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Koc A, Koc DS, Askin CI, Kara H, Ozturk Fincan GS, Ozger Ilhan S, Sarioglu Y. Effects of hydrogen sulfide on relaxation responses in the lower esophageal sphincter in rabbits: the potential role of potassium channels. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1537-1550. [PMID: 37668686 DOI: 10.1007/s00210-023-02695-z] [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: 04/06/2023] [Accepted: 08/25/2023] [Indexed: 09/06/2023]
Abstract
Hydrogen sulfide (H2S) is a significant physiologic inhibitory neurotransmitter. The main goal of this research was to examine the contribution of diverse potassium (K+) channels and nitric oxide (NO) in mediating the H2S effect on electrical field stimulation (EFS)-induced neurogenic contractile responses in the lower esophageal sphincter (LES). EFS-induced contractile responses of rabbit isolated LES strips were recorded using force transducers in organ baths that contain Krebs-Henseleit solutions (20 ml). Cumulative doses of NaHS, L-cysteine, PAG, and AOAA were evaluated in NO-dependent and NO-independent groups. The experiments were conducted again in the presence of K+ channel blockers. In both NO-dependent and NO-independent groups, NaHS, L-cysteine, PAG, and AOAA significantly reduced EFS-induced contractile responses. In the NO-dependent group, the effect of NaHS and L-cysteine decreased in the presence of 4-AP, and also the effect of NaHS decreased in the NO-dependent and independent group in the presence of TEA. In the NO-independent group, K+ channel blockers didn't change L-cysteine-induced relaxations. K+ channel blockers had no impact on the effects of PAG and AOAA. In addition, NaHS significantly relaxed 80-mM KCl-induced contractions, whereas L-cysteine, PAG, and AOAA did not. In the present study, H2S decreased the amplitudes of EFS-induced contraction responses. These results suggest that Kv channels and NO significantly contribute to exogenous H2S and endogenous H2S precursor L-cysteine inhibitory effect on lower esophageal sphincter smooth muscle.
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Affiliation(s)
- Aysegul Koc
- Department of Medical Pharmacology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Derya Sebile Koc
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Celil Ilker Askin
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Halil Kara
- Department of Medical Pharmacology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey.
| | | | - Sevil Ozger Ilhan
- Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Yusuf Sarioglu
- Department of Medical Pharmacology, Faculty of Medicine, Istinye University, Istanbul, Turkey
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Chen H, Li K, Qin Y, Zhou J, Li T, Qian L, Yang C, Ji X, Wu D. Recent advances in the role of endogenous hydrogen sulphide in cancer cells. Cell Prolif 2023; 56:e13449. [PMID: 36929586 PMCID: PMC10472536 DOI: 10.1111/cpr.13449] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/16/2023] [Accepted: 03/02/2023] [Indexed: 03/18/2023] Open
Abstract
Hydrogen sulphide (H2 S) is a gaseous neurotransmitter that can be self-synthesized by living organisms. With the deepening of research, the pathophysiological mechanisms of endogenous H2 S in cancer have been increasingly elucidated: (1) promote angiogenesis, (2) stimulate cell bioenergetics, (3) promote migration and proliferation thereby invasion, (4) inhibit apoptosis and (5) activate abnormal cell cycle. However, the increasing H2 S levels via exogenous sources show the opposite trend. This phenomenon can be explained by the bell-shaped pharmacological model of H2 S, that is, the production of endogenous (low concentration) H2 S promotes tumour growth while the exogenous (high concentration) H2 S inhibits tumour growth. Here, we review the impact of endogenous H2 S synthesis and metabolism on tumour progression, summarize the mechanism of action of H2 S in tumour growth, and discuss the possibility of H2 S as a potential target for tumour treatment.
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Affiliation(s)
- Hao‐Jie Chen
- School of Basic Medical SciencesHenan UniversityKaifengHenan475004China
- Henan International Joint Laboratory for Nuclear Protein RegulationHenan UniversityKaifengHenan475004China
| | - Ke Li
- School of Basic Medical SciencesHenan UniversityKaifengHenan475004China
- Henan International Joint Laboratory for Nuclear Protein RegulationHenan UniversityKaifengHenan475004China
| | - Yang‐Zhe Qin
- School of Basic Medical SciencesHenan UniversityKaifengHenan475004China
- Henan International Joint Laboratory for Nuclear Protein RegulationHenan UniversityKaifengHenan475004China
| | - Jing‐Jing Zhou
- School of Basic Medical SciencesHenan UniversityKaifengHenan475004China
- Henan International Joint Laboratory for Nuclear Protein RegulationHenan UniversityKaifengHenan475004China
| | - Tao Li
- School of Basic Medical SciencesHenan UniversityKaifengHenan475004China
- Henan International Joint Laboratory for Nuclear Protein RegulationHenan UniversityKaifengHenan475004China
| | - Lei Qian
- School of Basic Medical SciencesHenan UniversityKaifengHenan475004China
- Henan International Joint Laboratory for Nuclear Protein RegulationHenan UniversityKaifengHenan475004China
| | - Chang‐Yong Yang
- School of Nursing and HealthHenan UniversityKaifengHenan475004China
| | - Xin‐Ying Ji
- School of Basic Medical SciencesHenan UniversityKaifengHenan475004China
- Henan International Joint Laboratory for Nuclear Protein RegulationHenan UniversityKaifengHenan475004China
- Kaifeng Key Laboratory of Infection and Biological Safety, School of Basic Medical SciencesHenan UniversityKaifengHenan475004China
| | - Dong‐Dong Wu
- School of Basic Medical SciencesHenan UniversityKaifengHenan475004China
- Henan International Joint Laboratory for Nuclear Protein RegulationHenan UniversityKaifengHenan475004China
- School of StomatologyHenan UniversityKaifengHenan475004China
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Rao SP, Dobariya P, Bellamkonda H, More SS. Role of 3-Mercaptopyruvate Sulfurtransferase (3-MST) in Physiology and Disease. Antioxidants (Basel) 2023; 12:antiox12030603. [PMID: 36978851 PMCID: PMC10045210 DOI: 10.3390/antiox12030603] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/25/2023] [Accepted: 02/26/2023] [Indexed: 03/05/2023] Open
Abstract
3-mercaptopyruvate sulfurtransferase (3-MST) plays the important role of producing hydrogen sulfide. Conserved from bacteria to Mammalia, this enzyme is localized in mitochondria as well as the cytoplasm. 3-MST mediates the reaction of 3-mercaptopyruvate with dihydrolipoic acid and thioredoxin to produce hydrogen sulfide. Hydrogen sulfide is also produced through cystathionine beta-synthase and cystathionine gamma-lyase, along with 3-MST, and is known to alleviate a variety of illnesses such as cancer, heart disease, and neurological conditions. The importance of cystathionine beta-synthase and cystathionine gamma-lyase in hydrogen sulfide biogenesis is well-described, but documentation of the 3-MST pathway is limited. This account compiles the current state of knowledge about the role of 3-MST in physiology and pathology. Attempts at targeting the 3-MST pathway for therapeutic benefit are discussed, highlighting the potential of 3-MST as a therapeutic target.
