstract
Endocannabinoid anandamide (N-arachidonoyl ethanolamide; AEA) has been shown to cause negative inotropic and antiarrhythmic effects in ventricular myocytes. In this study, using whole-cell patch clamp technique, we have investigated the effects of AEA on cardiac Na(+)/Ca(2+) exchanger (NCX1)-mediated currents. AEA suppressed NCX1 with an IC50 value of 4.7 μM. Both inward and outward components of exchanger currents were suppressed by AEA equally. AEA inhibition was mimicked by the metabolically stable analogue, methanandamide (metAEA, 10 μM) while it was not influenced by inhibition of fatty acid amide hydrolase with 1 μM URB597 incubation. The effect of AEA, was not altered in the presence of cannabinoid receptor 1 and 2 antagonists AM251 (1 μM) and AM630 (1 μM), respectively. In addition, inhibition by AEA remained unchanged after pertussis toxin (PTX, 2 μg/ml) treatment or following the inclusion of GDP-β-S (1 mM) in pipette solution. Currents mediated by NCX1 expressed in HEK-293 cells were also inhibited by 10 μM AEA a partially reversible manner. Confocal microscopy images indicated that the intensity of YFP-NCX1 expression on cell surface was not altered by AEA. Collectively, the results indicate that AEA directly inhibits the function of NCX1 in rat ventricular myocytes and in HEK-293 cells expressing NCX1.
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Affiliation(s)
- Lina T Al Kury
- Laboratory of Functional Lipidomics, Department of Pharmacology, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
| | - Keun-Hang Susan Yang
- Department of Biological Sciences, Schmid College of Science and Engineering, Chapman University, One University Drive, Orange, CA 92866, USA
| | - Faisal T Thayyullathil
- Department of Biochemistry, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
| | - Mohanraj Rajesh
- Laboratory of Functional Lipidomics, Department of Pharmacology, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
| | - Ramez M Ali
- Laboratory of Functional Lipidomics, Department of Pharmacology, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
| | - Yaroslav M Shuba
- Bogomoletz Institute of Physiology and International Center of Molecular Physiology, National Academy of Sciences of Ukraine, Kyiv 24, Ukraine
| | - Frank Christopher Howarth
- Department of Physiology, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
| | - Sehamuddin Galadari
- Department of Biochemistry, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
| | - Murat Oz
- Laboratory of Functional Lipidomics, Department of Pharmacology, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
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Sánchez-Pastor E, Andrade F, Sánchez-Pastor JM, Elizalde A, Huerta M, Virgen-Ortiz A, Trujillo X, Rodríguez-Hernández A. Cannabinoid receptor type 1 activation by arachidonylcyclopropylamide in rat aortic rings causes vasorelaxation involving calcium-activated potassium channel subunit alpha-1 and calcium channel, voltage-dependent, L type, alpha 1C subunit. Eur J Pharmacol 2014; 729:100-6. [PMID: 24561046 DOI: 10.1016/j.ejphar.2014.02.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 02/13/2014] [Accepted: 02/14/2014] [Indexed: 01/12/2023]
Abstract
Cannabinoids are key regulators of vascular tone, some of the mechanisms involved include the activation of cannabinoid receptor types 1 and 2 (CB); the transient receptor potential cation channel, subfamily V, member 1 (TRPV1); and non-(CB(1))/non-CB2 receptors. Here, we used the potent, selective CB(1) agonist arachidonylcyclopropylamide (ACPA) to elucidate the mechanism underlying vascular tone regulation. Immunohistochemistry and confocal microscopy revealed that CB(1) was expressed in smooth muscle and endothelial cells in rat aorta. We performed isometric tension recordings in aortic rings that had been pre-contracted with phenylephrine. In these conditions, ACPA caused vasorelaxation in an endothelium-independent manner. To confirm that the effect of ACPA was mediated by CB(1) receptor, we repeated the experiment after blocking these receptors with a selective antagonist, AM281. In these conditions, ACPA did not cause vasorelaxation. We explored the role of K(+) channels in the effect of ACPA by applying high-K(+) solution to induce contraction in aortic rings. In these conditions, the ACPA-induced vasorelaxation was about half that observed with phenylephrine-induced contraction. Thus, K(+) channels were involved in the ACPA effect. Furthermore, the vasorelaxation effect was similarly reduced when we specifically blocked calcium-activated potassium channel subunit alpha-1 (KCa1.1) (MaxiK; BKCa) prior to adding ACPA. Finally, ACPA-induced vasorelaxation was also diminished when we specifically blocked the calcium channel, voltage-dependent, L type, alpha 1C subunit (Ca(v)1.2). These results showed that ACPA activation of CB(1) in smooth muscle caused vasorelaxation of aortic rings through a mechanism involving the activation of K(Ca)1.1 and the inhibition of Ca(v)1.2.
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Affiliation(s)
- E Sánchez-Pastor
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio No. 965, Apdo. Postal No. 11, CP 28040 Colima, Colima, Mexico
| | - F Andrade
- Instituto Tecnológico de Colima, Avenida Tecnológico No. 1, CP 28976 Villa de Álvarez, Colima, Mexico
| | - J M Sánchez-Pastor
- Instituto Tecnológico de Colima, Avenida Tecnológico No. 1, CP 28976 Villa de Álvarez, Colima, Mexico
| | - A Elizalde
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio No. 965, Apdo. Postal No. 11, CP 28040 Colima, Colima, Mexico
| | - M Huerta
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio No. 965, Apdo. Postal No. 11, CP 28040 Colima, Colima, Mexico.
| | - A Virgen-Ortiz
- Departamento de Ciencias Químico Biológicas, División de Ciencias e Ingenierías, Unidad Regional Sur, Campus Navojoa, Universidad de Sonora, Lázaro Cárdenas No. 100, Colonia Francisco Villa, CP 85800 Navojoa, Sonora, Mexico
| | - X Trujillo
- Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio No. 965, Apdo. Postal No. 11, CP 28040 Colima, Colima, Mexico
| | - A Rodríguez-Hernández
- Facultad de Medicina, Universidad de Colima, Av. Universidad 333, Las Víboras, 28040 Colima, Colima, Mexico
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Andrag E, Curtis MJ. Feasibility of targeting ischaemia-related ventricular arrhythmias by mimicry of endogenous protection by endocannabinoids. Br J Pharmacol 2014; 169:1840-8. [PMID: 23713981 DOI: 10.1111/bph.12252] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 05/03/2013] [Accepted: 05/15/2013] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE The hypothesis that endocannabinoids protect hearts against ventricular fibrillation (VF) induced by myocardial ischaemia and reperfusion was examined, and the concept that cannabinoids may represent a new class of anti-VF drug was tested. EXPERIMENTAL APPROACH In rat isolated hearts (Langendorff perfusion), VF evoked by reperfusion after 60 min regional ischaemia is known to be exacerbated by inhibitors of endogenous protectants such as nitric oxide. This preparation was used to assay the effects of cannabinoid agonists and antagonists, and the protocols were varied to examine mechanisms. KEY RESULTS Reperfusion-induced VF was not facilitated by relatively selective CB1 (1 μM AM251) or CB2 (1 μM AM630) antagonists. VF evoked during early (30 min) acute ischaemia was also unaffected. However, AM251 significantly increased the incidence of VF and the duration of VF episodes occurring during the later stage of acute ischaemia (30-60 min). AM630 had no such effects. In a separate study, cannabinoid perfusion (anandamide or 2-arachidonoylglycerol, both 0.01-1 μM) failed to reduce VF incidence concentration-dependently during 30 min ischaemia. In all these studies, changes in ancillary variables (QT, PR, heart rate) were unrelated to changes in VF. CONCLUSIONS AND IMPLICATIONS Endocannabinoids are not endogenous anti-VF mediators during reperfusion, but may have a weak protective effect during the late stages of ischaemia, mediated via CB1 agonism. This does not suggest endocannabinoids are important endogenous protectants in these settings, or that CB1 (or CB2) receptors are useful novel targets for developing drugs for VF.
