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Aydinoglu F, Toyran T, Ogulener N. Age- and Urothelium-related Changes in Hydrogen Sulfide-induced Responses in Mouse Bladder. JOURNAL OF PHYSIOLOGICAL INVESTIGATION 2025; 68:22-30. [PMID: 39676081 DOI: 10.4103/ejpi.ejpi-d-24-00078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 10/25/2024] [Indexed: 12/17/2024]
Abstract
ABSTRACT The alterations in bladder function are associated with aging. Hydrogen sulfide (H 2 S) is a gaseous neurotransmitter that is synthesized in the urinary bladder and is suggested to regulate bladder smooth muscle tone. The effects of age and urothelium on the L-cysteine/H 2 S-induced relaxant responses were investigated in young (3-4 months) and aged (23-24 months) mice. The relaxant responses to endogenous H 2 S (L-cysteine) augmented in denuded urothelium bladder tissue in both age groups. However, the relaxant responses to exogenous H 2 S (sodium hydrogen sulfide: 1 μM - 3 mM) did not change by disruption of the urothelium. The contractile response to carbachol increased in intact bladder tissues of aged mice compared to young mice. On the other hand, contractile responses to carbachol decreased in the denuded bladder tissues of aged compared to young mice. In addition, cystathionine-β-synthase, cystathionine-γ-lyase (CSE), and 3 mercaptopyruvate sulfurtransferase (3-MST) enzymes which are responsible for H 2 S synthesis were intensively detected in the urothelium and vascular smooth muscle of bladder by immunohistochemistry. CSE and 3-MST were observed lesser in the smooth muscle of aged bladder tissue. These results suggest that relaxation to the L-cysteine/H 2 S pathway and contraction to carbachol of the bladder are affected by aging and urothelium. H 2 S- and urothelium-related molecular and biological changes may be responsible for bladder dysfunctions by aging. Understanding the mechanisms involved in chemical and mechanical signaling of the H 2 S pathway may provide important insights into the development of novel targets for the clinical management of age-related bladder dysfunctions in human such as overactive bladder, lower urinary tract symptoms, and other urological diseases. In this context, it is important to note that L-cysteine/H 2 S pathway may be recognized a new therapeutic target bladder disorders.
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Affiliation(s)
- Fatma Aydinoglu
- Department of Pharmacology, Pharmacy Faculty, Cukurova University, Adana, Turkey
| | - Tugba Toyran
- Department of Pathology, Medical Faculty, Cukurova University, Adana, Turkey
| | - Nuran Ogulener
- Department of Pharmacology, Medical Faculty, Cukurova University, Adana, Turkey
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Salehiyeh S, Faiz AF, Manzourolhojeh M, Bagheri AM, Lorian K. The functions of hydrogen sulfide on the urogenital system of both males and females: from inception to the present. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:6391-6415. [PMID: 38689070 DOI: 10.1007/s00210-024-03086-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 04/04/2024] [Indexed: 05/02/2024]
Abstract
Hydrogen sulfide (H2S) is known as a chemical gas in nature with both enzymatic and non-enzymatic biosynthesis in different human organs. A couple of studies have demonstrated the function of H2S in regulating the homeostasis of the human body. Additionally, they have shown its synthesis, measurement, chemistry, protective effects, and interaction in various aspects of scientific evidence. Furthermore, many researches have demonstrated the beneficial impacts of H2S on genital organs and systems. According to various studies, it is recognized that H2S-producing enzymes and the endogenous production of H2S are expressed in male and female reproductive systems in different mammalian species. The main goal of this comprehensive review is to assess the potential therapeutic impacts of this gasotransmitter in the male and female urogenital system and find underlying mechanisms of this agent. This narrative review investigated the articles that were published from the 1970s to 2022. The review's primary focus is the impacts of H2S on the male and female urogenital system. Medline, CINAHL, PubMed, and Google scholar databases were searched. Keywords used in this review were "Hydrogen sulfide," "H2S," "urogenital system," and "urogenital tract". Numerous studies have demonstrated the therapeutic and protective effects of sodium hydrosulfide (Na-HS) as an H2S donor on male and female infertility disorders. Furthermore, it has been observed that H2S plays a significant role in improving different diseases such as ameliorating sperm parameters. The specific localization of H2S enzymes in the urogenital system provides an excellent opportunity to comprehend its function and role in various disorders related to this system. It is noteworthy that H2S has been demonstrated to be produced in endocrine organs and exhibit diverse activities. Moreover, it is important to recognize that alterations in H2S biosynthesis are closely linked to endocrine disorders. Therefore, hormones can be pivotal in regulating H2S production, and H2S synthesis pathways may aid in establishing novel therapeutic strategies. H2S possesses pharmacological effects on essential disorders, such as anti-inflammation, anti-apoptosis, and anti-oxidant activities, which render it a valuable therapeutic agent for human urogenital disease. Furthermore, this agent shows promise in ameliorating the detrimental effects of various male and female diseases. Despite the limited clinical research, studies have demonstrated that applying H2S as an anti-oxidant source could ameliorate adverse effects of different conditions in the urogenital system. More clinical studies are required to confirm the role of this component in clinical settings.
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Affiliation(s)
- Sajad Salehiyeh
- Andrology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Physiology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Research and Clinical Center for Infertility, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ahmad Faisal Faiz
- Department of Paraclinic, School of Medicine, Herat University, Herat, Afghanistan
| | - Mohammad Manzourolhojeh
- Department of Medical Laboratory Sciences, Gorgan Branch, Islamic Azad University, Gorgan, Iran
| | - Amir Mohammad Bagheri
- Department of Medical Genetics, Shahid Sadoughi university of Medical Sciences, Yazd, Iran
| | - Keivan Lorian
- Andrology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
- Research and Clinical Center for Infertility, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Song Y, Mao C, Zhong Q, Zhang R, Jiang D, Sun X. Role of hydrogen sulfide in the male reproductive system. Front Endocrinol (Lausanne) 2024; 15:1377090. [PMID: 38883604 PMCID: PMC11177757 DOI: 10.3389/fendo.2024.1377090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 05/16/2024] [Indexed: 06/18/2024] Open
Abstract
As an important gas signaling molecule, hydrogen sulfide (H2S) affects multiple organ systems, including the nervous, cardiovascular, digestive, and genitourinary, reproductive systems. In particular, H2S not only regulates female reproductive function but also holds great promise in the treatment of male reproductive diseases and disorders, such as erectile dysfunction, prostate cancer, varicocele, and infertility. In this review, we summarize the relationship between H2S and male reproductive organs, including the penis, testis, prostate, vas deferens, and epididymis. As lower urinary tract symptoms have a significant impact on penile erection disorders, we also address the potential ameliorative effects of H2S in erectile dysfunction resulting from bladder disease. Additionally, we discuss the regulatory role of H2S in cavernous smooth muscle relaxation, which involves the NO/cGMP pathway, the RhoA/Rho-kinase pathway, and K+ channel activation. Recently, various compounds that can alleviate erectile dysfunction have been reported to be at least partly dependent on H2S. Therefore, understanding the role of H2S in the male reproductive system may help develop novel strategies for the clinical treatment of male reproductive system diseases.