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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: 239] [Impact Index Per Article: 79.7] [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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Zhu C, Liu Q, Li X, Wei R, Ge T, Zheng X, Li B, Liu K, Cui R. Hydrogen sulfide: A new therapeutic target in vascular diseases. Front Endocrinol (Lausanne) 2022; 13:934231. [PMID: 36034427 PMCID: PMC9399516 DOI: 10.3389/fendo.2022.934231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Hydrogen sulfide (H2S) is one of most important gas transmitters. H2S modulates many physiological and pathological processes such as inflammation, oxidative stress and cell apoptosis that play a critical role in vascular function. Recently, solid evidence show that H2S is closely associated to various vascular diseases. However, specific function of H2S remains unclear. Therefore, in this review we systemically summarized the role of H2S in vascular diseases, including hypertension, atherosclerosis, inflammation and angiogenesis. In addition, this review also outlined a novel therapeutic perspective comprising crosstalk between H2S and smooth muscle cell function. Therefore, this review may provide new insight inH2S application clinically.
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Affiliation(s)
- Cuilin Zhu
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Qing Liu
- Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan
| | - Xin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Ran Wei
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Tongtong Ge
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Xiufen Zheng
- Department of Surgery, Western University, London, ON, Canada
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
| | - Kexiang Liu
- Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Ranji Cui, ; Kexiang Liu,
| | - Ranji Cui
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Ranji Cui, ; Kexiang Liu,
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The Role of Hydrogen Sulfide in Respiratory Diseases. Biomolecules 2021; 11:biom11050682. [PMID: 34062820 PMCID: PMC8147381 DOI: 10.3390/biom11050682] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 04/27/2021] [Accepted: 04/27/2021] [Indexed: 02/08/2023] Open
Abstract
Respiratory diseases are leading causes of death and disability around the globe, with a diverse range of health problems. Treatment of respiratory diseases and infections has been verified to be thought-provoking because of the increasing incidence and mortality rate. Hydrogen sulfide (H2S) is one of the recognized gaseous transmitters involved in an extensive range of cellular functions, and physiological and pathological processes in a variety of diseases, including respiratory diseases. Recently, the therapeutic potential of H2S for respiratory diseases has been widely investigated. H2S plays a vital therapeutic role in obstructive respiratory disease, pulmonary fibrosis, emphysema, pancreatic inflammatory/respiratory lung injury, pulmonary inflammation, bronchial asthma and bronchiectasis. Although the therapeutic role of H2S has been extensively studied in various respiratory diseases, a concrete literature review will have an extraordinary impact on future therapeutics. This review provides a comprehensive overview of the effective role of H2S in respiratory diseases. Besides, we also summarized H2S production in the lung and its metabolism processes in respiratory diseases.
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Fuschillo S, Palomba L, Capparelli R, Motta A, Maniscalco M. Nitric Oxide and Hydrogen Sulfide: A Nice Pair in the Respiratory System. Curr Med Chem 2020; 27:7136-7148. [DOI: 10.2174/0929867327666200310120550] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 01/25/2020] [Accepted: 02/05/2020] [Indexed: 01/15/2023]
Abstract
Nitric Oxide (NO) is internationally regarded as a signal molecule involved in several
functions in the respiratory tract under physiological and pathogenic conditions. Hydrogen Sulfide
(H2S) has also recently been recognized as a new gasotransmitter with a diverse range of functions
similar to those of NO.
Depending on their respective concentrations, both these molecules act synergistically or antagonistically
as signals or damage promoters. Nevertheless, available evidence shows that the complex
biological connections between NO and H2S involve multiple pathways and depend on the site of
action in the respiratory tract, as well as on experimental conditions. This review will provide an
update on these two gasotransmitters in physiological and pathological processes.
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Affiliation(s)
- Salvatore Fuschillo
- Istituti Clinici Scientifici Maugeri IRCCS, Pulmonary Rehabilitation Division of the Telese Terme Institute, 82037 Telese Terme (BN), Italy
| | - Letizia Palomba
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino (PU), Italy
| | - Rosanna Capparelli
- Department of Agriculture, University of Naples “Federico II”, 80055 Portici, (NA), Italy
| | - Andrea Motta
- Institute of Biomolecular Chemistry, National Research Council, 80078 Pozzuoli (NA), Italy
| | - Mauro Maniscalco
- Istituti Clinici Scientifici Maugeri IRCCS, Pulmonary Rehabilitation Division of the Telese Terme Institute, 82037 Telese Terme (BN), Italy
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Zuhra K, Augsburger F, Majtan T, Szabo C. Cystathionine-β-Synthase: Molecular Regulation and Pharmacological Inhibition. Biomolecules 2020; 10:E697. [PMID: 32365821 PMCID: PMC7277093 DOI: 10.3390/biom10050697] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/11/2022] Open
Abstract
Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used "CBS inhibitors" (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.
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Affiliation(s)
- Karim Zuhra
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
| | - Fiona Augsburger
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
| | - Tomas Majtan
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Csaba Szabo
- Chair of Pharmacology, Section of Medicine, University of Fribourg, 1702 Fribourg, Switzerland; (K.Z.); (F.A.)
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Gan X, Huang JC, Zhou C, He S, Zhou W. Relationship between selenium removal efficiency and production of lipid and hydrogen by Chlorella vulgaris. CHEMOSPHERE 2019; 217:825-832. [PMID: 30458418 DOI: 10.1016/j.chemosphere.2018.11.075] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 10/27/2018] [Accepted: 11/11/2018] [Indexed: 06/09/2023]
Abstract
In our previous studies, Chlorella vulgaris had proven highly efficient in removing selenium (Se) from water, while the disposal of Se containing in algal biomass was still an issue of concern. Firstly, this research suggests algal Se could be released back to water, posing risks to aquatic wildlife. Thus, we further explored the possibility of using C. vulgaris to remove Se and produce lipid and hydrogen simultaneously. Our results show the higher percentage of saturated fatty acids, especially palmitic acid, was found in the sulfur (S) deprived algae exposed to either selenate or selenite, although the highest lipid content (21.9%) was found in the selenite treated algae in full BG11 medium. In addition, compared with the Se free algae, hydrogen production rate was 2.1- and 4.3-fold higher for the selenate and selenite treated algae, respectively. Se removal efficiency achieved by the selenite treated algae through accumulation and volatilization was 2.3-fold higher than the selenate treatment under hypoxic condition with S deprived, which is in contrast to the results obtained under aerobic conditions.
