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Introduction: Hydrogen sulfide (H2S), known as a third gasotransmitter, is a signaling molecule that plays a regulatory role in physiological and pathophysiological processes. Decreased H2S levels were reported in inflammatory respiratory diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension. H2S donors or drugs that increase H2S have emerged as novel treatments for inflammatory respiratory diseases. We previously showed that resveratrol (RVT) causes vascular relaxation and antioxidant effects by inducing H2S production. In the current study, we synthesized a new molecule Cpd2, as an RVT analog. We examined the effect of Cpd2 and its precursor chalcone compound (Cpd1) on H2S formation under both healthy and oxidative stress conditions in the lung, as well as vascular relaxation in the aorta., Methods: Cpd2 synthesized from Cpd1 with microwaved in basic conditions. H2S formation was measured by H2S biosensor in the mice lungs under both healthy and pyrogallol-induced oxidative stress conditions in the presence/absence of H2S synthesis inhibitor aminooxyacetic acid (AOAA). The effect of compounds on vascular tonus is investigated in mice aorta by DMT myograph., Results: RVT and Cpd2 significantly increased l-cysteine (l-cys) induced-H2S formation in the lung homogenates of healthy mice, but Cpd1 did not. Superoxide anion generator pyrogallol caused a decrease in H2S levels in mice lungs and Cpd2 restored it. Inhibition of Cpd2-induced H2S formation by AOAA confirmed that Cpd2 increases endogenous H2S formation in both healthy and oxidative stress conditions. Furthermore, we found that both Cpd1 and Cpd2 (10-8-10-4 M) caused vascular relaxation in mice aorta., Discussion and Conclusion: We found that Cpd2, a newly synthesized RVT analog, is an H2S-inducing molecule and vasorelaxant similar to RVT. Since H2S has antioxidant and anti-inflammatory effects, Cpd2 has a potential for the treatment of respiratory diseases where oxidative stress and decreased H2S levels are present., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Pulmonary arterial hypertension is caused by complex structural and functional changes in the endothelial and smooth muscle cells of pulmonary arteries. Hydrogen sulfide (H 2 S), a gasotransmitter, can potentially treat pulmonary hypertension by relaxing the pulmonary arteries and decreasing bronchial pressure. Although the role of H 2 S in systemic circulation has been examined, the H 2 S levels in pulmonary arteries, the role of H 2 S in endothelium-dependent vasorelaxation and the L-cysteine/H 2 S pathway in monocrotaline-induced pulmonary arterial hypertension have not been investigated. The rats were divided into control, monocrotaline, monocrotaline + Na 2 S, and Na 2 S groups. The right ventricular pressure and hypertrophy were evaluated. KCl, acetylcholine, and L-cysteine responses were obtained in the main pulmonary arteries by wire myograph. H 2 S levels were measured in pulmonary arteries and lungs by methylene blue assay. Right ventricular pressure and hypertrophy were increased by monocrotaline and ameliorated by Na 2 S. The KCl-induced contractions and relaxing responses to acetylcholine and L-cysteine in pulmonary arteries and H 2 S production in the lungs and pulmonary arteries were significantly attenuated in the monocrotaline group and augmented in the monocrotaline + Na 2 S group. These findings suggest that H 2 S levels were reduced, and L-cysteine-induced and endothelium-dependent relaxations were impaired in the pulmonary arteries in monocrotaline-induced pulmonary arterial hypertension. The H 2 S donor, Na 2 S, prevented endothelial dysfunction and increased pulmonary artery pressure and hypertrophy. Also, Na 2 S enhanced the L-cysteine-mediated responses and restored the diminished H 2 S levels in pulmonary arteries and the lungs. The treatments targeting H 2 S might be beneficial for promoting vascular alterations, i.e. endothelial dysfunction and impaired H 2 S-mediated relaxation in pulmonary arterial hypertension., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The gasotransmitter nitric oxide (NO) has an important role in vascular function and a decrease in its bioavailability is accepted as a main pathological mechanism for cardiovascular diseases. However, other gasotransmitters such as hydrogen sulfide (H 2 S) are also generated by the endothelium and can also affect vascular tone and a crosstalk may exist between H 2 S and NO. We therefore investigated the consequences of deficiency, replacement or overexpression of endothelial nitric oxide synthase (eNOS) on H 2 S-induced vascular responses in murine carotid arteries. In pre-contracted carotid arteries from wild-type (WT) mice, l-cysteine elicited relaxation that was inhibited by the H 2 S synthesis inhibitor amino-oxyacetic acid (AOAA). Genetic deletion of eNOS increased l-cysteine-induced relaxation compared to WT, but the replacement of eNOS by adenoviral transfection or H 2 S synthesis inhibition by AOAA reversed it. Furthermore, eNOS deletion did not alter NaHS-induced relaxation in carotid arteries while eNOS overexpression/replacement increased NaHS-induced relaxation responses in carotid arteries from WT or eNOS -/- . We suggest that, endogenously produced H 2 S can compensate for impaired vasodilatory responses in the absence of NO to maintain vascular patency; while, eNOS abundance can limit endogenous H 2 S-induced vascular responses in mice carotid arteries. Our result suggests that endogenous vs. exogenous H 2 S-induced relaxation are reciprocally regulated by NO in mice carotid arteries., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Reactive oxygen species (ROS) decreases bioavailability of nitric oxide (NO) and impairs NO-dependent relaxations. Like NO, hydrogen sulfide (H 2 S) is an antioxidant and vasodilator; however, the effect of ROS on H 2 S-induced relaxations is unknown. Here we investigated whether ROS altered the effect of H 2 S on vascular tone in mouse aorta and determined whether resveratrol (RVT) protects it via H 2 S. Pyrogallol induced ROS formation. It also decreased H 2 S formation and relaxation induced by l-cysteine and in mouse aorta. Pyrogallol did not alter sodium hydrogensulfide (NaHS)-induced relaxation suggesting that the pyrogallol effect on l-cysteine relaxations was due to endogenous H 2 S formation. RVT inhibited ROS formation, enhanced l-cysteine-induced relaxations and increased H 2 S level in aortas exposed to pyrogallol suggesting that RVT protects against "H 2 S-dysfunctions" by inducing H 2 S formation. Indeed, H 2 S synthesis inhibitor AOAA inhibited the protective effects of RVT. RVT had no effect on Ach-induced relaxation that is NO dependent and the stimulatory effect of RVT on H 2 S-dependent relaxation was also independent of NO. These results demonstrate that oxidative stress impairs endogenous H 2 S-induced relaxations and RVT offers protection by inducing H 2 S suggesting that targeting endogenous H 2 S pathway may prevent vascular dysfunctions associated by oxidative stress., (Copyright © 2016. Published by Elsevier Inc.)

Erectile dysfunction (ED) is considered as a marker for cardiovascular diseases. Nitric oxide (NO) deficiency is the major cause of erectile dysfunction (ED). The role of hydrogen sulfide (H 2 S) in erection has recently been recognized and is receiving attention as a pharmacological target. Several studies have focused on the effect of H 2 S on NO-dependent relaxation, but the role of NO on H 2 S in penile tissue has not been studied yet. Unlike NO, H 2 S is mainly synthesized from smooth muscle cells rather than endothelial cells. We hypothesized that H 2 S may compensate for the decreased NO bioavailability and may be beneficial in severe ED where endothelial dysfunction is present. Thus we studied the effect of NO deficiency on H 2 S formation and vasorelaxation induced by l-cysteine, which is the substrate of the H 2 S producing enzymes in mice corpus cavernosum (MCC). NO deficiency induced by Nω-Nitro-l-arginine (L-NNA) was confirmed by the inhibition of acetylcholine-induced relaxation. l-cysteine, the substrate for the endogenous H 2 S production, caused a concentration-dependent relaxation that was reduced by CBS/CSE inhibitor aminooxyacetic acid (AOAA) in MCC strips. L-NNA caused a significant increase in l-cysteine-induced relaxation, and this effect was reversed by AOAA. On the contrary, no change in relaxation to NaHS (exogenous H 2 S donor) in MCC was observed. L-NNA increased H 2 S formation stimulated by l-cysteine in wild type MCC but not in CSE -/- mice. In parallel, the expression of both cysthationine γ lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3-MST) was increased, whereas cysthationine-β synthase (CBS) was decreased in eNOS -/- MCC. We conclude that H 2 S plays a compensatory role in the absence of NO by enhancing the relaxation induced by endogenous H 2 S through CSE and 3-MPST in MCC, without altering downstream mechanisms. We suggest that H 2 S-targeting drugs may provide the maintenance of compensatory treatment in ED patients. This may be more relevant in ED with severe endothelial dysfunction, as H 2 S is mainly derived from smooth muscle., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Resveratrol (RVT) found in red wine protects against erectile dysfunction and relaxes penile tissue (corpus cavernosum) via a nitric oxide (NO) independent pathway. However, the