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Affiliation(s)
- Yunjia Song
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Caiyun Mao
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Qing Zhong
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Rong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Deyou Jiang
- Department of Typhoid, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xutao Sun
- Department of Synopsis of the Golden Chamber, School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China
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Dalkir FT, Aydinoglu F, Ogulener N. The role of rhoA/rho-kinase and PKC in the inhibitory effect of L-cysteine/H 2S pathway on the carbachol-mediated contraction of mouse bladder smooth muscle. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:2023-2038. [PMID: 36894621 DOI: 10.1007/s00210-023-02440-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/20/2023] [Indexed: 03/11/2023]
Abstract
We investigated the role of RhoA/Rho-kinase (ROCK) and PKC in the inhibitory effect of L-cysteine/hydrogen sulfide (H2S) pathway on the carbachol-mediated contraction of mouse bladder smooth muscle. Carbachol (10-8-10-4 M) induced a concentration-dependent contraction in bladder tissues. L-cysteine (H2S precursor; 10-2 M) and exogenous H2S (NaHS; 10-3 M) reduced the contractions evoked by carbachol by ~ 49 and ~ 53%, respectively, relative to control. The inhibitory effect of L-cysteine on contractions to carbachol was reversed by 10-2 M PAG (~ 40%) and 10-3 M AOAA (~ 55%), cystathionine-gamma-lyase (CSE) and cystathionine-β-synthase (CBS) inhibitor, respectively. Y-27632 (10-6 M) and GF 109203X (10-6 M), a specific ROCK and PKC inhibitor, respectively, reduced contractions evoked by carbachol (~ 18 and ~ 24% respectively), and the inhibitory effect of Y-27632 and GF 109203X on contractions was reversed by PAG (~ 29 and ~ 19%, respectively) but not by AOAA. Also, Y-27632 and GF 109203X reduced the inhibitory responses of L-cysteine on the carbachol-induced contractions (~ 38 and ~ 52% respectively), and PAG abolished the inhibitory effect of L-cysteine on the contractions in the presence of Y-27632 (~ 38%). Also, the protein expressions of CSE, CBS, and 3-MST enzymes responsible for endogenous H2S synthesis were detected by Western blot method. H2S level was increased by L-cysteine, Y-27632, and GF 109203X (from 0.12 ± 0.02 to 0.47 ± 0.13, 0.26 ± 0.03, and 0.23 ± 0.06 nmol/mg respectively), and this augmentation in H2S level decreased with PAG (0.17 ± 0.02, 0.15 ± 0.03, and 0.07 ± 0.04 nmol/mg respectively). Furthermore, L-cysteine and NaHS reduced carbachol-induced ROCK-1, pMYPT1, and pMLC20 levels. Inhibitory effects of L-cysteine on ROCK-1, pMYPT1, and pMLC20 levels, but not of NaHS, were reversed by PAG. These results suggest that there is an interaction between L-cysteine/H2S and RhoA/ROCK pathway via inhibition of ROCK-1, pMYPT1, and pMLC20, and the inhibition of RhoA/ROCK and/or PKC signal pathway may be mediated by the CSE-generated H2S in mouse bladder.
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Affiliation(s)
- Fatma Tugce Dalkir
- Department of Pharmacology, Medical Faculty, Cukurova University, Adana, Turkey
| | - Fatma Aydinoglu
- Department of Pharmacology, Pharmacy Faculty, Cukurova University, Adana, Turkey
| | - Nuran Ogulener
- Department of Pharmacology, Medical Faculty, Cukurova University, Adana, Turkey.
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Sun HZ, Li CY, Shi Y, Li JJ, Wang YY, Han LN, Zhu LJ, Zhang YF. Effect of exogenous hydrogen sulfide in the nucleus tractus solitarius on gastric motility in rats. World J Gastroenterol 2023; 29:4557-4570. [PMID: 37621756 PMCID: PMC10445002 DOI: 10.3748/wjg.v29.i29.4557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/29/2023] [Accepted: 07/19/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND Hydrogen sulfide (H2S) is a recently discovered gaseous neurotransmitter in the nervous and gastrointestinal systems. It exerts its effects through multiple signaling pathways, impacting various physiological activities. The nucleus tractus solitarius (NTS), a vital nucleus involved in visceral sensation, was investigated in this study to understand the role of H2S in regulating gastric function in rats. AIM To examine whether H2S affects the nuclear factor kappa-B (NF-κB) and transient receptor potential vanilloid 1 pathways and the neurokinin 1 (NK1) receptor in the NTS. METHODS Immunohistochemical and fluorescent double-labeling techniques were employed to identify cystathionine beta-synthase (CBS) and c-Fos co-expressed positive neurons in the NTS during rat stress. Gastric motility curves were recorded by inserting a pressure-sensing balloon into the pylorus through the stomach fundus. Changes in gastric motility were observed before and after injecting different doses of NaHS (4 nmol and 8 nmol), physiological saline, Capsazepine (4 nmol) + NaHS (4 nmol), pyrrolidine dithiocarbamate (PDTC, 4 nmol) + NaHS (4 nmol), and L703606 (4 nmol) + NaHS (4 nmol). RESULTS We identified a significant increase in the co-expression of c-Fos and CBS positive neurons in the NTS after 1 h and 3 h of restraint water-immersion stress compared to the expressions observed in the control group. Intra-NTS injection of NaHS at different doses significantly inhibited gastric motility in rats (P < 0.01). However, injection of saline, first injection NF-κB inhibitor PDTC or transient receptor potential vanilloid 1 (TRPV1) antagonist Capsazepine or NK1 receptor blockers L703606 and then injection NaHS did not produce significant changes (P > 0.05). CONCLUSION NTS contains neurons co-expressing CBS and c-Fos, and the injection of NaHS into the NTS can suppress gastric motility in rats. This effect may be mediated by activating TRPV1 and NK1 receptors via the NF-κB channel.
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Affiliation(s)
- Hong-Zhao Sun
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Chen-Yu Li
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Yuan Shi
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Jin-Jin Li
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Yi-Ya Wang
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Li-Na Han
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Lu-Jie Zhu
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Ya-Fei Zhang
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
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Hydrogen sulfide as a neuromodulator of the vascular tone. Eur J Pharmacol 2023; 940:175455. [PMID: 36549499 DOI: 10.1016/j.ejphar.2022.175455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/29/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Hydrogen sulfide (H2S) is a unique signaling molecule that, along with carbon monoxide and nitric oxide, belongs to the gasotransmitters family. H2S is endogenously synthesized by enzymatic and non-enzymatic pathways. Three enzymatic pathways involving cystathionine-γ-lyase, cystathionine-β-synthetase, and 3-mercaptopyruvate sulfurtransferase are known as endogenous sources of H2S. This gaseous molecule has recently emerged as a regulator of many systems and physiological functions, including the cardiovascular system where it controls the vascular tone of small arteries. In this context, H2S leads to vasorelaxation by regulating the activity of vascular smooth muscle cells, endothelial cells, and perivascular nerves. Specifically, H2S modulates the functionality of different ion channels to inhibit the autonomic sympathetic outflow-by either central or peripheral mechanisms-or to stimulate perivascular sensory nerves. These mechanisms are particularly relevant for those pathological conditions associated with impaired neuromodulation of vascular tone. In this regard, exogenous H2S administration efficiently attenuates the increased activity of the sympathetic nervous system often seen in patients with certain pathologies. These effects of H2S on the autonomic sympathetic outflow will be the primary focus of this review. Thereafter, we will discuss the central and peripheral regulatory effects of H2S on vascular tone. Finally, we will provide the audience with a detailed summary of the current pathological implications of H2S modulation on the neural regulation of vascular tone.
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Huerta de la Cruz S, Medina-Terol GJ, Sánchez-López A, Centurión D. TRPA1, but not TRPV1, is involved in the increase of the non-adrenergic non-cholinergic outflow induced by hydrogen sulfide in pithed rats. Peptides 2022; 157:170861. [PMID: 35973467 DOI: 10.1016/j.peptides.2022.170861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/20/2022] [Accepted: 08/11/2022] [Indexed: 01/21/2023]
Abstract
Hydrogen sulfide (H2S) is a gasotransmitter that modulates the peripheral transmission regulating the vascular tone. In vitro studies have suggested that H2S induces vasodilation by stimulating capsaicin-sensitive sensory neurons. This study was designed to determine the effects of H2S on the non-adrenergic/non-cholinergic (NANC) outflow in the pithed rat, and the underlying mechanisms. For that purpose, 72 male Wistar rats were anesthetized, pithed and the carotid, femoral and jugular veins were cannulated and then divided into two main sets. The first set of animals (n = 48) was used to determine the effect of NaHS (H2S donor) on the vasodepressor responses induced by: 1) NANC outflow electrical stimulation (n = 24); and 2) i.v. bolus of α-CGRP (n = 24) and subdivided into 4 groups (n = 6 each): 1) control group (without infusion); continuous infusion of: 2) PBS (vehicle; 0.02 ml/kg·min); 3) NaHS 10 μg/kg·min; and 4) NaHS 18 μg/kg·min. The second set of animals (n = 24) received an i.v. bolus of either (1) HC 030031 (TRPA1 channel antagonist; 18 μg/kg; n = 12) or (2) capsazepine (TRPV1 channel antagonist; 100 μg/kg; n = 12) in presence and absence of 18 µg/kg·min NaHS i.v. continuous infusion to determine the underlying mechanism of the NaHS effect on the NANC outflow. Our results show that NaHS infusion increased the vasodepressor responses induced by electrical stimulation, but not by α-CGRP, effect that was abolished by HC030031 and remained unaffected after capsazepine. These data suggest that activation of TRPA1 channels, but no TRPV1, is responsible for the NaHS-induced NANC neurotransmission stimulation.