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Affiliation(s)
- Xinyu Gan
- School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China
| | - Jung-Chen Huang
- School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China.
| | - Chuanqi Zhou
- School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China
| | - Shengbing He
- School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China
| | - Weili Zhou
- School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, PR China
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10
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Abstract
In several animal and human studies, the contribution of the endothelium, nitric oxide/soluble guanosine monophosphate (NO/cGMP) pathway, adenylyl cyclase, phosphodiesterase (PDE), potassium (K+) channels, L-type calcium channels, Na+-K+-ATPase, muscarinic acetylcholine receptors, RhoA/Rho-kinase pathway, and cyclooxygenase (COX)/arachidonic acid cascade on the relaxant mechanism of L-cysteine/H2S pathway in corpus cavernosum has been investigated. In this chapter the relaxant mechanisms of H2S in corpus cavernosum is discussed with data available in the current relevant literature. Also, in vitro experimental procedure for mice corpus cavernosum which used to investigate the relaxant effect of H2S is given in detail.
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Donovan J, Wong PS, Garle MJ, Alexander SPH, Dunn WR, Ralevic V. Coronary artery hypoxic vasorelaxation is augmented by perivascular adipose tissue through a mechanism involving hydrogen sulphide and cystathionine-β-synthase. Acta Physiol (Oxf) 2018; 224:e13126. [PMID: 29896909 DOI: 10.1111/apha.13126] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 06/08/2018] [Accepted: 06/09/2018] [Indexed: 11/28/2022]
Abstract
AIM Hypoxia causes vasodilatation of coronary arteries which protects the heart from ischaemic damage through mechanisms including the generation of hydrogen sulphide (H2 S), but the influence of the perivascular adipose tissue (PVAT) and myocardium is incompletely understood. This study aimed to determine whether PVAT and the myocardium modulate the coronary artery hypoxic response and whether this involves hydrogen sulphide. METHODS Porcine left circumflex coronary arteries were prepared as cleaned segments and with PVAT intact, myocardium intact or both PVAT and myocardium intact, and contractility investigated using isometric tension recording. Immunoblotting was used to measure levels of H2 S-synthesizing enzymes: cystathionine-β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (MPST). RESULTS All three H2 S-synthesizing enzymes were detected in the artery and myocardium, but only CBS and MPST were detected in PVAT. Hypoxia elicited a biphasic response in cleaned artery segments consisting of transient contraction followed by prolonged relaxation. In arteries with PVAT intact, hypoxic contraction was attenuated and relaxation augmented. In arteries with myocardium intact, hypoxic contraction was attenuated, but relaxation was unaffected. In replacement experiments, replacement of dissected PVAT and myocardium attenuated artery contraction and augmented relaxation to hypoxia, mimicking the effect of in situ PVAT and indicating involvement of a diffusible factor(s). In arteries with intact PVAT, augmentation of hypoxic relaxation was reversed by amino-oxyacetate (CBS inhibitor), but not DL-propargylglycine (CSE inhibitor) or aspartate (inhibits MPST pathway). CONCLUSION PVAT augments hypoxic relaxation of coronary arteries through a mechanism involving H2 S and CBS, pointing to an important role in regulation of coronary blood flow during hypoxia.
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Affiliation(s)
- J. Donovan
- School of Life Sciences; University of Nottingham; Nottingham UK
| | - P. S. Wong
- School of Life Sciences; University of Nottingham; Nottingham UK
| | - M. J. Garle
- School of Life Sciences; University of Nottingham; Nottingham UK
| | | | - W. R. Dunn
- School of Life Sciences; University of Nottingham; Nottingham UK
| | - V. Ralevic
- School of Life Sciences; University of Nottingham; Nottingham UK
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12
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The interaction of l -cysteine/H 2 S pathway and muscarinic acetylcholine receptors (mAChRs) in mouse corpus cavernosum. Nitric Oxide 2017; 70:51-58. [DOI: 10.1016/j.niox.2017.08.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 07/26/2017] [Accepted: 08/22/2017] [Indexed: 12/19/2022]
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13
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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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14
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Tan XX, Lian KQ, Li X, Li N, Wang W, Kang WJ, Shi HM. Development of a derivatization method for the quantification of hydrogen sulfide and its application in vascular calcification rats. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1055-1056:8-14. [DOI: 10.1016/j.jchromb.2017.04.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Revised: 02/28/2017] [Accepted: 04/12/2017] [Indexed: 01/27/2023]
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15
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Donovan J, Wong PS, Roberts RE, Garle MJ, Alexander SPH, Dunn WR, Ralevic V. A critical role for cystathionine-β-synthase in hydrogen sulfide-mediated hypoxic relaxation of the coronary artery. Vascul Pharmacol 2017; 93-95:20-32. [PMID: 28552745 DOI: 10.1016/j.vph.2017.05.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 05/22/2017] [Accepted: 05/22/2017] [Indexed: 01/27/2023]
Abstract
Hypoxia-induced coronary artery vasodilatation protects the heart by increasing blood flow under ischemic conditions, however its mechanism is not fully elucidated. Hydrogen sulfide (H2S) is reported to be an oxygen sensor/transducer in the vasculature. The present study aimed to identify and characterise the role of H2S in the hypoxic response of the coronary artery, and to define the H2S synthetic enzymes involved. Immunoblotting and immunohistochemistry showed expression of all three H2S-producing enzymes, cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST), in porcine coronary artery. Artery segments were mounted for isometric tension recording; hypoxia caused a transient endothelium-dependent contraction followed by prolonged endothelium-independent relaxation. The CBS inhibitor amino-oxyacetate (AOAA) reduced both phases of the hypoxic response. The CSE inhibitor dl-propargylglycine (PPG) and aspartate (limits MPST) had no effect alone, but when applied together with AOAA the hypoxic relaxation response was further reduced. Exogenous H2S (Na2S and NaHS) produced concentration-dependent contraction followed by prolonged relaxation. Responses to both hypoxia and exogenous H2S were dependent on the endothelium, NO, cGMP, K+ channels and Cl-/HCO3- exchange. H2S production in coronary arteries was blocked by CBS inhibition (AOAA), but not by CSE inhibition (PPG). These data show that H2S is an endogenous mediator of the hypoxic response in coronary arteries. Of the three H2S-producing enzymes, CBS, expressed in the vascular smooth muscle, appears to be the most important for H2S generated during hypoxic relaxation of the coronary artery. A contribution from other H2S-producing enzymes only becomes apparent when CBS activity is inhibited.
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Affiliation(s)
- J Donovan
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - P S Wong
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - R E Roberts
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - M J Garle
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - S P H Alexander
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - W R Dunn
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - V Ralevic
- School of Life Sciences, University of Nottingham, Nottingham, UK.