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Affiliation(s)
- Ellen Andrag
- Cardiovascular Division, King's College London, London, UK
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Al Kury LT, Voitychuk OI, Ali RM, Galadari S, Yang KHS, Howarth FC, Shuba YM, Oz M. Effects of endogenous cannabinoid anandamide on excitation-contraction coupling in rat ventricular myocytes. Cell Calcium 2014; 55:104-18. [PMID: 24472666 DOI: 10.1016/j.ceca.2013.12.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 11/25/2013] [Accepted: 12/26/2013] [Indexed: 02/08/2023]
Abstract
A role for anandamide (N-arachidonoyl ethanolamide; AEA), a major endocannabinoid, in the cardiovascular system in various pathological conditions has been reported in earlier reports. In the present study, the effects of AEA on contractility, Ca2+ signaling, and action potential (AP) characteristics were investigated in rat ventricular myocytes. Video edge detection was used to measure myocyte shortening. Intracellular Ca2+ was measured in cells loaded with the fluorescent indicator fura-2 AM. AEA (1 μM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca2+ transients. However, the amplitudes of caffeine-evoked Ca2+ transients and the rate of recovery of electrically evoked Ca2+ transients following caffeine application were not altered. Biochemical studies in sarcoplasmic reticulum (SR) vesicles from rat ventricles indicated that AEA affected Ca2+ -uptake and Ca2+ -ATPase activity in a biphasic manner. [3H]-ryanodine binding and passive Ca2+ release from SR vesicles were not altered by 10 μM AEA. Whole-cell patch-clamp technique was employed to investigate the effect of AEA on the characteristics of APs. AEA (1 μM) significantly decreased the duration of AP. The effect of AEA on myocyte shortening and AP characteristics was not altered in the presence of pertussis toxin (PTX, 2 μg/ml for 4 h), AM251 and SR141716 (cannabinoid type 1 receptor antagonists; 0.3 μM) or AM630 and SR 144528 (cannabinoid type 2 receptor antagonists; 0.3 μM). The results suggest that AEA depresses ventricular myocyte contractility by decreasing the action potential duration (APD) in a manner independent of CB1 and CB2 receptors.
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MESH Headings
- Action Potentials/drug effects
- Animals
- Arachidonic Acids/pharmacology
- Caffeine/pharmacology
- Calcium/analysis
- Calcium/metabolism
- Calcium Signaling/drug effects
- Endocannabinoids/pharmacology
- Fura-2/chemistry
- Heart Ventricles/cytology
- In Vitro Techniques
- Indoles/pharmacology
- Male
- Myocardial Contraction/drug effects
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/physiology
- Pertussis Toxin/toxicity
- Piperidines/pharmacology
- Polyunsaturated Alkamides/pharmacology
- Pyrazoles/pharmacology
- Rats
- Rats, Wistar
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/antagonists & inhibitors
- Receptor, Cannabinoid, CB2/metabolism
- Sarcoplasmic Reticulum/metabolism
- Transport Vesicles/drug effects
- Transport Vesicles/metabolism
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Affiliation(s)
- Lina T Al Kury
- Laboratory of Functional Lipidomics, Department of Pharmacology, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Oleg I Voitychuk
- Bogomoletz Institute of Physiology and International Center of Molecular Physiology, National Academy of Sciences of Ukraine, Kyiv-24, Ukraine
| | - Ramiz M Ali
- Laboratory of Functional Lipidomics, Department of Pharmacology, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Sehamuddin Galadari
- Department of Biochemistry, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Keun-Hang Susan Yang
- Department of Biological Sciences, Schmid College of Science and Engineering, Chapman University, One University Drive, Orange, CA 92866, USA
| | - Frank Christopher Howarth
- Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Yaroslav M Shuba
- Bogomoletz Institute of Physiology and International Center of Molecular Physiology, National Academy of Sciences of Ukraine, Kyiv-24, Ukraine
| | - Murat Oz
- Laboratory of Functional Lipidomics, Department of Pharmacology, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi, United Arab Emirates.
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19
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Li Q, Cui N, Du Y, Ma H, Zhang Y. Anandamide reduces intracellular Ca2+ concentration through suppression of Na+/Ca2+ exchanger current in rat cardiac myocytes. PLoS One 2013; 8:e63386. [PMID: 23667607 PMCID: PMC3646750 DOI: 10.1371/journal.pone.0063386] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Accepted: 04/03/2013] [Indexed: 11/22/2022] Open
Abstract
Purpose Anandamide, one of the endocannabinoids, has been reported to exhibit cardioprotective properties, particularly in its ability to limit the damage produced by ischemia reperfusion injury. However, the mechanisms underlying the effect are not well known. This study is to investigate whether anandamide alter Na+/Ca2+ exchanger and the intracellular free Ca2+ concentration ([Ca2+]i). Methods Na+/Ca2+ exchanger current (INCX) was recorded and analysed by using whole-cell patch-clamp technique and [Ca2+]i was measured by loading myocytes with the fluorescent Ca2+ indicator Fura-2/AM. Results We found that INCX was enhanced significantly after perfusion with simulated ischemic external solution; [Ca2+]i was also significantly increased by simulated ischemic solution. The reversal potential of INCX was shifted to negative potentials in simulated ischemic external solution. Anandamide (1–100 nM) failed to affect INCX and [Ca2+]i in normal solution. However, anandamide (1–100 nM) suppressed the increase in INCX in simulated ischemic external solution concentration-dependently and normalized INCX reversal potential. Furthermore, anandamide (100 nM) significantly attenuated the increase in [Ca2+]i in simulated ischemic solution. Blocking CB1 receptors with the specific antagonist AM251 (500 nM) failed to affect the effects of anandamide on INCX and [Ca2+]i in simulated ischemic solution. CB2 receptor antagonist AM630 (100 nM) eliminated the effects of anandamide on INCX and [Ca2+]i in simulated ischemic solution, and CB2 receptor agonist JWH133 (100 nM) simulated the effects of anandamide that suppressed the increase in INCX and [Ca2+]i in simulated ischemic solution. In addition, pretreatment with the Gi/o-specific inhibitor pertussis toxin (PTX, 500 ng/ml) eliminated the effects of anandamide and JWH133 on INCX in simulated ischemic solution. Conclusions Collectively, these findings suggest that anandamide suppresses calcium overload through inhibition of INCX during perfusion with simulated ischemic solution; the effects may be mediated by CB2 receptor via PTX-sensitive Gi/o proteins. This mechanism is importantly involved in the anti-ischemia injury caused by endocannabinoids.
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Affiliation(s)
- Qian Li
- Department of Physiology, Hebei Medical University, Shijiazhuang, China
| | - Na Cui
- Department of Reproduction, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yuanjie Du
- Department of Reproduction, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Huijie Ma
- Department of Physiology, Hebei Medical University, Shijiazhuang, China
| | - Yi Zhang
- Department of Physiology, Hebei Medical University, Shijiazhuang, China
- * E-mail:
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20
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Slavic S, Lauer D, Sommerfeld M, Kemnitz UR, Grzesiak A, Trappiel M, Thöne-Reineke C, Baulmann J, Paulis L, Kappert K, Kintscher U, Unger T, Kaschina E. Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome. J Mol Med (Berl) 2013; 91:811-23. [DOI: 10.1007/s00109-013-1034-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 03/13/2013] [Accepted: 03/19/2013] [Indexed: 12/27/2022]
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Stein PD, Matta F, Goldman J. Obesity and pulmonary embolism: The mounting evidence of risk and the mortality paradox. Thromb Res 2011; 128:518-23. [DOI: 10.1016/j.thromres.2011.10.019] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Revised: 10/13/2011] [Accepted: 10/19/2011] [Indexed: 11/29/2022]
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22
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Cunha P, Romão AM, Mascarenhas-Melo F, Teixeira HM, Reis F. Endocannabinoid system in cardiovascular disorders - new pharmacotherapeutic opportunities. J Pharm Bioallied Sci 2011; 3:350-60. [PMID: 21966155 PMCID: PMC3178941 DOI: 10.4103/0975-7406.84435] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Revised: 05/01/2011] [Accepted: 05/20/2011] [Indexed: 01/28/2023] Open
Abstract
The long history of Cannabis sativa had its development stimulated and oriented for medicine after the discovery and chemical characterization of its main active ingredient, the 9-tetrahydrocannabinol (9-THC). Consequently, a binding site for 9-THC was identified in rat brains and the first cannabinoid receptor (CB1) was cloned, followed by the CB2 and by the discover of two endogenous agonists: anandamide and 2-arachidonoyl glycerol. Cannabinoid receptors, endocannabinoids and the enzymes that catalyze its synthesis and degradation constitute the endocannabinoid system (ECS), which plays an important role in the cardiovascular system. In vivo experiments with rats have demonstrated the action of anandamide and 2-AG on the development of atherosclerotic plaque, as well as an effect on heart rate, blood pressure, vasoactivity and energy metabolism (action in dyslipidemia and obesity). Recent studies with an antagonist of CB1 receptors showed that the modulation of ECS can play an important role in reducing cardiovascular risk in obese and dyslipidemic patients. Similarly, studies in rats have demonstrated the action of CB2 receptors in adhesion, migration, proliferation and function of immune cells involved in the atherosclerotic plaque formation process. The evidence so far gathered shows that the modulation of ECS (as agonism or antagonism of its receptors) is an enormous potential field for research and intervention in multiple areas of human pathophysiology. The development of selective drugs for the CB1 and CB2 receptors may open a door to new therapeutic regimens.This review article aims to address the key findings and evidences on the modulation of ECS, in order to prospect future forms of therapeutic intervention at the cardiovascular level. A recent, emerging, controversial and of undoubted scientific interest subject, which states as a potential therapeutic target to reach in the 21st century.