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Affiliation(s)
- Saúl Huerta de la Cruz
- Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios 235, Col. Granjas-Coapa, Del. Tlalpan, C.P. 14330 México D.F., Mexico.
| | - Grecia J Medina-Terol
- Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios 235, Col. Granjas-Coapa, Del. Tlalpan, C.P. 14330 México D.F., Mexico.
| | - Araceli Sánchez-López
- Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios 235, Col. Granjas-Coapa, Del. Tlalpan, C.P. 14330 México D.F., Mexico.
| | - David Centurión
- Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios 235, Col. Granjas-Coapa, Del. Tlalpan, C.P. 14330 México D.F., Mexico.
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Zou S, Shimizu T, Kurabayashi A, Yamamoto M, Shimizu S, Higashi Y, Shimizu N, Karashima T, Saito M. Protective effects of hydrogen sulfide pretreatment on cyclophosphamide-induced bladder dysfunction in rats via suppression of bladder afferent nerves. Nitric Oxide 2022; 127:54-63. [PMID: 35918055 DOI: 10.1016/j.niox.2022.07.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 11/17/2022]
Abstract
Cyclophosphamide (CYP), a broad-spectrum anticancer drug, causes serious side effects, such as haemorrhagic cystitis (HC). Hydrogen sulfide (H2S), an endogenous gasotransmitter, has physiological properties, including anti-inflammation, anti-oxidation, and neuromodulation. In this study, we investigated the effects of NaHS (H2S donor) pretreatment on bladder dysfunction in CYP-treated rats. Male Wistar rats were intraperitoneally pretreated with NaHS (3 or 10 μmol/kg) or vehicle once daily for 7 days before cystometry, and CYP (150 mg/kg) or saline was intraperitoneally administered 2 days before cystometry. After cystometry, the bladder tissues were collected for haematoxylin and eosin staining. In some rats, capsaicin (CAP), which can desensitise CAP-sensitive afferent nerves, was subcutaneously injected at 125 mg/kg 4 days before cystometry. CYP reduced intercontraction intervals (ICI) and bladder compliance (Comp) and increased the number of non-voiding contractions (NVCs) compared with the saline-treated control group. NaHS pretreatment dose-dependently improved the CYP-induced these changes. In bladder tissues, CYP increased histological scores of neutrophil infiltration, haemorrhage, and oedema, while NaHS had no effect on these CYP-induced changes. CAP showed a tendency to suppress CYP-induced changes in ICI. NaHS-induced improvement in CYP-induced changes in urodynamic parameters were not detected in CAP-treated rats. These findings suggest that NaHS pretreatment prevented bladder dysfunction in CYP-treated rats by suppressing CAP-sensitive bladder afferent nerves, but not by suppressing bladder inflammation. Therefore, H2S represents a new candidate as a protective drug for bladder dysfunction induced by HC, a side effect of CYP chemotherapy.
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Affiliation(s)
- Suo Zou
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Takahiro Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan.
| | - Atsushi Kurabayashi
- Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Masaki Yamamoto
- Department of Pediatrics, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Shogo Shimizu
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Youichirou Higashi
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Nobutaka Shimizu
- Department of Pelvic Floor Center, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Takashi Karashima
- Department of Urology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
| | - Motoaki Saito
- Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan
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Cirino G, Szabo C, Papapetropoulos A. Physiological roles of hydrogen sulfide in mammalian cells, tissues and organs. Physiol Rev 2022; 103:31-276. [DOI: 10.1152/physrev.00028.2021] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
H2S belongs to the class of molecules known as gasotransmitters, which also includes nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized as endogenous sources of H2S in various cells and tissues: cystathionine g-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). The current article reviews the regulation of these enzymes as well as the pathways of their enzymatic and non-enzymatic degradation and elimination. The multiple interactions of H2S with other labile endogenous molecules (e.g. NO) and reactive oxygen species are also outlined. The various biological targets and signaling pathways are discussed, with special reference to H2S and oxidative posttranscriptional modification of proteins, the effect of H2S on channels and intracellular second messenger pathways, the regulation of gene transcription and translation and the regulation of cellular bioenergetics and metabolism. The pharmacological and molecular tools currently available to study H2S physiology are also reviewed, including their utility and limitations. In subsequent sections, the role of H2S in the regulation of various physiological and cellular functions is reviewed. The physiological role of H2S in various cell types and organ systems are overviewed. Finally, the role of H2S in the regulation of various organ functions is discussed as well as the characteristic bell-shaped biphasic effects of H2S. In addition, key pathophysiological aspects, debated areas, and future research and translational areas are identified A wide array of significant roles of H2S in the physiological regulation of all organ functions emerges from this review.
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Affiliation(s)
- Giuseppe Cirino
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, Switzerland
| | - Andreas Papapetropoulos
- Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece & Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece
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Zhang T, Qin Z, Liu D, Wei M, Fu Z, Wang Q, Ma Y, Zhang Z. A novel transcription factor MRPS27 up-regulates the expression of sqr, a key gene of mitochondrial sulfide metabolism in echiuran worm Urechis unicinctus. Comp Biochem Physiol C Toxicol Pharmacol 2021; 243:108997. [PMID: 33549829 DOI: 10.1016/j.cbpc.2021.108997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 12/15/2022]
Abstract
Hydrogen sulfide is a natural, widely distributed, poisonous substance and sulfide: quinone oxidoreductase (SQR) is responsible for oxidizing hydrogen sulfide to less toxic sulfur compounds. The increase of SQR mRNA level is an important mechanism for organisms to adapt to hydrogen sulfide-rich environments. However, its transcriptional regulation mechanism is not very clear. In this study, a mitochondrial 28S ribosomal protein S27 (MRPS27), which has never been reported as a transcription factor, was screened by yeast one-hybrid experiment from the echiuran worm Urechis unicinctus, a benthic organism living in marine sediments. Western blotting indicated that UuMRPS27 contents increased significantly in the nuclear extract of hindgut under exposed to 150 μM sulfide. ChIP and EMSA assays demonstrated that UuMRPS27 did bind to the sqr proximal promoter, the key binding sequence was CTAGAG (+12 to +17 of the promoter) detected by DNase I footprinting assay as well as transient transfection experiments. Furthermore, UuMRPS27, as a transcription activator, exhibited the highest transcription activity compared with other reported sqr transcription factors. Our data revealed for the first time the role of MRPS27 acting as a transcription factor which expanded the understanding of sqr transcriptional regulation in sulfide metabolism mechanism.
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Affiliation(s)
- Tingting Zhang
- Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
| | - Zhenkui Qin
- Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
| | - Danwen Liu
- Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
| | - Maokai Wei
- Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
| | - Zhong Fu
- Hebei Research Institute of Marine and Fishery Science, Qinhuangdao 066002, China
| | - Qing Wang
- Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
| | - Yubin Ma
- Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.
| | - Zhifeng Zhang
- Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.
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Nin DS, Idres SB, Song ZJ, Moore PK, Deng LW. Biological Effects of Morpholin-4-Ium 4 Methoxyphenyl (Morpholino) Phosphinodithioate and Other Phosphorothioate-Based Hydrogen Sulfide Donors. Antioxid Redox Signal 2020; 32:145-158. [PMID: 31642346 DOI: 10.1089/ars.2019.7896] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Significance: Hydrogen sulfide (H2S) is regarded as the third gasotransmitter along with nitric oxide and carbon monoxide. Extensive studies have demonstrated a variety of biological roles for H2S in neurophysiology, cardiovascular disease, endocrine regulation, and other physiological and pathological processes. Recent Advances: Novel H2S donors have proved useful in understanding the biological functions of H2S, with morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate (GYY4137) being one of the most common pharmacological tools used. One advantage of GYY4137 over sulfide salts is its ability to release H2S in a slow and sustained manner akin to endogenous H2S production, rather than the delivery of H2S as a single concentrated burst. Critical Issues: Here, we summarize recent progress made in the characterization of the biological activities and pharmacological effects of GYY4137 in a range of in vitro and in vivo systems. Recent developments in the structural modification of GYY4137 to generate new compounds and their biological effects are also discussed. Future Directions: Slow-releasing H2S donor, GYY4137, and other phosphorothioate-based H2S donors are potent tools to study the biological functions of H2S. Despite recent progress, more work needs to be performed on these new compounds to unravel the mechanisms behind H2S release and pace of its discharge, as well as to define the effects of by-products of donors after H2S liberation. This will not only lead to better in-depth understanding of the biological effects of H2S but will also shed light on the future development of a new class of therapeutic agents with potential to treat a wide range of human diseases.