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Sensitivity of salivary hydrogen sulfide to psychological stress and its association with exhaled nitric oxide and affect. Physiol Behav 2017; 179:99-104. [PMID: 28527680 DOI: 10.1016/j.physbeh.2017.05.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/28/2017] [Accepted: 05/17/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hydrogen sulfide (H2S) is the third gasotransmitter recently discovered after nitric oxide (NO) and carbon monoxide. Both NO and H2S are involved in multiple physiological functions. Whereas NO has been shown to vary with psychological stress, the influence of stress on H2S and the relationship between H2S and NO are unknown. We therefore examined levels of salivary H2S and NO in response to a stressful final academic exam period. METHODS Measurements of stress, negative affect, and fraction of exhaled NO (FENO), were obtained from students (N=16) and saliva was collected at three time points: low-stress period in the semester, early exam period, and late exam period. Saliva was immediately analyzed for H2S with the fluorescent probe Sulfidefluor-4. RESULTS H2S increased significantly during the early exam period and FENO decreased gradually towards the late exam period. H2S, FENO, negative affect, and stress ratings were positively associated with each other: as stress level and negative affect increased, values of H2S increased; in addition, as FENO levels decreased, H2S also decreased. Asthma status did not modify these associations. CONCLUSION Sustained academic stress increases H2S and these changes are correlated with NO and the experience of stress and negative affect. These findings motivate research with larger samples to further explore the interaction and function of H2S and FENO during psychological stress.
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Aydinoglu F, Ogulener N. Characterization of relaxant mechanism of H2 S in mouse corpus cavernosum. Clin Exp Pharmacol Physiol 2016; 43:503-11. [PMID: 26845078 DOI: 10.1111/1440-1681.12554] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 01/28/2016] [Accepted: 01/29/2016] [Indexed: 01/22/2023]
Abstract
The aim of this study was to investigate the mechanism of H2 S-induced relaxation in mouse corpus cavernosal tissue. l-cysteine (10(-6) × 10(-3) mol/L) and exogenous H2 S (NaHS; 10(-6) to 10(-3) mol/L) induced concentration-dependent relaxation. l-cysteine-induced relaxations was reduced by d,l-propargylglycine, a cystathionine gamma lyase (CSE) inhibitor but not influenced by aminooxyacetic acid, a cystathionine beta synthase (CBS) inhibitor. l-cysteine induced relaxations, but not of those of H2 S diminished in endothelium-denuded tissues. N(ω) -nitro-l-arginine (l-NA; 10(-4) mol/L), a nitric oxide synthase inhibitor, and ODQ (10(-4) mol/L), a guanylyl cyclase inhibitor, increased the H2 S-induced relaxation. Zaprinast (5 × 10(-6) mol/L) and sildenafil (10(-6) mol/L), phosphodiesterase inhibitors, inhibited H2 S-induced relaxation. Adenylyl cyclase inhibitors N-ethylmaleimide (2.5 × 10(-5) mol/L) and SQ22536 (10(-4) mol/L) reduced relaxation to H2 S. Also, H2 S-induced relaxation was reduced by KCl (50 mmol/L), 4-aminopyridine (10(-3) mol/L), a Kv inhibitor, glibenclamide (10(-5) mol/L), a KATP inhibitor or barium chloride (10(-5) mol/L), a KIR inhibitor. However, H2 S-induced relaxation was not influenced by apamin (10(-6) mol/L), a SKC a (2+) inhibitor, charybdotoxin (10(-7) mol/L), an IKC a (2+) and BKC a (2+) inhibitor or combination of apamin and charybdotoxin. Nifedipine (10(-6) mol/L), an L-type calcium channel blocker and atropine (10(-6) mol/L), a muscarinic receptor blocker, inhibited H2 S-induced relaxation. However, H2 S-induced relaxation was not influenced by ouabain (10(-4) mol/L), a Na(+) /K(+) -ATPase inhibitor. This study suggests that H2 S endogenously synthesizes from l-cysteine by CSE endothelium-dependent in mouse corpus cavernosum tissue, and exogenous H2 S may cause endothelium-independent relaxations via activation of K channels (KATP channel, KV channels, KIR channels), L-type voltage-gated Ca(2+) channels, adenylyl cyclase/cAMP pathway and muscarinic receptor, and there is the interaction between H2 S and NO/cGMP.
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Affiliation(s)
- Fatma Aydinoglu
- Department of Pharmacology, Pharmacy Faculty, Çukurova University, Adana, Turkey
| | - Nuran Ogulener
- Department of Pharmacology, Medical Faculty, Çukurova University, Adana, Turkey
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18
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Fernandes VS, Recio P, López-Oliva E, Martínez MP, Ribeiro AS, Barahona MV, Martínez AC, Benedito S, Agis-Torres Á, Cabañero A, Muñoz GM, García-Sacristán A, Orensanz LM, Hernández M. Role of endogenous hydrogen sulfide in nerve-evoked relaxation of pig terminal bronchioles. Pulm Pharmacol Ther 2016; 41:1-10. [PMID: 27603231 DOI: 10.1016/j.pupt.2016.09.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 08/05/2016] [Accepted: 09/02/2016] [Indexed: 12/26/2022]
Abstract
Hydrogen sulfide (H2S) is a gasotransmitter employed for intra- and inter-cellular communication in almost all organ systems. This study investigates the role of endogenous H2S in nerve-evoked relaxation of pig terminal bronchioles with 260 μm medium internal lumen diameter. High expression of the H2S synthesis enzyme cystathionine γ-lyase (CSE) in the bronchiolar muscle layer and strong CSE-immunoreactivity within nerve fibers distributed along smooth muscle bundles were observed. Further, endogenous H2S generated in bronchiolar membranes was reduced by CSE inhibition. In contrast, cystathionine β-synthase expression, another H2S synthesis enzyme, however was not consistently detected in the bronchiolar smooth muscle layer. Electrical field stimulation (EFS) and the H2S donor P-(4-methoxyphenyl)-P-4-morpholinylphosphinodithioic acid (GYY4137) evoked smooth muscle relaxation. Inhibition of CSE, nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and of ATP-dependent K+, transient receptor potential A1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) channels reduced the EFS relaxation but failed to modify the GYY4137 response. Raising extracellular K+ concentration inhibited the GYY4137 relaxation. Large conductance Ca2+-activated K+ channel blockade reduced both EFS and GYY4137 responses. GYY4137 inhibited the contractions induced by histamine and reduced to a lesser extent the histamine-induced increases in intracellular [Ca2+]. These results suggest that relaxation induced by EFS in the pig terminal bronchioles partly involves the H2S/CSE pathway. H2S response is produced via NO/sGC-independent mechanisms involving K+ channels and intracellular Ca2+ desensitization-dependent pathways. Thus, based on our current results H2S donors might be useful as bronchodilator agents for the treatment of lung diseases with persistent airflow limitation, such as asthma and chronic obstructive lung disease.