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Affiliation(s)
- Pedro Cunha
- Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Medicine Faculty, University of Coimbra, Portugal
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Abstract
Liver cirrhosis is associated with a wide range of cardiovascular abnormalities including hyperdynamic circulation, cirrhotic cardiomyopathy, and pulmonary vascular abnormalities. The pathogenic mechanisms of these cardiovascular changes are multifactorial and include neurohumoral and vascular dysregulations. Accumulating evidence suggests that cirrhosis-related cardiovascular abnormalities play a major role in the pathogenesis of multiple life-threatening complications including hepatorenal syndrome, ascites, spontaneous bacterial peritonitis, gastroesophageal varices, and hepatopulmonary syndrome. Treatment targeting the circulatory dysfunction in these patients may improve the short-term prognosis while awaiting liver transplantation. Careful fluid management in the immediate post-transplant period is extremely important to avoid cardiac-related complications. Liver transplantation results in correction of portal hypertension and reversal of all the pathophysiological mechanisms that lead to the cardiovascular abnormalities, resulting in restoration of a normal circulation. The following is a review of the pathogenesis and clinical implications of the cardiovascular changes in cirrhosis.
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Affiliation(s)
- Waleed K. Al-Hamoudi
- Gastroenterology and Hepatology Unit, Department of Medicine, King Saud University, Riyadh, Saudi Arabia,Address for correspondence: Dr. Waleed Al-Hamoudi, Gastroenterology and Hepatology Unit (59), Department of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia. E-mail:
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24
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Substantially altered expression pattern of cannabinoid receptor 2 and activated endocannabinoid system in patients with severe heart failure. J Mol Cell Cardiol 2010; 48:1187-93. [DOI: 10.1016/j.yjmcc.2009.10.025] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2009] [Revised: 10/27/2009] [Accepted: 10/27/2009] [Indexed: 12/31/2022]
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25
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Gorzalka BB, Hill MN, Chang SCH. Male-female differences in the effects of cannabinoids on sexual behavior and gonadal hormone function. Horm Behav 2010; 58:91-9. [PMID: 19733173 DOI: 10.1016/j.yhbeh.2009.08.009] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2009] [Revised: 08/18/2009] [Accepted: 08/26/2009] [Indexed: 11/19/2022]
Abstract
The putative role of the endocannabinoid system and the effects of cannabis use in male and female sexual functioning are summarized. The influence of cannabis intake on sexual behavior and arousability appear to be dose-dependent in both men and women, although women are far more consistent in reporting facilitatory effects. Furthermore, evidence from nonhuman species indicate somewhat more beneficial than debilitating effects of cannabinoids on female sexual proceptivity and receptivity while suggesting predominantly detrimental effects on male sexual motivation and erectile functioning. Data from human and nonhuman species converge on the ephemeral nature of THC-induced testosterone decline. However, it is clear that cannabinoid-induced inhibition of male sexual behavior is independent of concurrent declines in testosterone levels. Investigations also reveal a suppression of gonadotropin release by cannabinoids across various species. Historical milestones and promising future directions in the area of cannabinoid and sexuality research are also outlined in this review.
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Affiliation(s)
- Boris B Gorzalka
- Department of Psychology, University of British Columbia, Vancouver, Canada, BC V6T 1Z4.
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26
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Maeda N, Osanai T, Kushibiki M, Fujiwara T, Tamura Y, Oowada S, Higuma T, Sasaki S, Yokoyama J, Yoshimachi F, Matsunaga T, Hanada H, Okumura K. Increased serum anandamide level at ruptured plaque site in patients with acute myocardial infarction. Fundam Clin Pharmacol 2009; 23:351-7. [PMID: 19527302 DOI: 10.1111/j.1472-8206.2009.00679.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Inflammation caused by activated macrophages and T lymphocytes may trigger plaque rapture in acute coronary syndrome (ACS). Anandamide and 2-arachidonylglycerol (2-AG) are macrophage-derived signal lipids and may be involved in the pathogenesis of ACS, but no clinical relevant data have been reported. In 43 acute myocardial infarction (AMI) patients (66 +/- 2 years), blood samples were obtained from the aortic root and the infarct-related coronary artery (IRA) using a PercuSurge system during primary percutaneous coronary intervention (PCI). In six patients with stable effort angina (SEA) (56 +/- 6 years), blood samples were obtained from the site of stenosis during elective PCI. In 25 of the 43 AMI patients, anandamide was detected in the serum. Serum anandamide level was 35 +/- 20 pmol/mL in the aorta and was significantly increased to 401 +/- 134 pmol/mL in the IRA (P < 0.01). 2-AG was undetectable in most of the patients. In patients with SEA, neither anandamide nor 2-AG was detected in the serum at the plaque site. In AMI patients with anandamide detected, left ventricular ejection fraction at 2 weeks after PCI was increased by 3.7 +/- 2.1% compared with that at the acute phase, while it was decreased by 3.0 +/- 1.8% in those without anandamide detected (P < 0.05). The serum anandamide level at the culprit lesion was elevated compared with the systemic level in a significant number of AMI patients, indicating the synthesis of anandamide at the IRA. Anandamide was suggested to be derived from ruptured plaque and may exert beneficial effects in humans.
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Affiliation(s)
- Naotaka Maeda
- Department of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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Godlewski G, Offertáler L, Wagner JA, Kunos G. Receptors for acylethanolamides-GPR55 and GPR119. Prostaglandins Other Lipid Mediat 2009; 89:105-11. [PMID: 19615459 DOI: 10.1016/j.prostaglandins.2009.07.001] [Citation(s) in RCA: 170] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Accepted: 07/07/2009] [Indexed: 02/07/2023]
Abstract
Acylethanolamides are lipid substances widely distributed in the body, generated from a membrane phospholipid precursor, N-acylphosphatidylethanolamine (NAPE). The recent identification of arachidonoyl ethanolamide (anandamide or AEA) as an endogenous cannabinoid ligand has focused attention on acylethanolamides, which has further increased with the subsequent identification of related additional acylethanolamides with signaling function, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Most of the biological functions of anandamide are mediated by the two G protein-coupled cannabinoid receptors identified to date, CB(1) and CB(2), with the transient receptor potential vanilloid-1 receptor being an additional potential target. There has been increasing pharmacological evidence for the existence of additional cannabinoid receptors, with the orphan G protein-coupled receptor GPR55 being the most actively scrutinized, and is one of the subjects of this review. The other receptor reviewed here is GPR119, which can recognize OEA and PEA. These two acylethanolamides, although structurally related to anandamide, do not interact with classical cannabinoid receptors. Instead, they have high affinity for the nuclear receptor PPARalpha, which is believed to mediate many of their biological effects.