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Affiliation(s)
- Dawn Sijin Nin
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Shabana Binte Idres
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Zhi Jian Song
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Philip K Moore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Lih-Wen Deng
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,National University Cancer Institute, National University Health System, Singapore, Singapore
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12
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Hydrogen Sulfide: Emerging Role in Bladder, Kidney, and Prostate Malignancies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2360945. [PMID: 31781328 PMCID: PMC6875223 DOI: 10.1155/2019/2360945] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 07/22/2019] [Accepted: 09/30/2019] [Indexed: 12/23/2022]
Abstract
Hydrogen sulfide (H2S) is the latest member of the gasotransmitter family and known to play essential roles in cancer pathophysiology. H2S is produced endogenously and can be administered exogenously. Recent studies showed that H2S in cancers has both pro- and antitumor roles. Understanding the difference in the expression and localization of tissue-specific H2S-producing enzymes in healthy and cancer tissues allows us to develop tools for cancer diagnosis and treatment. Urological malignancies are some of the most common cancers in both men and women, and their early detection is vital since advanced cancers are recurrent, metastatic, and often resistant to treatment. This review summarizes the roles of H2S in cancer and looks at current studies investigating H2S activity and expression of H2S-producing enzymes in urinary cancers. We specifically focused on urothelial carcinoma, renal cell carcinoma, and prostate cancer, as they form the majority of newly diagnosed urinary cancers. Recent studies show that besides the physiological activity of H2S in cancer cells, there are patterns between the development and prognosis of urinary cancers and the expression of H2S-producing enzymes and indirectly the H2S levels. Though controversial and not completely understood, studying the expression of H2S-producing enzymes in cancer tissue may represent an avenue for novel diagnostic and therapeutic strategies for addressing urological malignancies.
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13
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Chen W, Ni D, Rosenkrans ZT, Cao T, Cai W. Smart H 2S-Triggered/Therapeutic System (SHTS)-Based Nanomedicine. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1901724. [PMID: 31763153 PMCID: PMC6864508 DOI: 10.1002/advs.201901724] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/13/2019] [Indexed: 05/02/2023]
Abstract
Hydrogen sulfide (H2S) is of vital importance in several biological and physical processes. The significance of H2S-specific detection and monitoring is emphasized by its elevated levels in various diseases such as cancer. Nanotechnology enhances the performance of chemical sensing nanoprobes due to the enhanced efficiency and sensitivity. Recently, extensive research efforts have been dedicated to developing novel smart H2S-triggered/therapeutic system (SHTS) nanoplatforms for H2S-activated sensing, imaging, and therapy. Herein, the latest SHTS-based nanomaterials are summarized and discussed in detail. In addition, therapeutic strategies mediated by endogenous H2S as a trigger or exogenous H2S delivery are also included. A comprehensive understanding of the current status of SHTS-based strategies will greatly facilitate innovation in this field. Lastly, the challenges and key issues related to the design and development of SHTS-based nanomaterials (e.g., morphology, surface modification, therapeutic strategies, appropriate application, and selection of nanomaterials) are outlined.
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Affiliation(s)
- Weiyu Chen
- Departments of Radiology and Medical PhysicsUniversity of Wisconsin‐MadisonMadisonWI53705USA
| | - Dalong Ni
- Departments of Radiology and Medical PhysicsUniversity of Wisconsin‐MadisonMadisonWI53705USA
| | - Zachary T. Rosenkrans
- Department of Pharmaceutical SciencesUniversity of Wisconsin‐MadisonMadisonWI53705USA
| | - Tianye Cao
- Departments of Radiology and Medical PhysicsUniversity of Wisconsin‐MadisonMadisonWI53705USA
| | - Weibo Cai
- Departments of Radiology and Medical PhysicsUniversity of Wisconsin‐MadisonMadisonWI53705USA
- Department of Pharmaceutical SciencesUniversity of Wisconsin‐MadisonMadisonWI53705USA
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14
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Bladder Dysfunction in an Obese Zucker Rat: The Role of TRPA1 Channels, Oxidative Stress, and Hydrogen Sulfide. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5641645. [PMID: 31531184 PMCID: PMC6721245 DOI: 10.1155/2019/5641645] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 03/08/2019] [Accepted: 05/16/2019] [Indexed: 12/27/2022]
Abstract
Purpose This study investigates whether functionality and/or expression changes of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) channels, oxidative stress, and hydrogen sulfide (H2S) are involved in the bladder dysfunction from an insulin-resistant obese Zucker rat (OZR). Materials and Methods Detrusor smooth muscle (DSM) samples from the OZR and their respective controls, a lean Zucker rat (LZR), were processed for immunohistochemistry for studying the expression of TRPA1 and TRPV1 and the H2S synthase cystathionine beta-synthase (CBS) and cysthathionine-γ-lyase (CSE). Isometric force recordings to assess the effects of TRPA1 agonists and antagonists on DSM contractility and measurement of oxidative stress and H2S production were also performed. Results Neuronal TRPA1 expression was increased in the OZR bladder. Electrical field stimulation- (EFS-) elicited contraction was reduced in the OZR bladder. In both LZR and OZR, TRPA1 activation failed to modify DSM basal tension but enhanced EFS contraction; this response is inhibited by the TRPA1 blockade. In the OZR bladder, reactive oxygen species, malondialdehyde, and protein carbonyl contents were increased and antioxidant enzyme activities (superoxide dismutase, catalase, GR, and GPx) were diminished. CSE expression and CSE-generated H2S production were also reduced in the OZR. Both TRPV1 and CBS expressions were not changed in the OZR. Conclusions These results suggest that an increased expression and functionality of TRPA1, an augmented oxidative stress, and a downregulation of the CSE/H2S pathway are involved in the impairment of nerve-evoked DSM contraction from the OZR.
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15
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Tinker A, Aziz Q, Li Y, Specterman M. ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles. Compr Physiol 2018; 8:1463-1511. [DOI: 10.1002/cphy.c170048] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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16
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Phosphodiesterase type 4 inhibition enhances nitric oxide- and hydrogen sulfide-mediated bladder neck inhibitory neurotransmission. Sci Rep 2018; 8:4711. [PMID: 29549279 PMCID: PMC5856743 DOI: 10.1038/s41598-018-22934-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 03/02/2018] [Indexed: 01/01/2023] Open
Abstract
Nitric oxide (NO) and hydrogen sulfide (H2S) play a pivotal role in nerve-mediated relaxation of the bladder outflow region. In the bladder neck, a marked phosphodiesterase type 4 (PDE4) expression has also been described and PDE4 inhibitors, as rolipram, produce smooth muscle relaxation. This study investigates the role of PDE4 isoenzyme in bladder neck gaseous inhibitory neurotransmission. We used Western blot and double immunohistochemical staining for the detection of NPP4 (PDE4) and PDE4A and organ baths for isometric force recording to roflumilast and tadalafil, PDE4 and PDE5, respectively, inhibitors in pig and human samples. Endogenous H2S production measurement and electrical field stimulation (EFS) were also performed. A rich PDE4 and PDE4A expression was observed mainly limited to nerve fibers of the smooth muscle layer of both species. Moreover, roflumilast produced a much more potent smooth muscle relaxation than that induced by tadalafil. In porcine samples, H2S generation was diminished by H2S and NO synthase inhibition and augmented by roflumilast. Relaxations elicited by EFS were potentiated by roflumilast. These results suggest that PDE4, mainly PDE4A, is mostly located within nerve fibers of the pig and human bladder neck, where roflumilast produces a powerful smooth muscle relaxation. In pig, the fact that roflumilast increases endogenous H2S production and EFS-induced relaxations suggests a modulation of PDE4 on NO- and H2S-mediated inhibitory neurotransmission.