mechanism remains to be elucidated. Hydrogen sulfide (H2 S) is a potent vasodilator and neuromodulator generated in corpus cavernosum., Aims: We investigated whether RVT caused the relaxation of mice corpus cavernosum (MCC) through H2 S., Methods: H2 S formation is measured by methylene blue assay and vascular reactivity experiments have been performed by DMT strip myograph in CD1 MCC strips., Main Outcome Measures: Endothelial NO synthase (eNOS) inhibitor Nω-Nitro-L-arginine (L-NNA, 0.1 mM) or H2 S inhibitor aminooxyacetic acid (AOAA, 2 mM) which inhibits both cystathionine-β-synthase (CBS) and cystathionine-gamma-lyase (CSE) enzyme or combination of AOAA with PAG (CSE inhibitor) has been used in the presence/absence of RVT (0.1 mM, 30 min) to elucidate the role of NO or H2 S pathways on the effects of RVT in MCC. Concentration-dependent relaxations to RVT, L-cysteine, sodium hydrogen sulfide (NaHS) and acetylcholine (ACh) were studied., Results: Exposure of murine corpus cavernosum to RVT increased both basal and L-cysteine-stimulated H2 S formation. Both of these effects were reversed by AOAA but not by L-NNA. RVT caused concentration-dependent relaxation of MCC and that RVT-induced relaxation was significantly inhibited by AOAA or AOAA + PAG but not by L-NNA. L-cysteine caused concentration-dependent relaxations, which are inhibited by AOAA or AOAA + PAG significantly. Incubation of MCC with RVT significantly increased L-cysteine-induced relaxation, and this effect was inhibited by AOAA + PAG. However, RVT did not alter the effect of exogenous H2 S (NaHS) or ACh-induced relaxations., Conclusions: These results demonstrate that RVT-induced relaxation is at least partly dependent on H2 S formation and acts independent of eNOS pathway. In phosphodiesterase 5 inhibitor (PDE-5i) nonresponder population, combination therapy with RVT may reverse erectile dysfunction via stimulating endogenous H2 S formation., (© 2015 International Society for Sexual Medicine.)

The ability to get and keep an erection is important to men for several reasons and the inability is known as erectile dysfunction (ED). ED has started to be accepted as an early indicator of systemic endothelial dysfunction and subsequently of cardiovascular diseases. The role of NO in endothelial relaxation and erectile function is well accepted. The discovery of NO as a small signalling gasotransmitter led to the investigation of the role of other endogenously derived gases, carbon monoxide (CO) and hydrogen sulphide (H2 S) in physiological and pathophysiological conditions. The role of NO and CO in sexual function and dysfunction has been investigated more extensively and, recently, the involvement of H2 S in erectile function has also been confirmed. In this review, we focus on the role of these three sister gasotransmitters in the physiology, pharmacology and pathophysiology of sexual function in man, specifically erectile function. We have also reviewed the role of soluble guanylyl cyclase/cGMP pathway as a common target of these gasotransmitters. Several studies have proposed alternative therapies targeting different mechanisms in addition to PDE-5 inhibition for ED treatment, since some patients do not respond to these drugs. This review highlights complementary and possible coordinated roles for these mediators and treatments targeting these gasotransmitters in erectile function/ED., (© 2014 The British Pharmacological Society.)

Summary: Erectile dysfunction (ED) is defined in relation to the metabolic syndrome (metS). Hydrogen sulphide (H2S), a gasotransmitter, has been revealed to get involved in hypertension, insulin secretion and regulation of vascular tone especially in erectile physiology. This study aimed to investigate the effect of H2S on metS‐induced ED. Animals were divided into two groups as control and metS, which were fed with standard diet or 60% high‐fructose diet for 10 weeks respectively. The metS model was evaluated with biochemical analyses, waist circumference/tibia length ratio and HOMA index. Penile hemodynamic parameters were evaluated by the measurement of intracavernous pressure/mean arterial pressure ratio during cavernous nerve stimulation in the presence and absence of intracavernous injection of NaHS (100 μg/50 μl) and its control 0.9%NaCl (50 μl) in both groups. H2S levels were measured in penile tissues by methylene blue assay. H2S levels were significantly decreased in the penile tissues of the metS group. Decreased intracavernous pressure/mean arterial pressure ratio improved after intracavernous administration of NaHS in the metS group. These results suggest the significant role of H2S in the metS‐induced erectile dysfunction that could be a new therapeutic target. [ABSTRACT FROM AUTHOR]