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Affiliation(s)
- Grzegorz Godlewski
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
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Abstract
Endocannabinoids, such as anandamide and 2-arachidonoylglycerol, are synthesized from membrane phospholipids in the heart and other cardiovascular tissues. They activate cannabinoid CB1 and CB2 receptors, transient receptor potential V1 (TRPV1), peroxisome proliferator-activated receptors, and perhaps a novel vascular G-protein-coupled receptor. Inactivation is by cellular uptake and fatty acid amide hydrolase. Endocannabinoids relax coronary and other arteries and decrease cardiac work but seem not to be involved in tonic regulation of cardiovascular function. They act as a stress response system, which is activated, for example, in myocardial infarction and circulatory shock. Endocannabinoids are largely protective; they decrease tissue damage and arrhythmia in myocardial infarction and may reduce progression of atherosclerosis (CB2 receptor stimulation inhibits lesion progression), and fatty acid amide hydrolase knockout mice (which have enhanced endocannabinoid levels) show decreased cardiac dysfunction with age compared with wild types. However, endocannabinoids may mediate doxorubicin-induced cardiac dysfunction. Their signaling pathways are not fully elucidated but they can lead to changed expression of a variety of genes, including those involved in inflammatory responses. There is potential for therapeutic targeting of endocannabinoids and their receptors, but their apparent involvement in both protective and deleterious actions on the heart means that careful risk assessment is needed before any treatment can be introduced.
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Affiliation(s)
- C Robin Hiley
- Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.
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Currie S, Rainbow RD, Ewart MA, Kitson S, Pliego EH, Kane KA, McCarron JG. IP(3)R-mediated Ca(2+) release is modulated by anandamide in isolated cardiac nuclei. J Mol Cell Cardiol 2008; 45:804-11. [PMID: 18692061 DOI: 10.1016/j.yjmcc.2008.07.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2008] [Accepted: 07/03/2008] [Indexed: 12/29/2022]
Abstract
Cannabinoids (CBs) are known to alter coronary vascular tone and cardiac performance. They also exhibit cardioprotective properties, particularly in their ability to limit the damage produced by ischaemia reperfusion injury. The mechanisms underlying these effects are unknown. Here we investigate the intracellular localisation of CB receptors in the heart and examine whether they may modulate localised nuclear Ca(2+) release. In isolated cardiac nuclear preparations, expression of both the inositol 1,4,5-trisphosphate receptor type 2 (IP(3)R) and CB receptors (CB(1)R and CB(2)R) was demonstrated by immunoblotting. Both receptors localised to the nucleus and purity of the nuclear preparations was confirmed by co-expression of the nuclear marker protein nucleolin but absence of cytoplasmic actin. To measure effects of IP(3)R and CBR agonists on nuclear Ca(2+) release, isolated nuclei were loaded with Fluo5N-AM. This dye accumulates in the nuclear envelope. Isolated nuclei responded to IP(3) with rapid and transient Ca(2+) release from the nuclear envelope. Anandamide inhibited this IP(3)-mediated release. Preincubation of nuclear preparations with either the CB(1)R antagonist (AM251) or the CB(2)R antagonist (AM630) reversed anandamide-mediated inhibition to 80% and 60% of control values respectively. When nuclei were pre-treated with both CBR antagonists, anandamide-mediated inhibition of IP(3)-induced Ca(2+) release was completely reversed. These results are the first to demonstrate the existence of cardiac nuclear CB receptors. They are also the first to show that anandamide can negatively modulate IP(3)-mediated nuclear Ca(2+) release. As such, this provides evidence for a novel key mechanism underlying the action of CBs and CBRs in the heart.
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MESH Headings
- Animals
- Arachidonic Acids/pharmacology
- Calcium/metabolism
- Cannabinoid Receptor Modulators/pharmacology
- Cardiotonic Agents/pharmacology
- Cell Nucleus/metabolism
- Endocannabinoids
- Guinea Pigs
- Inositol 1,4,5-Trisphosphate Receptors/agonists
- Inositol 1,4,5-Trisphosphate Receptors/metabolism
- Male
- Myocardium/metabolism
- Phosphoproteins
- Polyunsaturated Alkamides/pharmacology
- RNA-Binding Proteins
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/metabolism
- Nucleolin
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Affiliation(s)
- Susan Currie
- Division of Physiology and Pharmacology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
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30
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Moezi L, Gaskari SA, Lee SS. Endocannabinoids and liver disease. V. endocannabinoids as mediators of vascular and cardiac abnormalities in cirrhosis. Am J Physiol Gastrointest Liver Physiol 2008; 295:G649-53. [PMID: 18703639 DOI: 10.1152/ajpgi.90352.2008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cirrhosis is associated with marked cardiovascular disturbances. These include hyperdynamic circulation characterized by reduced peripheral vascular resistance and mean arterial pressure and increased cardiac output. Despite the baseline increase in cardiac output, ventricular responsiveness to stimuli is blunted. A number of cellular signaling pathways have been shown to contribute to these abnormalities, including central nervous system cardiovascular dysregulation and humoral factors such as nitric oxide. Endogenous and exogenous cannabinoids have significant cardiovascular effects. Recent evidence suggests that increased activity of the endocannabinoid system at multiple levels contributes to development of both cardiac and vascular changes in cirrhosis. This brief review surveys recent in vivo and in vitro findings in an attempt to highlight the areas of agreement and areas of controversy in the field. The endocannabinoid system affects key cardiovascular regulators, including the autonomic nervous system, cardiac muscle, and vascular smooth muscle. The interplay among these modes of action further complicates interpretation of the in vivo findings. The broad range of cardiovascular actions of endocannabinoids provides ample opportunities for pharmacological manipulation. At the same time, it increases the possibility of undesirable side effects, which need to be carefully evaluated in long-term studies.
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Affiliation(s)
- Leila Moezi
- Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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31
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Lasukova OV, Maslov LN, Ermakov SY, Crawford D, Barth F, Krylatov AV, Hanus LO. Role of cannabinoid receptors in regulation of cardiac tolerance to ischemia and reperfusion. BIOL BULL+ 2008. [DOI: 10.1134/s1062359008040134] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Abstract
The effects of exogenous and endogenous cannabinoids on the cardiovascular system have been the focus of extensive research. The direct and indirect effects of cannabinoids on heart and blood vessels depend upon experimental conditions, animal species, and, in humans, clinical background. Cannabinoids decrease blood pressure in hypertensive rodents primarily because of decrease cardiac contractility, leading researchers to postulate a role in the treatment of hypertension and cardiac hypertrophy. Rimonabant, the CB(1) receptor blocker in clinical use in many countries, induced a marked and sustained increase in cardiac contractility and blood pressure in hypertensive rats but, on the contrary, contributed to decrease blood pressure in weight-loss clinical trials especially in obese patients with hypertension. In the midst of the obesity pandemic and from the cardiometabolic point of view, the overactivation of the endocannabinoid system present in intra-abdominal obesity appears to be very harmful. Moreover, novel human findings suggest a relationship between CB(1)-mediated overactive endocannabinoid system and nephrovascular damage. Overall, it appears that CB(1) blockade in obese patients behaves as a 'multiplier' of the many beneficial effects of body weight loss induced by a hypocaloric diet and increased physical activity (the 'lifestyle changes' that are so difficult to start and maintain). Thus, the concept - based mostly on experimental results using in vitro or animal models - that CB(1)-mediated endocannabinoid effects are beneficial for the cardiovascular system should be revised at least in obese patients. The results of long-term clinical trials such as the STRADIVARIUS and the CRESCENDO trials will tell whether the improvement in the cardiometabolic risk profile induced by Rimonabant translates into vascular changes, reducing the risk of myocardial infarction, stroke and cardiovascular death in patients with abdominal obesity. Time (and much more work) will tell us much more about cannabinoids and the human heart.
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Affiliation(s)
- R Sarzani
- Department of Internal Medicine, University of Ancona - Politecnica delle Marche, Hypertension Excellence Centre - ESH, University Hospital Ospedali Riuniti, Ancona, Italy.