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17
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Centurión D, de la Cruz SH, Castillo-Santiago SV, Becerril-Chacón ME, Torres-Pérez JA, Sánchez-López A. NaHS prejunctionally inhibits the cardioaccelerator sympathetic outflow in pithed rats. Eur J Pharmacol 2018; 823:35-40. [DOI: 10.1016/j.ejphar.2018.01.030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 01/16/2018] [Accepted: 01/23/2018] [Indexed: 01/08/2023]
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18
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Wang W, Bo Q, Du J, Yu X, Zhu K, Cui J, Zhao H, Wang Y, Shi B, Zhu Y. Endogenous H 2S sensitizes PAR4-induced bladder pain. Am J Physiol Renal Physiol 2018; 314:F1077-F1086. [PMID: 29357418 DOI: 10.1152/ajprenal.00526.2017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Bladder pain is a prominent symptom of interstitial cystitis/painful bladder syndrome. Hydrogen sulfide (H2S) generated by cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE) facilitates bladder hypersensitivity. We assessed involvement of the H2S pathway in protease-activated receptor 4 (PAR4)-induced bladder pain. A bladder pain model was induced by intravesical instillation of PAR4-activating peptide in mice. The role of H2S in this model was evaluated by intraperitoneal preadministration of d,l-propargylglycine (PAG), aminooxyacetic acid (AOAA), or S-adenosylmethionine or the preintravesical administration of NaHS. SV-HUC-1 cells were treated in similar manners. Assessments of CBS, CSE, and macrophage migration inhibitory factor (MIF) expression, bladder voiding function, bladder inflammation, H2S production, and referred bladder pain were performed. The CSE and CBS pathways existed in both mouse bladders and SV-HUC-1 cells. H2S signaling was upregulated in PAR4-induced bladder pain models, and H2S-generating enzyme activity was upregulated in human bladders, mouse bladders, and SV-HUC-1 cells. Pretreatment with AOAA or NaHS inhibited or promoted PAR4-induced mechanical hyperalgesia, respectively; however, PAG only partially inhibited PAR4-induced bladder pain. Treatment with PAG or AOAA decreased H2S production in both mouse bladders and SV-HUC-1 cells. Pretreatment with AOAA increased MIF protein levels in bladder tissues and cells, whereas pretreatment with NaHS lowered MIF protein levels. Bladder pain triggered by the H2S pathway was not accompanied by inflammation or altered micturition behavior. Thus endogenous H2S generated by CBS or CSE caused referred hyperalgesia mediated through MIF in mice with PAR4-induced bladder pain, without causing bladder injury or altering micturition behavior.
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Affiliation(s)
- Wenfu Wang
- Department of Urology, Qilu Hospital of Shandong University , Jinan , China
| | - Qiyu Bo
- Department of First Operation Room, Qilu Hospital of Shandong University , Jinan , China
| | - Jian Du
- Department of Urology, Qilu Hospital of Shandong University , Jinan , China
| | - Xin Yu
- Department of Physiology, Shandong University School of Physiology , Jinan , China
| | - Kejia Zhu
- Department of Urology, Qilu Hospital of Shandong University , Jinan , China
| | - Jianfeng Cui
- Department of Urology, Qilu Hospital of Shandong University , Jinan , China
| | - Hongda Zhao
- Department of Urology, Qilu Hospital of Shandong University , Jinan , China
| | - Yong Wang
- Department of Urology, Qilu Hospital of Shandong University , Jinan , China
| | - Benkang Shi
- Department of Urology, Qilu Hospital of Shandong University , Jinan , China
| | - Yaofeng Zhu
- Department of Urology, Qilu Hospital of Shandong University , Jinan , China
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19
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d'Emmanuele di Villa Bianca R, Fusco F, Mirone V, Cirino G, Sorrentino R. The Role of the Hydrogen Sulfide Pathway in Male and Female Urogenital System in Health and Disease. Antioxid Redox Signal 2017; 27:654-668. [PMID: 28398118 DOI: 10.1089/ars.2017.7079] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
SIGNIFICANCE The endogenous hydrogen sulfide (H2S) pathway produces an array of biological effects that vary depending on the bodily region. In addition, the H2S pathway's relevance often changes depending on a healthy or disease state. There is abundant evidence pointing to a key role for this pathway in male and female genito-urinary diseases, suggesting it as a possible target for new therapeutic approaches. Recent Advances: The tissue-specific localization of the H2S enzymes in the genito-urinary tract has allowed for a better understanding of its role in the body's pathophysiology. Indeed, in humans, cystathionine-γ-lyase (CSE) plays a major role in corpus cavernosum whereas cystathionine-β-synthase (CBS) plays a role in bladder functioning. The prostate epithelium expresses CBS and CSE, but stromal CSE only. In the uterus, up- or downregulation of CBS and CSE varies strongly depending on the female's hormonal cycle or pregnancy. CRITICAL ISSUES There is still the need to better define the male and female's sexual hormonal roles in regulating the H2S pathway, particularly in human pathological conditions. The lack of a correlation between human and animal data should be carefully considered when planning preclinical studies. The unmet need for selective enzymatic inhibitors and the different methodologies for H2S measurements still represent a critical issue in this research field. FUTURE DIRECTIONS It is feasible that the L-cysteine/H2S pathway can represent an alternative therapeutic target in genito-urinary tract disorders. The research should focus on erectile dysfunction and preeclampsia, characterized by vascular defect, as well as on bladder disorders where the urothelium is compromised. Antioxid. Redox Signal. 27, 654-668.
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Affiliation(s)
- Roberta d'Emmanuele di Villa Bianca
- 1 Department of Pharmacy, School of Medicine, University of Naples Federico II , Naples, Italy .,2 Interdepartmental Centre for Sexual Medicine, School of Medicine, University of Naples Federico II , Naples, Italy
| | - Ferdinando Fusco
- 2 Interdepartmental Centre for Sexual Medicine, School of Medicine, University of Naples Federico II , Naples, Italy .,3 Department of Neurosciences, Human Reproduction and Odontostomatology, School of Medicine, University of Naples Federico II , Naples, Italy
| | - Vincenzo Mirone
- 2 Interdepartmental Centre for Sexual Medicine, School of Medicine, University of Naples Federico II , Naples, Italy .,3 Department of Neurosciences, Human Reproduction and Odontostomatology, School of Medicine, University of Naples Federico II , Naples, Italy
| | - Giuseppe Cirino
- 1 Department of Pharmacy, School of Medicine, University of Naples Federico II , Naples, Italy .,2 Interdepartmental Centre for Sexual Medicine, School of Medicine, University of Naples Federico II , Naples, Italy
| | - Raffaella Sorrentino
- 1 Department of Pharmacy, School of Medicine, University of Naples Federico II , Naples, Italy .,2 Interdepartmental Centre for Sexual Medicine, School of Medicine, University of Naples Federico II , Naples, Italy
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20
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Aydinoglu F, Ogulener N. The role of arachidonic acid/cyclooxygenase cascade, phosphodiesterase IV and Rho-kinase in H 2 S-induced relaxation in the mouse corpus cavernosum. Pharmacol Rep 2017; 69:610-615. [DOI: 10.1016/j.pharep.2017.02.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 01/10/2017] [Accepted: 02/22/2017] [Indexed: 12/19/2022]
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21
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Ückert S, Albrecht K, Bannowsky A, Sohn M, Kuczyk MA, Hedlund P. Expression and distribution of the transient receptor potential cationic channel A1 (TRPA1) in the human clitoris-comparison to male penile erectile tissue. Int J Impot Res 2017; 29:179-183. [PMID: 28469181 DOI: 10.1038/ijir.2017.15] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 12/22/2016] [Accepted: 03/20/2017] [Indexed: 01/05/2023]
Abstract
The transient receptor potential cationic channel ankyrin 1 (TRPA1) is a channel protein assumed to act in various human tissues as mechano- and pain sensor and play a role in neurotransmission. The expression of TRPA has already been investigated in the human prostate and urethra, however, only very few studies have addressed the expression and distribution in the male and female genital tract. The present study aimed to investigate by means of immunohistochemistry (double-labeling technique, laser fluorescence microscopy) in the human clitoris and penile erectile tissue the localization of TRPA1 in relation to nNOS, the vasoactive intestinal polypeptide (VIP) and vesicular acetylcholine transporter (VAChT). In the clitoral tissue, TRPA1 was observed in basal epithelial cells and slender nNOS-positive nerve fibers transversing the subepithelial space. To a certain degree, in the clitoral epithelial cells, TRPA1 was found co-localized with vimentin. In human corpus cavernosum, immunoreactivity for TRPA1 was seen in nerves transversing the cavernous sinusoidal space and running alongside small arteries, these nerves also displayed expression of the vesicular acetylcholine transporter protein (VAChT). Varicose nerves containing nNOS or VIP were not immunoreactive for TRPA1. It seems likely that TRPA1 is involved in nitric oxide-mediated afferent sensory transmission in the clitoris while, in penile erectile tissue, a role for TRPA1 in cholinergic signaling might be assumed.