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Affiliation(s)
- Vítor S Fernandes
- 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
| | - Elvira López-Oliva
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - María Pilar Martínez
- Departamento de Anatomía y Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Ana Sofía Ribeiro
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - María Victoria Barahona
- Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Ana Cristina Martínez
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Sara Benedito
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Ángel Agis-Torres
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Alberto Cabañero
- Servicio de Cirugía Torácica, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Gemma M Muñoz
- Servicio de Cirugía Torácica, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Albino García-Sacristán
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Luis M Orensanz
- Servicio de Neurobiología-Investigación, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Medardo Hernández
- Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
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Krause NC, Kutsche HS, Santangelo F, DeLeon ER, Dittrich NP, Olson KR, Althaus M. Hydrogen sulfide contributes to hypoxic inhibition of airway transepithelial sodium absorption. Am J Physiol Regul Integr Comp Physiol 2016; 311:R607-17. [DOI: 10.1152/ajpregu.00177.2016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 07/13/2016] [Indexed: 01/23/2023]
Abstract
In lung epithelial cells, hypoxia decreases the expression and activity of sodium-transporting molecules, thereby reducing the rate of transepithelial sodium absorption. The mechanisms underlying the sensing of hypoxia and subsequent coupling to sodium-transporting molecules remain unclear. Hydrogen sulfide (H2S) has recently been recognized as a cellular signaling molecule whose intracellular concentrations critically depend on oxygen levels. Therefore, it was questioned whether endogenously produced H2S contributes to hypoxic inhibition of sodium transport. In electrophysiological Ussing chamber experiments, hypoxia was established by decreasing oxygen concentrations in the chambers. Hypoxia concentration dependently and reversibly decreased amiloride-sensitive sodium absorption by cultured H441 monolayers and freshly dissected porcine tracheal epithelia due to inhibition of basolateral Na+/K+-ATPase. Exogenous application of H2S by the sulfur salt Na2S mimicked the effect of hypoxia and inhibited amiloride-sensitive sodium absorption by both tissues in an oxygen-dependent manner. Hypoxia increased intracellular concentrations of H2S and decreased the concentration of polysulfides. Pretreatment with the cystathionine-γ-lyase inhibitor d/l-propargylglycine (PAG) decreased hypoxic inhibition of sodium transport by H441 monolayers, whereas inhibition of cystathionine-β-synthase (with aminooxy-acetic acid; AOAA) or 3-mercaptopyruvate sulfurtransferase (with aspartate) had no effect. Inhibition of all of these H2S-generating enzymes with a combination of AOAA, PAG, and aspartate decreased the hypoxic inhibition of sodium transport by H441 cells and pig tracheae and decreased H2S production by tracheae. These data suggest that airway epithelial cells endogenously produce H2S during hypoxia, and this contributes to hypoxic inhibition of transepithelial sodium absorption.
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Affiliation(s)
- Nicole C. Krause
- Institute for Animal Physiology, Justus-Liebig-University, Giessen, Germany; and
| | - Hanna S. Kutsche
- Institute for Animal Physiology, Justus-Liebig-University, Giessen, Germany; and
| | - Fabrizio Santangelo
- Institute for Animal Physiology, Justus-Liebig-University, Giessen, Germany; and
| | - Eric R. DeLeon
- Department of Physiology, Indiana University School of Medicine-South Bend, South Bend, Indiana
| | - Nikolaus P. Dittrich
- Institute for Animal Physiology, Justus-Liebig-University, Giessen, Germany; and
| | - Kenneth R. Olson
- Department of Physiology, Indiana University School of Medicine-South Bend, South Bend, Indiana
| | - Mike Althaus
- Institute for Animal Physiology, Justus-Liebig-University, Giessen, Germany; and
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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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21
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Meng G, Ma Y, Xie L, Ferro A, Ji Y. Emerging role of hydrogen sulfide in hypertension and related cardiovascular diseases. Br J Pharmacol 2015; 172:5501-11. [PMID: 25204754 PMCID: PMC4667855 DOI: 10.1111/bph.12900] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Revised: 08/18/2014] [Accepted: 08/28/2014] [Indexed: 12/31/2022] Open
Abstract
Hydrogen sulfide (H2 S) has traditionally been viewed as a highly toxic gas; however, recent studies have implicated H2 S as a third member of the gasotransmitter family, exhibiting properties similar to NO and carbon monoxide. Accumulating evidence has suggested that H2 S influences a wide range of physiological and pathological processes, among which blood vessel relaxation, cardioprotection and atherosclerosis have been particularly studied. In the cardiovascular system, H2 S production is predominantly catalyzed by cystathionine γ-lyase (CSE). Decreased endogenous H2 S levels have been found in hypertensive patients and animals, and CSE(-/-) mice develop hypertension with age, suggesting that a deficiency in H2 S contributes importantly to BP regulation. H2 S supplementation attenuates hypertension in different hypertensive animal models. The mechanism by which H2 S was originally proposed to attenuate hypertension was by virtue of its action on vascular tone, which may be related to effects on different ion channels. Both H2 S and NO cause vasodilatation and there is cross-talk between these two molecules to regulate BP. Suppression of oxidative stress may also contribute to antihypertensive effects of H2 S. This review also summarizes the state of research on H2 S and hypertension in China. A better understanding of the role of H2 S in hypertension and related cardiovascular diseases will allow novel strategies to be devised for their treatment.
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Affiliation(s)
- Guoliang Meng
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research CentreNanjing Medical UniversityNanjingChina
| | - Yan Ma
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research CentreNanjing Medical UniversityNanjingChina
| | - Liping Xie
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research CentreNanjing Medical UniversityNanjingChina
| | - Albert Ferro
- Department of Clinical PharmacologyCardiovascular DivisionSchool of MedicineKing's College LondonLondonUK
| | - Yong Ji
- Key Laboratory of Cardiovascular Disease and Molecular Intervention, State Key Laboratory of Reproductive Medicine, Atherosclerosis Research CentreNanjing Medical UniversityNanjingChina
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22
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Hatziefthimiou A, Stamatiou R. Role of hydrogen sulphide in airways. World J Respirol 2015; 5:152-159. [DOI: 10.5320/wjr.v5.i2.152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 02/04/2015] [Accepted: 03/09/2015] [Indexed: 02/06/2023] Open
Abstract
The toxicity of hydrogen sulfide (H2S) has been known for a long time, as it is prevalent in the atmosphere. However accumulative data suggest that H2S is also endogenously produced in mammals, including man, and is the third important gas signaling molecule, besides nitric oxide and carbon monoxide. H2S can be produced via non enzymatic pathways, but is mainly synthesized from L-cysteine by the enzymes cystathionine-γ-lyase, cystathionine-β-synthetase, cysteine amino transferase and 3-mercaptopyruvate sulfurtransferase (3MTS). The formation of H2S from D-cysteine via the enzyme D-amino acid oxidase and 3MTS has also been described. Endogenous H2S not only participates in the regulation of physiological functions of the respiratory system, but also seems to contribute to the pathophysiology of airway diseases such as chronic obstructive pulmonary disease, asthma and pulmonary fibrosis, as well as in inflammation, suggesting its possible use as a biomarker for these diseases. This review summarizes the different implications of hydrogen sulfide in the physiology of airways and the pathophysiology of airway diseases.