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33
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Hajrasouliha AR, Tavakoli S, Ghasemi M, Jabehdar-Maralani P, Sadeghipour H, Ebrahimi F, Dehpour AR. Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. Eur J Pharmacol 2008; 579:246-52. [DOI: 10.1016/j.ejphar.2007.09.034] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2007] [Revised: 09/26/2007] [Accepted: 09/27/2007] [Indexed: 11/28/2022]
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McDougall JJ, Yu V, Thomson J. In vivo effects of CB2 receptor-selective cannabinoids on the vasculature of normal and arthritic rat knee joints. Br J Pharmacol 2007; 153:358-66. [PMID: 17982474 DOI: 10.1038/sj.bjp.0707565] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND PURPOSE Cannabinoids (CBs) are known to be vasoactive and to regulate tissue inflammation. The present study examined the in vivo vasomotor effects of the CB2 receptor agonists JWH015 and JWH133 in rat knee joints. The effect of acute and chronic joint inflammation on CB2 receptor-mediated responses was also tested. EXPERIMENTAL APPROACH Blood flow was assessed in rat knee joints by laser Doppler imaging both before and following topical administration of CB2 receptor agonists. Vasoactivity was measured in normal, acute kaolin/carrageenan inflamed and Freund's complete adjuvant chronically inflamed knees. KEY RESULTS In normal animals, JWH015 and JWH133 caused a concentration-dependent increase in synovial blood flow which in the case of JWH133 was blocked by the selective CB2 receptor antagonist AM630 as well as the transient receptor potential vanilloid-1 (TRPV1) antagonist SB366791. The vasodilator effect of JWH133 was significantly attenuated in both acute and chronically inflamed knees. Given alone, AM630 had no effect on joint blood flow. CONCLUSION AND IMPLICATIONS In normal joints, the cannabinomimetic JWH133 causes hyperaemia via a CB2 and TRPV1 receptor mechanism. During acute and chronic inflammation, however, this vasodilatatory response is significantly attenuated.
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Affiliation(s)
- J J McDougall
- Department of Physiology & Biophysics, University of Calgary, Calgary, Alberta, Canada.
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35
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Wheal AJ, Bennett T, Randall MD, Gardiner SM. Cardiovascular effects of cannabinoids in conscious spontaneously hypertensive rats. Br J Pharmacol 2007; 152:717-24. [PMID: 17700721 PMCID: PMC2190006 DOI: 10.1038/sj.bjp.0707410] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2007] [Accepted: 07/18/2007] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND PURPOSE In anaesthetized spontaneously hypertensive rats (SHR), there is evidence for up-regulation of cannabinoid (CB1) receptors: antagonism of CB1 receptors causes a rise in blood pressure, and administration of the endocannabinoid, anandamide, or inhibition of anandamide degradation causes hypotension. These findings have led to the suggestion that the endocannabinoid system may be a therapeutic target in hypertension. However, since the cardiovascular responses to cannabinoids are substantially influenced by anaesthesia, the purpose of this study was to assess regional haemodynamic responses to cannabinoid receptor stimulation and inhibition in conscious SHR. EXPERIMENTAL APPROACH Cardiovascular responses to i.v. administration of anandamide, the cannabinoid receptor agonist, WIN 55212-2, and the CB(1) receptor antagonist, AM 251, were measured in male SHR, Wistar Kyoto rats and outbred Wistar rats, chronically instrumented for recording renal, mesenteric and hindquarters haemodynamics in the conscious, freely-moving state. KEY RESULTS Hypotensive responses to anandamide and WIN 55212-2 only occurred in SHR, but these were relatively modest and not associated with CB1 receptor-mediated vasodilatation. In SHR only, anandamide caused bradycardia, which was inhibited by AM 251. Furthermore, a pressor response to CB1 receptor antagonism occurred only in SHR, but was not associated with vasoconstriction. Moreover, there was some evidence for CB1 receptor-mediated vasoconstrictor actions of anandamide in SHR, which was not seen in the normotensive strains. CONCLUSIONS AND IMPLICATIONS The results are consistent with activation of CB1 receptors in SHR by endogenous ligands exerting an antihypertensive effect, but the findings do not indicate enhanced CB1 receptor-mediated vasodilator mechanisms in SHR.
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Affiliation(s)
- A J Wheal
- Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre Nottingham NG7 2UH, UK
| | - T Bennett
- Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre Nottingham NG7 2UH, UK
| | - M D Randall
- Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre Nottingham NG7 2UH, UK
| | - S M Gardiner
- Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre Nottingham NG7 2UH, UK
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Yang YY, Lin HC, Huang YT, Lee TY, Hou MC, Wang YW, Lee FY, Lee SD. Role of Ca2+-dependent potassium channels in in vitro anandamide-mediated mesenteric vasorelaxation in rats with biliary cirrhosis. Liver Int 2007; 27:1045-55. [PMID: 17845532 DOI: 10.1111/j.1478-3231.2007.01551.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIM Anandamide can activate potassium (K(+)) channels to induce an endothelium-dependent vasorelaxation in normal rat mesenteric arteries. Cannabinoids contribute partly to the splanchnic vasodilation in cirrhosis. This study investigated the roles of vascular K(+) channels in anandamide-induced mesenteric vasorelaxation in isolated rat cirrhotic vessels. METHODS The effects of the pretreatment of AM251, a specific CB(1) receptor antagonist, were assessed on the vascular reactivity to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh) and sodium nitroprusside (SNP). Additionally, cannabinoid (CB(1) and CB(2)) receptors' protein expression and the effects of different K(+) channel blockers on vascular reactivity to anandamide were also studied. RESULTS Cirrhotic mesenteric arteries showed an overexpression of CB(1) receptor associated with hyporeactivity to PE and KCl, and hyper-response to ACh, SNP and anandamide. Pretreatment with AM251 significantly improved the hyporeactivity to KCl and ameliorated the hyper-response to ACh in cirrhotic vessels. Increased relaxation response to anandamide was suppressed by combinations of vascular Ca(2+)-dependent K(+) channel blockers (including apamin+charybdotoxin+iberiotoxin or apamin+TRAM-34+iberiotoxin) (TRAM-34, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole). CONCLUSIONS In cirrhotic mesenteric arteries, vascular CB(1) receptor and anandamide contribute to the in vitro hyporeactivity to KCl. In addition, hyper-response to ACh may probably act through the modulation of vascular Ca(2+)-dependent K(+) channels.
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MESH Headings
- Acetylcholine/pharmacology
- Animals
- Apamin/pharmacology
- Arachidonic Acids/metabolism
- Cannabinoid Receptor Modulators/metabolism
- Charybdotoxin/pharmacology
- Common Bile Duct/surgery
- Dose-Response Relationship, Drug
- Endocannabinoids
- Glyburide/pharmacology
- Ligation
- Liver Cirrhosis, Biliary/metabolism
- Liver Cirrhosis, Biliary/physiopathology
- Liver Cirrhosis, Experimental/metabolism
- Liver Cirrhosis, Experimental/physiopathology
- Male
- Mesenteric Artery, Superior/drug effects
- Mesenteric Artery, Superior/metabolism
- Mesenteric Artery, Superior/physiopathology
- Nitroprusside/pharmacology
- Peptides/pharmacology
- Phenylephrine/pharmacology
- Piperidines/pharmacology
- Polyunsaturated Alkamides/metabolism
- Potassium/metabolism
- Potassium Channel Blockers/pharmacology
- Potassium Channels, Calcium-Activated/antagonists & inhibitors
- Potassium Channels, Calcium-Activated/metabolism
- Potassium Chloride/pharmacology
- Pyrazoles/pharmacology
- Rats
- Rats, Sprague-Dawley
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB2/metabolism
- Vasoconstrictor Agents/pharmacology
- Vasodilation/drug effects
- Vasodilator Agents/pharmacology
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Affiliation(s)
- Ying-Ying Yang
- Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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37
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Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts. Life Sci 2007; 81:1373-80. [DOI: 10.1016/j.lfs.2007.08.042] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2007] [Revised: 08/16/2007] [Accepted: 08/31/2007] [Indexed: 11/18/2022]
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38
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Abstract
CB1 and CB2 receptors mediate most responses to cannabinoids but not some of the cardiovascular actions of endocannabinoids such as anandamide and virodhamine, or those of some synthetic agents, like abnormal cannabidiol (abn-cbd). These agents induce vasorelaxation which is antagonised by rimonabant but only at high concentrations relative to those required to block CB1 receptors. Vasorelaxation to anandamide is sensitive to Pertussis toxin (though that to abn-cbd is not), and so is thought to be mediated by a G protein-coupled receptor through Gi/o. An orphan receptor, GPR55, apparently a cannabinoid receptor, is activated by abn-cbd, but is not the receptor mediating vasorelaxation to this agent, as the response persists in vessels from GPR55 knockout mice. However, the activity of anandamide in GPR55 knockout mice is not yet reported and so the role of GPR55 as a cannabinoid receptor mediating vascular responses has yet to be finalised.