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Affiliation(s)
- S Ückert
- Division of Surgery, Department of Urology and Urological Oncology, Hannover Medical School, Hannover, Germany
| | - K Albrecht
- Department of Legal (Forensic) Medicine, Hannover Medical School, Hannover, Germany
| | - A Bannowsky
- Department of Urology, Imland Klinik, Rendsburg, Germany
| | - M Sohn
- Department of Urology, AGAPLESION St Markus Hospital, Frankfurt, Germany
| | - M A Kuczyk
- Division of Surgery, Department of Urology and Urological Oncology, Hannover Medical School, Hannover, Germany
| | - P Hedlund
- Faculty of Medicine, Division of Clinical Pharmacology and Drug Research, Linköping University, Linköping, Sweden
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22
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Capsaicin-Sensitive Sensory Nerves Mediate the Cellular and Microvascular Effects of H2S via TRPA1 Receptor Activation and Neuropeptide Release. J Mol Neurosci 2016; 60:157-70. [PMID: 27525636 DOI: 10.1007/s12031-016-0802-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 07/28/2016] [Indexed: 12/28/2022]
Abstract
It is supposed that TRPA1 receptor can be activated by hydrogen sulphide (H2S). Here, we have investigated the role of TRPA1 receptor in H2S-induced [Ca(2+)]i increase in trigeminal ganglia (TRG) neurons, and the involvement of capsaicin-sensitive sensory nerves in H2S-evoked cutaneous vasodilatation. [Ca(2+)]i was measured with ratiometric technique on TRG neurons of TRPA1(+/+) and TRPA1(-/-) mice after NaHS, Na2S, allylisothiocyanate (AITC) or KCl treatment. Microcirculatory changes in the ear were detected by laser Doppler imaging in response to topical NaHS, AITC, NaOH, NaSO3 or NaCl. Mice were either treated with resiniferatoxin (RTX), or CGRP antagonist BIBN4096, or NK1 receptor antagonist CP99994, or K(+) ATP channel blocker glibenclamide. Alpha-CGRP(-/-) and NK1 (-/-) mice were also investigated. NaHS and Na2S increased [Ca(2+)]i in TRG neurons derived from TRPA(+/+) but not from TRPA1(-/-) mice. NaHS increased cutaneous blood flow, while NaOH, NaSO3 and NaCl did not cause significant changes. NaHS-induced vasodilatation was reduced in RTX-treated animals, as well as by pre-treatment with BIBN4096 or CP99994 alone or in combination. NaHS-induced vasodilatation was significantly smaller in alpha-CGRP(-/-) or NK1 (-/-) mice compared to wild-types. H2S activates capsaicin-sensitive sensory nerves through TRPA1 receptors and the resultant vasodilatation is mediated by the release of vasoactive sensory neuropeptides CGRP and substance P.
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23
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Fernandes VS, Hernández M. The Role of Nitric Oxide and Hydrogen Sulfide in Urinary Tract Function. Basic Clin Pharmacol Toxicol 2016; 119 Suppl 3:34-41. [PMID: 26866922 DOI: 10.1111/bcpt.12565] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 02/05/2016] [Indexed: 02/06/2023]
Abstract
This MiniReview focuses on the role played by nitric oxide (NO) and hydrogen sulfide (H2 S) in physiology of the upper and lower urinary tract. NO and H2 S, together with carbon monoxide, belong to the group of gaseous autocrine/paracrine messengers or gasotransmitters, which are employed for intra- and intercellular communication in almost all organ systems. Because they are lipid-soluble gases, gaseous transmitters are not constrained by cellular membranes, so that their storage in vesicles for later release is not possible. Gasotransmitter signals are terminated by falling concentrations upon reduction in production that are caused by reacting with cellular components (essentially reactive oxygen species and NO), binding to cellular components or diffusing away. NO and, more recently, H2 S have been identified as key mediators in neurotransmission of the urinary tract, involved in the regulation of ureteral smooth muscle activity and urinary flow ureteral resistance, as well as by playing a crucial role in the smooth muscle relaxation of bladder outlet region. Urinary bladder function is also dependent on integration of inhibitory mediators, such as NO, released from the urothelium. In the bladder base and distal ureter, the co-localization of neuronal NO synthase with substance P and calcitonin gene-related peptide in sensory nerves as well as the existence of a high nicotinamide adenine dinucleotide phosphate-diaphorase activity in dorsal root ganglion neurons also suggests the involvement of NO as a sensory neurotransmitter.
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Affiliation(s)
- Vítor S Fernandes
- Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain
| | - Medardo Hernández
- Department of Physiology, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain.
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24
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Abstract
In recent years, it has become apparent that the gaseous pollutant, hydrogen sulphide (H2S) can be synthesised in the body and has a multitude of biological actions. This review summarizes some of the actions of this 'gasotransmitter' in influencing the smooth muscle that is responsible for controlling muscular activity of hollow organs. In the vasculature, while H2S can cause vasoconstriction by complex interactions with other biologically important gases, such as nitric oxide, the prevailing response is vasorelaxation. While most vasorelaxation responses occur by a direct action of H2S on smooth muscle cells, it has recently been proposed to be an endothelium-derived hyperpolarizing factor. H2S also promotes relaxation in other smooth muscle preparations including bronchioles, the bladder, gastrointestinal tract and myometrium, opening up the opportunity of exploiting the pharmacology of H2S in the treatment of conditions where smooth muscle tone is excessive. The original concept, that H2S caused smooth muscle relaxation by activating ATP-sensitive K(+) channels, has been supplemented with observations that H2S can also modify the activity of other potassium channels, intracellular pH, phosphodiesterase activity and transient receptor potential channels on sensory nerves. While the enzymes responsible for generating endogenous H2S are widely expressed in smooth muscle preparations, it is much less clear what the physiological role of H2S is in determining smooth muscle contractility. Clarification of this requires the development of potent and selective inhibitors of H2S-generating enzymes.
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Affiliation(s)
- William R Dunn
- Pharmacology Research Group, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
| | - Stephen P H Alexander
- Pharmacology Research Group, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Vera Ralevic
- Pharmacology Research Group, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom
| | - Richard E Roberts
- Pharmacology Research Group, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom
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25
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Inhibitory action of hydrogen sulfide on esophageal striated muscle motility in rats. Eur J Pharmacol 2016; 771:123-9. [PMID: 26687631 DOI: 10.1016/j.ejphar.2015.12.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 11/24/2015] [Accepted: 12/09/2015] [Indexed: 02/08/2023]
Abstract
Hydrogen sulfide (H2S) is recognized as a gaseous transmitter and has many functions including regulation of gastrointestinal motility. The aim of the present study was to clarify the effects of H2S on the motility of esophageal striated muscle in rats. An isolated segment of the rat esophagus was placed in an organ bath and mechanical responses were recorded using a force transducer. Electrical stimulation of the vagus nerve evoked contractile response in the esophageal segment. The vagally mediated contraction was inhibited by application of an H2S donor. The H2S donor did not affect the contraction induced by electrical field stimulation, which can excite the striated muscle directly, not via vagus nerves. These results show that H2S has an inhibitory effect on esophageal motility not by directly attenuating striated muscle contractility but by blocking vagal motor nerve activity and/or neuromuscular transmissions. The inhibitory actions of H2S were not affected by pretreatment with the transient receptor potential vanniloid-1 blocker, transient receptor potential ankyrin-1 blocker, nitric oxide synthase inhibitor, blockers of potassium channels, and ganglionic blocker. RT-PCR and Western blot analysis revealed the expression of H2S-producing enzymes in esophageal tissue, whereas application of inhibitors of H2S-producing enzymes did not change vagally evoked contractions in the esophageal striated muscle. These findings suggest that H2S, which might be produced in the esophageal tissue endogenously, can regulate the motor activity of esophageal striated muscle via a novel inhibitory neural pathway.