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23
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Mijušković A, Kokić AN, Dušić ZO, Slavić M, Spasić MB, Blagojević D. Chloride channels mediate sodium sulphide-induced relaxation in rat uteri. Br J Pharmacol 2015; 172:3671-86. [PMID: 25857480 DOI: 10.1111/bph.13161] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 03/23/2015] [Accepted: 03/30/2015] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND AND PURPOSE Hydrogen sulphide reduces uterine contractility and is of potential interest as a treatment for uterine disorders. The aim of this study was to explore the mechanism of sodium sulphide (Na2 S)-induced relaxation of rat uterus, investigate the importance of redox effects and ion channel-mediated mechanisms, and any interactions between these two mechanisms. EXPERIMENTAL APPROACH Organ bath studies were employed to assess the pharmacological effects of Na2 S in uterine strips by exposing them to Na2 S with or without Cl(-) channel blockers (DIDS, NFA, IAA-94, T16Ainh-A01, TA), raised KCl (15 and 75 mM), K(+) channel inhibitors (glibenclamide, TEA, 4-AP), L-type Ca(2+) channel activator (S-Bay K 8644), propranolol and methylene blue. The activities of antioxidant enzymes were measured in homogenates of treated uteri. The expression of bestrophin channel 1 (BEST-1) was determined by Western blotting and RT-PCR. KEY RESULTS Na2 S caused concentration-dependent reversible relaxation of spontaneously active and calcium-treated uteri, affecting both amplitude and frequency of contractions. Uteri exposed to 75 mM KCl were less sensitive to Na2 S compared with uteri in 15 mM KCl. Na2 S-induced relaxations were abolished by DIDS, but unaffected by other modulators or by the absence of extracellular HCO3 (-) , suggesting the involvement of chloride ion channels. Na2 S in combination with different modulators provoked specific changes in the anti-oxidant profiles of uteri. The expression of BEST-1, both mRNA and protein, was demonstrated in rat uteri. CONCLUSIONS AND IMPLICATIONS The relaxant effects of Na2 S in rat uteri are mediated mainly via a DIDS-sensitive Cl(-) -pathway. Components of the relaxation are redox- and Ca(2+) -dependent.
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Affiliation(s)
- Ana Mijušković
- Department of Physiology, Institute for Biological Research 'Siniša Stanković', University of Belgrade, Belgrade, Serbia
| | - Aleksandra Nikolić Kokić
- Department of Physiology, Institute for Biological Research 'Siniša Stanković', University of Belgrade, Belgrade, Serbia
| | - Zorana Oreščanin Dušić
- Department of Physiology, Institute for Biological Research 'Siniša Stanković', University of Belgrade, Belgrade, Serbia
| | - Marija Slavić
- Department of Physiology, Institute for Biological Research 'Siniša Stanković', University of Belgrade, Belgrade, Serbia
| | - Mihajlo B Spasić
- Department of Physiology, Institute for Biological Research 'Siniša Stanković', University of Belgrade, Belgrade, Serbia
| | - Duško Blagojević
- Department of Physiology, Institute for Biological Research 'Siniša Stanković', University of Belgrade, Belgrade, Serbia
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Potential role of hydrogen sulphide from 3-mercaptopyruvate sulphurtransferase (3-MST) in epithelium-dependent relaxation of the airways. Nitric Oxide 2015. [DOI: 10.1016/j.niox.2015.02.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Agné AM, Baldin JP, Benjamin AR, Orogo-Wenn MC, Wichmann L, Olson KR, Walters DV, Althaus M. Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption. Am J Physiol Regul Integr Comp Physiol 2015; 308:R636-49. [PMID: 25632025 DOI: 10.1152/ajpregu.00489.2014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 01/19/2015] [Indexed: 01/11/2023]
Abstract
In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5-50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance.
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Affiliation(s)
- Alisa M Agné
- Institute of Animal Physiology, Department of Molecular Cell Physiology, Justus-Liebig University, Giessen, Germany
| | - Jan-Peter Baldin
- Institute of Animal Physiology, Department of Molecular Cell Physiology, Justus-Liebig University, Giessen, Germany
| | - Audra R Benjamin
- Division of Clinical Sciences, St. George's University of London, London, United Kingdom
| | - Maria C Orogo-Wenn
- Division of Clinical Sciences, St. George's University of London, London, United Kingdom
| | - Lukas Wichmann
- Institute of Animal Physiology, Department of Molecular Cell Physiology, Justus-Liebig University, Giessen, Germany
| | - Kenneth R Olson
- Department of Physiology, Indiana University School of Medicine-South Bend, South Bend, Indiana; and
| | - Dafydd V Walters
- Division of Clinical Sciences, St. George's University of London, London, United Kingdom
| | - Mike Althaus
- Institute of Animal Physiology, Department of Molecular Cell Physiology, Justus-Liebig University, Giessen, Germany;
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Módis K, Bos EM, Calzia E, van Goor H, Coletta C, Papapetropoulos A, Hellmich MR, Radermacher P, Bouillaud F, Szabo C. Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part II. Pathophysiological and therapeutic aspects. Br J Pharmacol 2014; 171:2123-46. [PMID: 23991749 DOI: 10.1111/bph.12368] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Revised: 07/30/2013] [Accepted: 08/05/2013] [Indexed: 12/15/2022] Open
Abstract
Emerging work demonstrates the dual regulation of mitochondrial function by hydrogen sulfide (H2 S), including, at lower concentrations, a stimulatory effect as an electron donor, and, at higher concentrations, an inhibitory effect on cytochrome C oxidase. In the current article, we overview the pathophysiological and therapeutic aspects of these processes. During cellular hypoxia/acidosis, the inhibitory effect of H2 S on complex IV is enhanced, which may shift the balance of H2 S from protective to deleterious. Several pathophysiological conditions are associated with an overproduction of H2 S (e.g. sepsis), while in other disease states H2 S levels and H2 S bioavailability are reduced and its therapeutic replacement is warranted (e.g. diabetic vascular complications). Moreover, recent studies demonstrate that colorectal cancer cells up-regulate the H2 S-producing enzyme cystathionine β-synthase (CBS), and utilize its product, H2 S, as a metabolic fuel and tumour-cell survival factor; pharmacological CBS inhibition or genetic CBS silencing suppresses cancer cell bioenergetics and suppresses cell proliferation and cell chemotaxis. In the last chapter of the current article, we overview the field of H2 S-induced therapeutic 'suspended animation', a concept in which a temporary pharmacological reduction in cell metabolism is achieved, producing a decreased oxygen demand for the experimental therapy of critical illness and/or organ transplantation.