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MESH Headings
- Animals
- Cannabinoids/pharmacology
- Humans
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/physiology
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB2/agonists
- Receptors, Cannabinoid
- Receptors, G-Protein-Coupled/agonists
- Receptors, G-Protein-Coupled/metabolism
- Vasodilation/drug effects
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Affiliation(s)
- C R Hiley
- Department of Pharmacology, University of Cambridge, Cambridge, UK.
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39
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Herradón E, Martín MI, López-Miranda V. Characterization of the vasorelaxant mechanisms of the endocannabinoid anandamide in rat aorta. Br J Pharmacol 2007; 152:699-708. [PMID: 17704831 PMCID: PMC2190007 DOI: 10.1038/sj.bjp.0707404] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND AND PURPOSE Studies in isolated preparations of vascular tissue (mainly resistance vessels) provide evidence that anandamide exerts vasorelaxation. The aim of the present work was to further characterize the mechanisms involved in the vascular response induced by anandamide in a conduit vessel, rat aorta. EXPERIMENTAL APPROACH Isometric tension changes in response to a cumulative concentration-response curve of anandamide (1 nM-100 micro M) were recorded in aortic rings from male Wistar rats. The involvement of a number of factors in this relaxation was investigated including endothelium-derived vasorelaxant products, cannabinoid and vanilloid receptors (transient potential vanilloid receptor-1 (TRPV1)), release of calcitonin gene-related peptide (CGRP), anandamide metabolism and the membrane transporter for anandamide. KEY RESULTS Anandamide caused a significant concentration-dependent vasorelaxation in rat aorta. This vasorelaxation was significantly inhibited by Pertussis toxin, by a non-CB1/non-CB2 cannabinoid receptor antagonist, by endothelial denudation, by inhibition of nitric oxide synthesis or inhibition of prostanoid synthesis via cyclooxygenase-2 (COX-2), by blockade of prostaglandin receptors EP4 and by a fatty acid amino hydrolase inhibitor. Antagonists for CB1, CB2, TRPV1 or CGRP receptors, an inhibitor of the release of endothelium-derived hyperpolarizing factor, and an inhibitor of anandamide transport did not modify the vascular response to anandamide. CONCLUSIONS AND IMPLICATIONS Our results demonstrate, for the first time, the involvement of the non-CB1/non-CB2 cannabinoid receptor and an anandamide-arachidonic acid-COX-2 derived metabolite (which acts on EP4 receptors) in the endothelial vasorelaxation caused by anandamide in rat aorta.
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MESH Headings
- Animals
- Aorta, Abdominal/drug effects
- Aorta, Abdominal/physiology
- Apamin/pharmacology
- Arachidonic Acids/pharmacology
- Benzamides/pharmacology
- Calcitonin Gene-Related Peptide/pharmacology
- Camphanes/pharmacology
- Cannabinoid Receptor Modulators/pharmacology
- Capsaicin/analogs & derivatives
- Capsaicin/pharmacology
- Carbamates/pharmacology
- Charybdotoxin/pharmacology
- Dose-Response Relationship, Drug
- Endocannabinoids
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/physiology
- In Vitro Techniques
- Indomethacin/pharmacology
- Isoindoles/pharmacology
- Male
- NG-Nitroarginine Methyl Ester/pharmacology
- Nitric Oxide/antagonists & inhibitors
- Nitric Oxide/biosynthesis
- Peptide Fragments/pharmacology
- Piperidines/pharmacology
- Polyunsaturated Alkamides/pharmacology
- Pyrazoles/administration & dosage
- Pyrazoles/pharmacology
- Rats
- Rats, Wistar
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB2/antagonists & inhibitors
- Rimonabant
- Sulfonamides/pharmacology
- Vasodilation/drug effects
- Vasodilation/physiology
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Affiliation(s)
- E Herradón
- Área de Farmacología, Dpto. Ciencias de la Salud III, Facultad Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón Madrid, Spain
| | - M I Martín
- Área de Farmacología, Dpto. Ciencias de la Salud III, Facultad Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón Madrid, Spain
| | - V López-Miranda
- Área de Farmacología, Dpto. Ciencias de la Salud III, Facultad Ciencias de la Salud, Universidad Rey Juan Carlos, Alcorcón Madrid, Spain
- Author for correspondence:
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40
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Gehani NC, Nalwalk JW, Razdan RK, Martin BR, Sun X, Wentland M, Abood ME, Hough LB. Significance of cannabinoid CB1 receptors in improgan antinociception. THE JOURNAL OF PAIN 2007; 8:850-60. [PMID: 17644043 PMCID: PMC2185743 DOI: 10.1016/j.jpain.2007.05.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2006] [Revised: 04/24/2007] [Accepted: 05/25/2007] [Indexed: 11/23/2022]
Abstract
UNLABELLED Improgan is a congener of the H(2) antagonist cimetidine, which produces potent antinociception. Because a) the mechanism of action of improgan remains unknown and b) this drug may indirectly activate cannabinoid CB(1) receptors, the effects of the CB(1) antagonist/inverse agonist rimonabant (SR141716A) and 3 congeners with varying CB(1) potencies were studied on improgan antinociception after intracerebroventricular (icv) dosing in rats. Consistent with blockade of brain CB(1) receptors, rimonabant (K(d) = 0.23 nM), and O-1691 (K(d) = 0.22 nM) inhibited improgan antinociception by 48% and 70% after icv doses of 43 nmol and 25 nmol, respectively. However, 2 other derivatives with much lower CB(1) affinity (O-1876, K(d) = 139 nM and O-848, K(d) = 352 nM) unexpectedly blocked improgan antinociception by 65% and 50% after icv doses of 300 nmol and 30 nmol, respectively. These derivatives have 600-fold to 1500-fold lower CB(1) potencies than that of rimonabant, yet they retained improgan antagonist activity in vivo. In vitro dose-response curves with (35)S-GTPgammaS on CB(1) receptor-containing membranes confirmed the approximate relative potency of the derivatives at the CB(1) receptor. Although antagonism of improgan antinociception by rimonabant has previously implicated a mechanistic role for the CB(1) receptor, current findings with rimonabant congeners suggest that receptors other than, or in addition to CB(1) may participate in the pain-relieving mechanisms activated by this drug. The use of congeners such as O-848, which lack relevant CB(1)-blocking properties, will help to identify these cannabinoid-like, non-CB(1) mechanisms. PERSPECTIVE This article describes new pharmacological characteristics of improgan, a pain-relieving drug that acts by an unknown mechanism. Improgan may use a marijuana-like (cannabinoid) pain-relieving mechanism, but it is shown presently that the principal cannabinoid receptor in the brain (CB(1)) is not solely responsible for improgan analgesia.
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MESH Headings
- Analgesics/administration & dosage
- Analysis of Variance
- Animals
- Cimetidine/administration & dosage
- Cimetidine/analogs & derivatives
- Cimetidine/chemistry
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Guanosine 5'-O-(3-Thiotriphosphate)/metabolism
- Injections, Intraventricular/methods
- Male
- Pain/drug therapy
- Pain Measurement/methods
- Pain Threshold/drug effects
- Piperidines/administration & dosage
- Piperidines/chemistry
- Pyrazoles/administration & dosage
- Pyrazoles/chemistry
- Rats
- Rats, Sprague-Dawley
- Reaction Time/drug effects
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB1/physiology
- Rimonabant
- Time Factors
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Affiliation(s)
- Neal C Gehani
- Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12208, USA
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41
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Pakdeechote P, Dunn WR, Ralevic V. Cannabinoids inhibit noradrenergic and purinergic sympathetic cotransmission in the rat isolated mesenteric arterial bed. Br J Pharmacol 2007; 152:725-33. [PMID: 17641668 PMCID: PMC2190027 DOI: 10.1038/sj.bjp.0707397] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND AND PURPOSE Noradrenaline and ATP are sympathetic co-transmitters. In the rat perfused mesenteric bed cannabinoids have been shown to modify the overall response to sympathetic nerve stimulation. This study has assessed whether cannabinoid receptor activation modulates differentially the noradrenergic and purinergic components of sympathetic vasoconstriction. EXPERIMENTAL APPROACH Rat mesenteric beds were perfused with physiological salt solution and the effects of cannabinoids on responses to nerve stimulation, or exogenous noradrenaline or alpha,beta-methylene ATP (alpha,beta-meATP; P2X receptor agonist) were determined after raising tone with U46619. The effects of cannabinoids on the noradrenaline and ATP components of sympathetic neurotransmission were assessed using the alpha 1-adrenoceptor antagonist, prazosin, or after P2X receptor desensitization with alpha,beta-meATP. KEY RESULTS Anandamide, WIN 55,212-2 and CP55,940 attenuated sympathetic neurogenic vasoconstrictor responses. The inhibitory actions of anandamide and WIN 55,212-2 were blocked by LY320135, a CB1 receptor antagonist, but not by SR144528, a CB2 receptor antagonist. The inhibitory actions of CP55,940 were unaffected by LY320135 and SR144528. WIN 55,212-3, the inactive S(-) enantiomer of WIN 55,212-2, had no effect on sympathetic neurogenic responses. None of the cannabinoids affected contractile responses to exogenous noradrenaline or alpha,beta-meATP. Anandamide and WIN 55,212-2 inhibited both the noradrenaline and ATP components of the sympathetic neurogenic contractile responses, with effects on the ATP component being most marked. CONCLUSIONS AND IMPLICATIONS These results indicate that prejunctional CB1-like receptors mediate the sympathoinhibitory action of anandamide and WIN 55,212-2, but not CP55,940, in the rat mesenteric bed. Cannabinoids inhibit both the noradrenergic and purinergic components of sympathetic neurotransmission.