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Hedegaard ER, Gouliaev A, Winther AK, Arcanjo DDR, Aalling M, Renaltan NS, Wood ME, Whiteman M, Skovgaard N, Simonsen U. Involvement of Potassium Channels and Calcium-Independent Mechanisms in Hydrogen Sulfide-Induced Relaxation of Rat Mesenteric Small Arteries. J Pharmacol Exp Ther 2016; 356:53-63. [PMID: 26493746 DOI: 10.1124/jpet.115.227017] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 10/21/2015] [Indexed: 11/22/2022] Open
Abstract
Endogenous hydrogen sulfide (H2S) is involved in the regulation of vascular tone. We hypothesized that the lowering of calcium and opening of potassium (K) channels as well as calcium-independent mechanisms are involved in H2S-induced relaxation in rat mesenteric small arteries. Amperometric recordings revealed that free [H2S] after addition to closed tubes of sodium hydrosulfide (NaHS), Na2S, and GYY4137 [P-(4-methoxyphenyl)-P-4-morpholinyl-phosphinodithioic acid] were, respectively, 14%, 17%, and 1% of added amount. The compounds caused equipotent relaxations in isometric myographs, but based on the measured free [H2S], GYY4137 caused more relaxation in relation to released free H2S than NaHS and Na2S in rat mesenteric small arteries. Simultaneous measurements of [H2S] and tension showed that 15 µM of free H2S caused 61% relaxation in superior mesenteric arteries. Simultaneous measurements of smooth muscle calcium and tension revealed that NaHS lowered calcium and caused relaxation of NE-contracted arteries, while high extracellular potassium reduced NaHS relaxation without corresponding calcium changes. In NE-contracted arteries, NaHS (1 mM) lowered the phosphorylation of myosin light chain, while phosphorylation of myosin phosphatase target subunit 1 remained unchanged. Protein kinase A and G, inhibitors of guanylate cyclase, failed to reduce NaHS relaxation, whereas blockers of voltage-gated KV7 channels inhibited NaHS relaxation, and blockers of mitochondrial complex I and III abolished NaHS relaxation. Our findings suggest that low micromolar concentrations of free H2S open K channels followed by lowering of smooth muscle calcium, and by another mechanism involving mitochondrial complex I and III leads to uncoupling of force, and hence vasodilation.
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Affiliation(s)
- Elise R Hedegaard
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
| | - Anja Gouliaev
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
| | - Anna K Winther
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
| | - Daniel D R Arcanjo
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
| | - Mathilde Aalling
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
| | - Nirthika S Renaltan
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
| | - Mark E Wood
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
| | - Matthew Whiteman
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
| | - Nini Skovgaard
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
| | - Ulf Simonsen
- Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark (E.R.H., A.G., A.K.W., D.D.R.A., M.A., N.S.R., N.S., U.S.); Biosciences, College of Life and Environmental Sciences (M.E.W.), and Medical School, St. Luke's Campus (M.W.), University of Exeter, Exeter, United Kingdom
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Guan NN, Svennersten K, de Verdier PJ, Wiklund NP, Gustafsson LE. Receptors involved in the modulation of guinea pig urinary bladder motility by prostaglandin D2. Br J Pharmacol 2015; 172:4024-37. [PMID: 25917171 DOI: 10.1111/bph.13174] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 04/17/2015] [Accepted: 04/22/2015] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND AND PURPOSE We have described a urothelium-dependent release of PGD2 -like activity which had inhibitory effects on the motility of guinea pig urinary bladder. Here, we have pharmacologically characterized the receptors involved and localized the sites of PGD2 formation and of its receptors. EXPERIMENTAL APPROACH In the presence of selective DP and TP receptor antagonists alone or combined, PGD2 was applied to urothelium-denuded diclofenac-treated urinary bladder strips mounted in organ baths. Antibodies against PGD2 synthase and DP1 receptors were used with Western blots and for histochemistry. KEY RESULTS PGD2 inhibited nerve stimulation -induced contractions in strips of guinea pig urinary bladder with estimated pIC50 of 7.55 ± 0.15 (n = 13), an effect blocked by the DP1 receptor antagonist BW-A868C. After blockade of DP1 receptors, PGD2 enhanced the contractions, an effect abolished by the TP receptor antagonist SQ-29548. Histochemistry revealed strong immunoreactivity for PGD synthase in the urothelium/suburothelium with strongest reaction in the suburothelium. Immunoreactive DP1 receptors were found in the smooth muscle of the bladder wall with a dominant localization to smooth muscle membranes. CONCLUSIONS AND IMPLICATIONS In guinea pig urinary bladder, the main effect of PGD2 is an inhibitory action via DP1 receptors localized to the smooth muscle, but an excitatory effect via TP receptors can also be evoked. The urothelium with its suburothelium might signal to the smooth muscle which is rich in PGD2 receptors of the DP1 type. The results are important for our understanding of regulation of bladder motility.
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Affiliation(s)
- Na N Guan
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Karl Svennersten
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Petra J de Verdier
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - N Peter Wiklund
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Lars E Gustafsson
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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Fernandes VS, Xin W, Petkov GV. Novel mechanism of hydrogen sulfide-induced guinea pig urinary bladder smooth muscle contraction: role of BK channels and cholinergic neurotransmission. Am J Physiol Cell Physiol 2015; 309:C107-16. [PMID: 25948731 DOI: 10.1152/ajpcell.00021.2015] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 05/02/2015] [Indexed: 12/13/2022]
Abstract
Hydrogen sulfide (H2S) is a key signaling molecule regulating important physiological processes, including smooth muscle function. However, the mechanisms underlying H2S-induced detrusor smooth muscle (DSM) contractions are not well understood. This study investigates the cellular and tissue mechanisms by which H2S regulates DSM contractility, excitatory neurotransmission, and large-conductance voltage- and Ca(2+)-activated K(+) (BK) channels in freshly isolated guinea pig DSM. We used a multidisciplinary experimental approach including isometric DSM tension recordings, colorimetric ACh measurement, Ca(2+) imaging, and patch-clamp electrophysiology. In isolated DSM strips, the novel slow release H2S donor, P-(4-methoxyphenyl)-p-4-morpholinylphosphinodithioic acid morpholine salt (GYY4137), significantly increased the spontaneous phasic and nerve-evoked DSM contractions. The blockade of neuronal voltage-gated Na(+) channels or muscarinic ACh receptors with tetrodotoxin or atropine, respectively, reduced the stimulatory effect of GYY4137 on DSM contractility. GYY4137 increased ACh release from bladder nerves, which was inhibited upon blockade of L-type voltage-gated Ca(2+) channels with nifedipine. Furthermore, GYY4137 increased the amplitude of the Ca(2+) transients and basal Ca(2+) levels in isolated DSM strips. GYY4137 reduced the DSM relaxation induced by the BK channel opener, NS11021. In freshly isolated DSM cells, GYY4137 decreased the amplitude and frequency of transient BK currents recorded in a perforated whole cell configuration and reduced the single BK channel open probability measured in excised inside-out patches. GYY4137 inhibited spontaneous transient hyperpolarizations and depolarized the DSM cell membrane potential. Our results reveal the novel findings that H2S increases spontaneous phasic and nerve-evoked DSM contractions by activating ACh release from bladder nerves in combination with a direct inhibition of DSM BK channels.
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Affiliation(s)
- Vítor S Fernandes
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina
| | - Wenkuan Xin
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina
| | - Georgi V Petkov
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina
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Abstract
Hydrogen sulfide (H2S) is now recognized as the so called "third gasotransmitter" taking its place alongside nitric oxide and carbon monoxide. In recent years, H2S has been reported to exhibit a diverse range of pharmacological effects in biological systems. Much of this evidence is derived from a combination of conventional pharmacological and genetic approaches coupled with the use of chemical compounds such as sodium hydrosulfide, a rapid H2S releasing donor. Developments in the design of new drug entities which attempt to take into account physicochemical properties, targeting to specific cellular organelles, triggering of H2S release upon specific chemical reactions in the cell, and controlling the release of H2S over extended periods of time have been described. For most of these molecules, little or no work has been conducted to determine their biological activity or possible therapeutic effects. It is therefore not clear whether such molecules have therapeutic potential which highlights the need for further in vivo studies. One exception to the general rule is GYY4137 (morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate), a slow releasing H2S donor, which has been evaluated for activity in a range of pharmacological models both in vitro and in vivo. GYY4137 was first reported to release H2S and exhibit vasodilator activity over 5 years ago and, to date, GYY4137 is becoming increasingly employed as a pharmacological "tool" to explore the biological functions of H2S.
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Affiliation(s)
- Peter Rose
- University of Lincoln, Lincoln, Lincolnshire, United Kingdom
| | - Brian W Dymock
- Department of Pharmacy, National University of Singapore, Singapore
| | - Philip K Moore
- Neurobiology Program, Life Science Institute and Department of Pharmacology, National University of Singapore, Singapore.