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Affiliation(s)
- Katalin Módis
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA
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Huang J, Luo YL, Hao Y, Zhang YL, Chen PX, Xu JW, Chen MH, Luo YF, Zhong NS, Xu J, Zhou WL. Cellular mechanism underlying hydrogen sulfide induced mouse tracheal smooth muscle relaxation: role of BKCa. Eur J Pharmacol 2014; 741:55-63. [PMID: 25034810 DOI: 10.1016/j.ejphar.2014.07.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Revised: 07/03/2014] [Accepted: 07/04/2014] [Indexed: 12/17/2022]
Abstract
Recent studies have suggested that hydrogen sulfide (H2S), an important endogenous signaling gaseous molecule, participates in relaxation of smooth muscle. Nevertheless, the mechanism of this relaxation effect on respiratory system is still unclear. The present study aims to investigate the physiological function as well as cellular mechanism of H2S in tracheal smooth muscle. Application of the H2S donor, sodium hydrosulphide (NaHS) and the precursor of H2S, l-cysteine (l-Cys) induced mouse tracheal smooth muscle (TSM) relaxation in an epithelium-independent manner. The relaxation of TSM induced by NaHS was abrogated by iberiotoxin (IbTX), the large conductance calcium activated potassium channel (BKCa) blocker. In primary cultured mouse TSM cells, NaHS remarkably increased potassium outward currents in whole-cell patch clamp, hyperpolarized TSM cells and inhibited the calcium influx. All of these effects were significantly blocked by IbTX. Consistent with the results in vitro, administration of NaHS in vivo also reduced airway hyperresponsiveness in Ovalbumin (OVA)-challenged asthmatic mice. Our present study indicates that NaHS can induce mouse TSM relaxation by activating BKCa. These observations reveal the physiological function of H2S in airway, which provides a promising pharmacological target for the treatment of asthma and other respiratory diseases associated with over-contraction of TSM.
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Affiliation(s)
- Jiehong Huang
- School of Life Sciences, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, PR China
| | - Yu-li Luo
- School of Life Sciences, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, PR China
| | - Yuan Hao
- School of Life Sciences, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, PR China
| | - Yi-lin Zhang
- School of Life Sciences, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, PR China
| | - Peng-xiao Chen
- School of Life Sciences, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, PR China
| | - Jia-wen Xu
- School of Life Sciences, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, PR China
| | - Min-hui Chen
- State Key Lab of Respiratory Disease and Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou Medical College, Guangzhou 510120, PR China
| | - Yong-feng Luo
- State Key Lab of Respiratory Disease and Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou Medical College, Guangzhou 510120, PR China
| | - Nan-Shan Zhong
- State Key Lab of Respiratory Disease and Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou Medical College, Guangzhou 510120, PR China
| | - Jun Xu
- State Key Lab of Respiratory Disease and Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou Medical College, Guangzhou 510120, PR China
| | - Wen-liang Zhou
- School of Life Sciences, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou 510275, PR China.
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28
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Erb A, Althaus M. Actions of hydrogen sulfide on sodium transport processes across native distal lung epithelia (Xenopus laevis). PLoS One 2014; 9:e100971. [PMID: 24960042 PMCID: PMC4069190 DOI: 10.1371/journal.pone.0100971] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 05/30/2014] [Indexed: 01/04/2023] Open
Abstract
Hydrogen sulfide (H2S) is well known as a highly toxic environmental chemical threat. Prolonged exposure to H2S can lead to the formation of pulmonary edema. However, the mechanisms of how H2S facilitates edema formation are poorly understood. Since edema formation can be enhanced by an impaired clearance of electrolytes and, consequently, fluid across the alveolar epithelium, it was questioned whether H2S may interfere with transepithelial electrolyte absorption. Electrolyte absorption was electrophysiologically measured across native distal lung preparations (Xenopus laevis) in Ussing chambers. The exposure of lung epithelia to H2S decreased net transepithelial electrolyte absorption. This was due to an impairment of amiloride-sensitive sodium transport. H2S inhibited the activity of the Na+/K+-ATPase as well as lidocaine-sensitive potassium channels located in the basolateral membrane of the epithelium. Inhibition of these transport molecules diminishes the electrochemical gradient which is necessary for transepithelial sodium absorption. Since sodium absorption osmotically facilitates alveolar fluid clearance, interference of H2S with the epithelial transport machinery provides a mechanism which enhances edema formation in H2S-exposed lungs.
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Affiliation(s)
- Alexandra Erb
- Institute of Animal Physiology, Justus-Liebig University of Giessen, Giessen, Germany
| | - Mike Althaus
- Institute of Animal Physiology, Justus-Liebig University of Giessen, Giessen, Germany
- * E-mail:
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29
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Ning N, Zhu J, Du Y, Gao X, Liu C, Li J. Dysregulation of hydrogen sulphide metabolism impairs oviductal transport of embryos. Nat Commun 2014; 5:4107. [PMID: 24914509 DOI: 10.1038/ncomms5107] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 05/13/2014] [Indexed: 02/07/2023] Open
Abstract
Embryo retention in the fallopian tube is thought to lead to ectopic pregnancy, which is a significant cause of morbidity. Hydrogen sulphide (H2S) is a gaseotransmitter produced mainly by cystathionine-γ-lyase and cystathionine-β-synthase. Here we show that cystathionine-γ-lyase and cystathionine -β-synthase are ubiquitously distributed in human fallopian tube epithelium and that H2S signalling relaxes the spontaneous contraction of the human oviduct. Furthermore, an aberration in H2S signalling, either silenced or enhanced activity induced by pharmacologic or genetic methods, causes embryo retention and developmental delay in the mouse oviduct, which is partly reversed by administration of either GYY4137, a slow-releasing H2S donor, or NaHS. Our findings reveal a new regulatory mechanism for oviductal embryo transport.
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Affiliation(s)
- Nannan Ning
- Department of Physiology, Shandong University School of Medicine, Jinan 250012, China
| | - Jianchun Zhu
- Department of Physiology, Shandong University School of Medicine, Jinan 250012, China
| | - Yahui Du
- Department of Physiology, Shandong University School of Medicine, Jinan 250012, China
| | - Xiaolin Gao
- Department of Obstetrics and Gynecology, Second Hospital, Shandong University, Jinan 250012, China
| | - Chuanyong Liu
- Department of Physiology, Shandong University School of Medicine, Jinan 250012, China
| | - Jingxin Li
- Department of Physiology, Shandong University School of Medicine, Jinan 250012, China
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30
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Koopmans T, Anaparti V, Castro-Piedras I, Yarova P, Irechukwu N, Nelson C, Perez-Zoghbi J, Tan X, Ward JPT, Wright DB. Ca2+ handling and sensitivity in airway smooth muscle: emerging concepts for mechanistic understanding and therapeutic targeting. Pulm Pharmacol Ther 2014; 29:108-20. [PMID: 24831539 DOI: 10.1016/j.pupt.2014.05.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Revised: 03/28/2014] [Accepted: 05/01/2014] [Indexed: 02/01/2023]
Abstract
Free calcium ions within the cytosol serve as a key secondary messenger system for a diverse range of cellular processes. Dysregulation of cytosolic Ca(2+) handling in airway smooth muscle (ASM) has been implicated in asthma, and it has been hypothesised that this leads, at least in part, to associated changes in both the architecture and function of the lung. Significant research is therefore directed towards furthering our understanding of the mechanisms which control ASM cytosolic calcium, in addition to those regulating the sensitivity of its downstream effector targets to calcium. Key aspects of the recent developments in this field were discussed at the 8th Young Investigators' Symposium on Smooth Muscle (2013, Groningen, The Netherlands), and are outlined in this review.