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MESH Headings
- 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology
- Adenosine Triphosphate/analogs & derivatives
- Adenosine Triphosphate/pharmacology
- Adrenergic Fibers/drug effects
- Adrenergic Fibers/physiology
- Animals
- Arachidonic Acids/pharmacology
- Benzofurans/pharmacology
- Benzoxazines/pharmacology
- Camphanes/pharmacology
- Cannabinoids/pharmacology
- Cyclohexanols/pharmacology
- Dose-Response Relationship, Drug
- Electric Stimulation
- Endocannabinoids
- In Vitro Techniques
- Male
- Mesenteric Arteries/drug effects
- Mesenteric Arteries/innervation
- Mesenteric Arteries/physiology
- Morpholines/pharmacology
- Muscle Tonus/drug effects
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/innervation
- Muscle, Smooth, Vascular/physiology
- Naphthalenes/pharmacology
- Norepinephrine/pharmacology
- Perfusion
- Polyunsaturated Alkamides/pharmacology
- Prazosin/pharmacology
- Pyrazoles/pharmacology
- Rats
- Rats, Wistar
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB2/antagonists & inhibitors
- Receptors, Purinergic P2/physiology
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Affiliation(s)
- P Pakdeechote
- Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham Nottingham, UK
| | - W R Dunn
- Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham Nottingham, UK
| | - V Ralevic
- Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham Nottingham, UK
- Author for correspondence:
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42
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Maslov LN, Lasukova OV, Krylatov AV, Hanus LO, Pertwee R, Ivanchuk II, Crowford D. Role of cannabinoid receptors in the regulation of cardiac contractility during ischemia/reperfusion. Bull Exp Biol Med 2007; 142:557-61. [PMID: 17415461 DOI: 10.1007/s10517-006-0417-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
We studied the effect of selective ligands of cannabinoid (CB) receptors on contractility of isolated Langendorff-perfused rat heart under conditions of 45-min total ischemia and 30-min reperfusion. Perfusion with a solution containing selective CB receptor agonist HU-210 for 10 min before ischemia increased the severity of reperfusion contractile dysfunction. This drug decreased left ventricular developed pressure and maximum rates of contraction and relaxation, but had no effect on heart rate and end-diastolic pressure. The negative inotropic effect of the drug was transitory and disappeared after 5-min reperfusion. Pretreatment with selective CB1 receptor antagonist SR141716A and selective CB2 receptor antagonist SR144528 had no effect on heart rate and myocardial contractility during reperfusion. Our results indicate that stimulation of CB receptors can increase the degree of reperfusion-induced cardiac contractile dysfunction. However, endogenous cannabinoids are not involved in the development of myocardial contractile dysfunction during ischemia/reperfusion of the isolated heart.
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Affiliation(s)
- L N Maslov
- Institute of Cardiology, Siberian Division of the Russian Academy of Medical Sciences, Tomsk.
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43
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Milani A, Zaccaria R, Bombardieri G, Gasbarrini A, Pola P. Cirrhotic cardiomyopathy. Dig Liver Dis 2007; 39:507-15. [PMID: 17383244 DOI: 10.1016/j.dld.2006.12.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2006] [Revised: 12/04/2006] [Accepted: 12/11/2006] [Indexed: 12/11/2022]
Abstract
Decompensated liver cirrhosis is characterized by a peripheral vasodilation with a low-resistance hyperdynamic circulation. The sustained increase of cardiac work load associated with such a condition may result in an inconstant and often subclinical series of heart abnormalities, constituting a new clinical entity known as "cirrhotic cardiomyopathy". Cirrhotic cardiomyopathy is variably associated with baseline increase in cardiac output, defective myocardial contractility and lowered systo-diastolic response to inotropic and chronotropic stimuli, down-regulated beta-adrenergic function, slight histo-morphological changes, and impaired electric "recovery" ability of ventricular myocardium. Cirrhotic cardiomyopathy is usually clinically latent or mild, likely because the peripheral vasodilation significantly reduces the left ventricle after-load, thus actually "auto-treating" the patient and masking any severe manifestation of heart failure. In cirrhotic patients, the presence of cirrhotic cardiomyopathy may become unmasked and clinically evident by certain treatment interventions that increase the effective blood volume and cardiac pre-load, including surgical or transjugular intrahepatic porto-systemic shunts, peritoneo-venous shunts (LeVeen) and orthotopic liver transplantation. Under these circumstances, an often transient overt congestive heart failure may develop, with increased cardiac output as well as right atrial, pulmonary artery and capillary wedge pressures.
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Affiliation(s)
- A Milani
- Department of Internal Medicine, Catholic University of Rome, Italy.
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44
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Mendizábal VE, Adler-Graschinsky E. Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions. Br J Pharmacol 2007; 151:427-40. [PMID: 17450170 PMCID: PMC2013961 DOI: 10.1038/sj.bjp.0707261] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
In addition to their classical known effects, such as analgesia, impairment of cognition and learning and appetite enhancement, cannabinoids have also been related to the regulation of cardiovascular responses and implicated in cardiovascular pathology. Elevated levels of endocannabinoids have been related to the extreme hypotension associated with various forms of shock as well as to the cardiovascular abnormalities that accompany cirrhosis. In contrast, cannabinoids have also been associated with beneficial effects on the cardiovascular system, such as a protective role in atherosclerosis progression and in cerebral and myocardial ischaemia. In addition, it has also been suggested that the pharmacological manipulation of the endocannabinoid system may offer a novel approach to antihypertensive therapy. During the last decades, the tremendous increase in the understanding of the molecular basis of cannabinoid activity has encouraged many pharmaceutical companies to develop more potent synthetic cannabinoid analogues and antagonists, leading to an explosion of basic research and clinical trials. Consequently. not only the synthetic THC dronabinol (Marinol) and the synthetic THC analogue nabilone (Cesamet) have been approved in the United States, but also the standardized cannabis extract (Sativex) in Canada. At least three strategies can be foreseen in the future clinical use of cannabinoid-based drugs: (a) the use of CB(1) receptor antagonists, such as the recently approved rimonabant (b) the use of CB(2)-selective agonists, and (c) the use of inhibitors of endocannabinoid degradation. In this context, the present review examines the effects of cannabinoids and of the pharmacological manipulation of the endocannabinoid system, in cardiovascular pathophysiology.
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Affiliation(s)
- V E Mendizábal
- Instituto de Investigaciones Farmacológicas (CONICET), Buenos Aires, Argentina.