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Abstract
In this chapter the role played by H2S in the physiopathology of urogenital tract revising animal and human data available in the current relevant literature is discussed. H2S pathway has been demonstrated to be involved in the mechanism underlying penile erection in human and experimental animal. Both cystathionine-β synthase (CBS) and cystathionine-γ lyase (CSE) are expressed in the human corpus cavernosum and exogenous H2S relaxes isolated human corpus cavernosum strips in an endothelium-independent manner. Hydrogen sulfide pathway also accounts for the direct vasodilatory effect operated by testosterone on isolated vessels. Convincing evidence suggests that H2S can influence the cGMP pathway by inhibiting the phosphodiesterase 5 (PDE-5) activity. All these findings taken together suggest an important role for the H2S pathway in human corpus cavernosum homeostasis. However, H2S effect is not confined to human corpus cavernosum but also plays an important role in human bladder. Human bladder expresses mainly CBS and generates in vitro detectable amount of H2S. In addition the bladder relaxant effect of the PDE-5 inhibitor sildenafil involves H2S as mediator. In conclusion the H2S pathway is not only involved in penile erection but also plays a role in bladder homeostasis. In addition the finding that it involved in the mechanism of action of PDE-5 inhibitors strongly suggests that modulation of this pathway can represent a therapeutic target for the treatment of erectile dysfunction and bladder diseases.
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Hydrogen sulfide plays a key role in the inhibitory neurotransmission to the pig intravesical ureter. PLoS One 2014; 9:e113580. [PMID: 25415381 PMCID: PMC4240656 DOI: 10.1371/journal.pone.0113580] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 10/25/2014] [Indexed: 01/29/2023] Open
Abstract
According to previous observations nitric oxide (NO), as well as an unknown nature mediator are involved in the inhibitory neurotransmission to the intravesical ureter. This study investigates the hydrogen sulfide (H2S) role in the neurogenic relaxation of the pig intravesical ureter. We have performed western blot and immunohistochemistry to study the expression of the H2S synthesis enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), measurement of enzymatic production of H2S and myographic studies for isometric force recording. Immunohistochemical assays showed a high CSE expression in the intravesical ureter muscular layer, as well as a strong CSE-immunoreactivity within nerve fibres distributed along smooth muscle bundles. CBS expression, however, was not consistently observed. On ureteral strips precontracted with thromboxane A2 analogue U46619, electrical field stimulation (EFS) and the H2S donor P-(4-methoxyphenyl)-P-4-morpholinylphosphinodithioic acid (GYY4137) evoked frequency- and concentration-dependent relaxations. CSE inhibition with DL-propargylglycine (PPG) reduced EFS-elicited responses and a combined blockade of both CSE and NO synthase (NOS) with, respectively, PPG and NG-nitro-L-arginine (L-NOARG), greatly reduced such relaxations. Endogenous H2S production rate was reduced by PPG, rescued by addition of GYY4137 and was not changed by L-NOARG. EFS and GYY4137 relaxations were also reduced by capsaicin-sensitive primary afferents (CSPA) desensitization with capsaicin and blockade of ATP-dependent K+ (KATP) channels, transient receptor potential A1 (TRPA1), transient receptor potential vanilloid 1 (TRPV1), vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypeptide (VIP/PACAP) and calcitonin gene-related peptide (CGRP) receptors with glibenclamide, HC030031, AMG9810, PACAP6–38 and CGRP8–37, respectively. These results suggest that H2S, synthesized by CSE, is involved in the inhibitory neurotransmission to the pig intravesical ureter, through an NO-independent pathway, producing smooth muscle relaxation via KATP channel activation. H2S also promotes the release of inhibitory neuropeptides, as PACAP 38 and/or CGRP from CSPA through TRPA1, TRPV1 and related ion channel activation.
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Ribeiro AS, Fernandes VS, Martínez‐Sáenz A, Martínez P, Barahona MV, Orensanz LM, Blaha I, Serrano‐Margüello D, Bustamante S, Carballido J, García‐Sacristán A, Prieto D, Hernández M. Powerful Relaxation of Phosphodiesterase Type 4 Inhibitor Rolipram in the Pig and Human Bladder Neck. J Sex Med 2014; 11:930-941. [DOI: 10.1111/jsm.12456] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Fernandes VS, Ribeiro ASF, Martínez-Sáenz A, Blaha I, Serrano-Margüello D, Recio P, Martínez AC, Bustamante S, Vázquez-Alba D, Carballido J, García-Sacristán A, Hernández M. Underlying mechanisms involved in progesterone-induced relaxation to the pig bladder neck. Eur J Pharmacol 2014; 723:246-52. [PMID: 24296318 DOI: 10.1016/j.ejphar.2013.11.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 11/12/2013] [Accepted: 11/22/2013] [Indexed: 10/25/2022]
Abstract
Progesterone increases bladder capacity and improves the bladder compliance by its relaxant action on the detrusor. A poor information, however, exists concerning to the role of this steroid hormone on the bladder outflow region contractility. This study investigates the progesterone-induced action on the smooth muscle tension of the pig bladder neck. To this aim, urothelium-denuded bladder neck strips were mounted in myographs for isometric force recordings and for simultaneous measurements of intracellular Ca(2+) concentration ([Ca(2+)]i) and tension. On phenylephrine (PhE)-precontracted strips, progesterone produced concentration-dependent relaxations only at high pharmacological concentrations. The blockade of progesterone receptors, nitric oxide (NO) synthase, guanylyl cyclase, large conductance Ca(2+)-activated K(+) (BKCa) or ATP-dependent K(+) (KATP) channels reduced the progesterone relaxations. The presence of the urothelium and the inhibition of cyclooxygenase (COX), intermediate- and small-conductance Ca(2+)-activated K(+) channels failed to modify these responses. In Ca(2+)-free potassium rich physiological saline solution, progesterone inhibited the contraction to CaCl2 and to the L-type voltage-operated Ca(2+) (VOC) channel activator BAY-K 8644. Relaxation induced by progesterone was accompanied by simultaneous decreases in smooth muscle [Ca(2+)]i. These results suggest that progesterone promotes relaxation of pig bladder neck through smooth muscle progesterone receptors via cGMP/NO pathway and involving the activation of BKCa and KATP channels and inhibition of the extracellular Ca(2+) entry through L-type VOC channels.
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Affiliation(s)
- Vítor S Fernandes
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Ana S F Ribeiro
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Ana Martínez-Sáenz
- Unidad Experimental, Fundación de Investigación Biomédica, Hospital Universitario Puerta de Hierro-Majadahonda, 28222 Madrid, Spain
| | - Igor Blaha
- Departamento de Urología, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain
| | - Daniel Serrano-Margüello
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Paz Recio
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Ana Cristina Martínez
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Salvador Bustamante
- Departamento de Urología, Hospital Universitario Puerta de Hierro-Majadahonda, 28222 Madrid, Spain
| | - David Vázquez-Alba
- Departamento de Urología, Hospital Universitario Puerta de Hierro-Majadahonda, 28222 Madrid, Spain
| | - Joaquín Carballido
- Departamento de Urología, Hospital Universitario Puerta de Hierro-Majadahonda, 28222 Madrid, Spain
| | - Albino García-Sacristán
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Medardo Hernández
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
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Sodium/calcium exchanger is upregulated by sulfide signaling, forms complex with the β1 and β3 but not β2 adrenergic receptors, and induces apoptosis. Pflugers Arch 2013; 466:1329-42. [PMID: 24114174 DOI: 10.1007/s00424-013-1366-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 09/06/2013] [Accepted: 09/20/2013] [Indexed: 10/26/2022]
Abstract
Hydrogen sulfide (H2S) as a novel gasotransmitter regulates variety of processes, including calcium transport systems. Sodium calcium exchanger (NCX) is one of the key players in a regulation calcium homeostasis. Thus, the aims of our work were to determine effect of sulfide signaling on the NCX type 1 (NCX1) expression and function in HeLa cells, to investigate the relationship of β-adrenergic receptors with the NCX1 in the presence and/or absence of H2S, and to determine physiological importance of this potential communication. As a H2S donor, we used morpholin-4-ium-4-methoxyphenyl(morpholino) phosphinodithioate-GYY4137. We observed increased levels of the NCX1 mRNA, protein, and activity after 24 h of GYY4137 treatment. This increase was accompanied by elevated cAMP due to the GYY4137 treatment, which was completely abolished, when NCX1 was silenced. Increased cAMP levels would point to upregulation of β-adrenergic receptors. Indeed, GYY4137 increased expression of β1 and β3 (but not β2) adrenergic receptors. These receptors co-precipitated, co-localized with the NCX1, and induced apoptosis in the presence of H2S. Our results suggest that sulfide signaling plays a role in regulation of the NCX1, β1 and β3 adrenergic receptors, their co-localization, and stimulation of apoptosis, which might be of a potential importance in cancer treatment.
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