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Affiliation(s)
- T Koopmans
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands
| | - V Anaparti
- Department of Immunology, University of Manitoba, Winnipeg, Canada
| | - I Castro-Piedras
- Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, TX, USA
| | - P Yarova
- Cardiff School of Biosciences, Cardiff University, UK
| | - N Irechukwu
- Division of Asthma, Allergy and Lung Biology, King's College London, UK
| | - C Nelson
- School of Science & Technology, Nottingham Trent University, Nottingham, UK
| | - J Perez-Zoghbi
- Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, TX, USA
| | - X Tan
- Lung Inflammation & Infection Lab, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - J P T Ward
- Division of Asthma, Allergy and Lung Biology, King's College London, UK
| | - D B Wright
- Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Division of Asthma, Allergy and Lung Biology, King's College London, UK.
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31
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Pharmacological actions of the slow release hydrogen sulfide donor GYY4137 on phenylephrine-induced tone in isolated bovine ciliary artery. Exp Eye Res 2013; 116:350-4. [DOI: 10.1016/j.exer.2013.10.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Revised: 09/27/2013] [Accepted: 10/05/2013] [Indexed: 11/20/2022]
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32
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Ariyaratnam P, Loubani M, Morice AH. Hydrogen sulphide vasodilates human pulmonary arteries: A possible role in pulmonary hypertension? Microvasc Res 2013; 90:135-7. [DOI: 10.1016/j.mvr.2013.09.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Revised: 09/01/2013] [Accepted: 09/03/2013] [Indexed: 12/26/2022]
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33
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Castro-Piedras I, Perez-Zoghbi JF. Hydrogen sulphide inhibits Ca2+ release through InsP3 receptors and relaxes airway smooth muscle. J Physiol 2013; 591:5999-6015. [PMID: 24144878 DOI: 10.1113/jphysiol.2013.257790] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hydrogen sulphide (H2S) is a signalling molecule that appears to regulate diverse cell physiological process in several organs and systems including vascular and airway smooth muscle cell (SMC) contraction. Decreases in endogenous H2S synthesis have been associated with the development of cardiovascular diseases and asthma. Here we investigated the mechanism of airway SMC relaxation induced by H2S in small intrapulmonary airways using mouse lung slices and confocal and phase-contrast video microscopy. Exogenous H2S donor Na2S (100 μm) reversibly inhibited Ca(2+) release and airway contraction evoked by inositol-1,4,5-trisphosphate (InsP3) uncaging in airway SMCs. Similarly, InsP3-evoked Ca(2+) release and contraction was inhibited by endogenous H2S precursor l-cysteine (10 mm) but not by l-serine (10 mm) or either amino acid in the presence of dl-propargylglycine (PPG). Consistent with the inhibition of Ca(2+) release through InsP3 receptors (InsP3Rs), Na2S reversibly inhibited acetylcholine (ACh)-induced Ca(2+) oscillations in airway SMCs. In addition, Na2S, the H2S donor GYY-4137, and l-cysteine caused relaxation of airways pre-contracted with either ACh or 5-hydroxytryptamine (5-HT). Na2S-induced airway relaxation was resistant to a guanylyl cyclase inhibitor (ODQ) and a protein kinase G inhibitor (Rp-8-pCPT-cGMPS). The effects of H2S on InsP3-evoked Ca(2+) release and contraction as well as on the relaxation of agonist-contracted airways were mimicked by the thiol-reducing agent dithiothreitol (DTT, 10 mm) and inhibited by the oxidizing agent diamide (30 μm). These studies indicate that H2S causes airway SMC relaxation by inhibiting Ca(2+) release through InsP3Rs and consequent reduction of agonist-induced Ca(2+) oscillations in SMCs. The results suggest a novel role for endogenously produced H2S that involves the modulation of InsP3-evoked Ca(2+) release - a cell-signalling system of critical importance for many physiological and pathophysiological processes.
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Affiliation(s)
- Isabel Castro-Piedras
- J. F. Perez-Zoghbi: Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79423, USA.
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34
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Castro-Piedras I, Perez-Zoghbi JF. Hydrogen sulphide inhibits Ca2+ release through InsP3 receptors and relaxes airway smooth muscle. J Physiol 2013. [PMID: 24144878 DOI: 10.1113/jphysiol.2013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hydrogen sulphide (H2S) is a signalling molecule that appears to regulate diverse cell physiological process in several organs and systems including vascular and airway smooth muscle cell (SMC) contraction. Decreases in endogenous H2S synthesis have been associated with the development of cardiovascular diseases and asthma. Here we investigated the mechanism of airway SMC relaxation induced by H2S in small intrapulmonary airways using mouse lung slices and confocal and phase-contrast video microscopy. Exogenous H2S donor Na2S (100 μm) reversibly inhibited Ca(2+) release and airway contraction evoked by inositol-1,4,5-trisphosphate (InsP3) uncaging in airway SMCs. Similarly, InsP3-evoked Ca(2+) release and contraction was inhibited by endogenous H2S precursor l-cysteine (10 mm) but not by l-serine (10 mm) or either amino acid in the presence of dl-propargylglycine (PPG). Consistent with the inhibition of Ca(2+) release through InsP3 receptors (InsP3Rs), Na2S reversibly inhibited acetylcholine (ACh)-induced Ca(2+) oscillations in airway SMCs. In addition, Na2S, the H2S donor GYY-4137, and l-cysteine caused relaxation of airways pre-contracted with either ACh or 5-hydroxytryptamine (5-HT). Na2S-induced airway relaxation was resistant to a guanylyl cyclase inhibitor (ODQ) and a protein kinase G inhibitor (Rp-8-pCPT-cGMPS). The effects of H2S on InsP3-evoked Ca(2+) release and contraction as well as on the relaxation of agonist-contracted airways were mimicked by the thiol-reducing agent dithiothreitol (DTT, 10 mm) and inhibited by the oxidizing agent diamide (30 μm). These studies indicate that H2S causes airway SMC relaxation by inhibiting Ca(2+) release through InsP3Rs and consequent reduction of agonist-induced Ca(2+) oscillations in SMCs. The results suggest a novel role for endogenously produced H2S that involves the modulation of InsP3-evoked Ca(2+) release - a cell-signalling system of critical importance for many physiological and pathophysiological processes.
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Affiliation(s)
- Isabel Castro-Piedras
- J. F. Perez-Zoghbi: Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79423, USA.
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