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45
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Breyne J, Van de Voorde J, Vanheel B. Characterization of the vasorelaxation to methanandamide in rat gastric arteries. Can J Physiol Pharmacol 2007; 84:1121-32. [PMID: 17218976 DOI: 10.1139/y06-058] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In the present study, the relaxant effect of the cannabinoid methanandamide was explored in rat gastric arteries. Since in some vessels cannabinoids have been shown to release calcitonin gene-related peptide (CGRP) from perivascular nerves, the influence of methanandamide was compared with that of exogenous CGRP. Methanandamide and CGRP elicited concentration-dependent, endothelium-independent relaxations. Methanandamide-induced relaxations were unaffected by the CB1 receptor antagonist AM251, the CB2 receptor antagonists AM630 and SR144528, and combined pre-exposure to AM251 and SR144528. Pre-exposure to O-1918, an antagonist of a novel nonCB1/nonCB2 cannabinoid receptor, did not influence the relaxations to methanandamide. Capsaicin or capsazepine treatment slightly inhibited methanandamide-induced relaxations. Preincubation with 30 mmol/L extracellular K+ or 3 mmol/L TEA had no significant effect on the responses elicited by methanandamide, but reduced CGRP-induced relaxations. Relaxation to 10(-5) mol/L methanandamide was significantly blunted by Bay K8644 and by preincubation with nifedipine. Furthermore, 10(-5) mol/L methanandamide significantly inhibited CaCl2-induced contractions in norepinephrine-stimulated vessels previously depleted of intra- and extracellular Ca2+. Finally, preincubation with 10(-5) mol/L methanandamide almost completely abolished high K+-induced contractions. These findings suggest that the vasorelaxant action of methanandamide in rat gastric arteries is not mediated by stimulation of known cannabinoid receptors and only partly related to stimulation of TRPV1 receptors on perivascular nerves. At high concentrations, methanandamide might induce relaxation by reducing calcium entry into the smooth muscle cells.
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MESH Headings
- 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology
- Animals
- Arachidonic Acids/pharmacology
- Arteries/drug effects
- Arteries/metabolism
- Calcitonin Gene-Related Peptide/pharmacology
- Calcium/metabolism
- Calcium Channel Blockers/pharmacology
- Calcium Chloride/metabolism
- Dose-Response Relationship, Drug
- Female
- In Vitro Techniques
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Nifedipine/pharmacology
- Potassium/metabolism
- Rats
- Rats, Wistar
- Receptors, Cannabinoid/drug effects
- Stomach/blood supply
- TRPV Cation Channels/drug effects
- Vasodilation/drug effects
- Vasodilator Agents/pharmacology
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Affiliation(s)
- Joke Breyne
- Department of Physiology and Physiopathology, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium
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46
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Abstract
Cirrhotic cardiomyopathy is the term used to describe a constellation of features indicative of abnormal heart structure and function in patients with cirrhosis. These include systolic and diastolic dysfunction, electrophysiological changes, and macroscopic and microscopic structural changes. The prevalence of cirrhotic cardiomyopathy remains unknown at present, mostly because the disease is generally latent and shows itself when the patient is subjected to stress such as exercise, drugs, hemorrhage and surgery. The main clinical features of cirrhotic cardiomyopathy include baseline increased cardiac output, attenuated systolic contraction or diastolic relaxation in response to physiologic, pharmacologic and surgical stress, and electrical conductance abnormalities (prolonged QT interval). In the majority of cases, diastolic dysfunction precedes systolic dysfunction, which tends to manifest only under conditions of stress. Generally, cirrhotic cardiomyopathy with overt severe heart failure is rare. Major stresses on the cardiovascular system such as liver transplantation, infections and insertion of transjugular intrahepatic portosystemic stent-shunts (TIPS) can unmask the presence of cirrhotic cardiomyopathy and thereby convert latent to overt heart failure. Cirrhotic cardiomyopathy may also contribute to the pathogenesis of hepatorenal syndrome. Pathogenic mechanisms of cirrhotic cardiomyopathy are multiple and include abnormal membrane biophysical characteristics, impaired β-adrenergic receptor signal transduction and increased activity of negative-inotropic pathways mediated by cGMP. Diagnosis and differential diagnosis require a careful assessment of patient history probing for excessive alcohol, physical examination for signs of hypertension such as retinal vascular changes, and appropriate diagnostic tests such as exercise stress electrocardiography, nuclear heart scans and coronary angiography. Current management recommendations include empirical, nonspecific and mainly supportive measures. The exact prognosis remains unclear. The extent of cirrhotic cardiomyopathy generally correlates to the degree of liver insufficiency. Reversibility is possible (either pharmacological or after liver transplantation), but further studies are needed.
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Affiliation(s)
- Soon Koo Baik
- Dept of Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea
| | | | - Samuel S Lee
- Liver Unit, University of Calgary, Calgary, Canada
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47
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Pharmacological characterization of receptor types mediating the dilator action of anandamide on blood vessels of the rat knee joint. Life Sci 2007; 80:1495-502. [DOI: 10.1016/j.lfs.2007.01.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2006] [Revised: 12/16/2006] [Accepted: 01/10/2007] [Indexed: 11/20/2022]
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48
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Drolet B, Simard C, Poirier P. Impact of weight-loss medications on the cardiovascular system: focus on current and future anti-obesity drugs. Am J Cardiovasc Drugs 2007; 7:273-88. [PMID: 17696568 DOI: 10.2165/00129784-200707040-00005] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Overweight and obesity have been rising dramatically worldwide and are associated with numerous co-morbidities such as cardiovascular disease (CVD), type 2 diabetes mellitus, hypertension, certain cancers, and sleep apnea. In fact, obesity is an independent risk factor for CVD and CVD risks have also been documented in obese children. The majority of overweight and obese patients who achieve a significant short-term weight loss do not maintain their lower bodyweight in the long term. This may be due to a lack of intensive counseling and support from a facilitating environment including dedicated healthcare professionals such as nutritionists, kinesiologists, and behavior specialists. As a result, there has been a considerable focus on the role of adjunctive therapy such as pharmacotherapy for long-term weight loss and weight maintenance. Beyond an unfavorable risk factor profile, overweight and obesity also impact upon heart structure and function. Since the beginning, the quest for weight loss drugs has encountered warnings from regulatory agencies and the withdrawal from the market of efficient but unsafe medications. Fenfluramine was withdrawn from the market because of unacceptable pulmonary and cardiac adverse effects. Nevertheless, there is extensive research directed at the development of new anti-obesity compounds. The effect of these molecules on CVD risk factors has been studied and reported but information regarding their impact on the cardiovascular system is sparse. Thus, instead of looking at the benefit of weight loss on metabolism and risk factor management, this article discusses the impact of weight loss medications on the cardiovascular system. The potential interaction of available and potential new weight loss drugs with heart function and structure is reviewed.
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Affiliation(s)
- Benoit Drolet
- Institut Universitaire de Cardiologie et de Pneumologie, Laval Hospital, Quebec City, Quebec, Canada
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49
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Opere CA, Zheng WD, Zhao M, Lee JS, Kulkarni KH, Ohia SE. Inhibition of potassium- and ischemia-evoked [3H] D-aspartate release from isolated bovine retina by cannabinoids. Curr Eye Res 2006; 31:645-53. [PMID: 16877273 DOI: 10.1080/02713680600762747] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
We investigated the effect of cannabinoids on potassium chloride (K+)- and ischemia-induced [3H]D-aspartate release from isolated bovine retinae. The superfusion method was employed for studies of [3H]-neurotransmitter release. Cannabinoid receptor CB1 agonists, but not the CB2 agonist JWH 015, inhibited K+ -induced [3H]D-aspartate release from bovine retinae with the following rank order of activity: anandamide > ACEA > methanandamide > WIN 55,212-2. In the ischemic model, the rank order of activity was as follows: methanandamide > ACEA > WIN 55,212-2. The CB1 receptor antagonist AM 251 blocked inhibitory responses produced by cannabinoids in both experimental conditions. In conclusion, cannabinoids inhibit evoked [3H]D-aspartate release from isolated bovine retinae via an effect on CB1 receptors.
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Affiliation(s)
- Catherine A Opere
- Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University Medical Center, Omaha, Nebrasaka 68178, USA.
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50
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Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006; 58:389-462. [PMID: 16968947 PMCID: PMC2241751 DOI: 10.1124/pr.58.3.2] [Citation(s) in RCA: 1513] [Impact Index Per Article: 79.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB(1) receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB(1) receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB(2) receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients' need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.
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Affiliation(s)
- Pál Pacher
- Laboratory of Physiological Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Room 2S-24, Bethesda, MD 20892-9413, USA
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