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Endogenous hydrogen sulfide (H2S) is involved in the regulation of vascular tone. We hypothesized that the lowering of calcium and opening of potassium (K) channels as well as calcium-independent mechanisms are involved in H2S-induced relaxation in rat mesenteric small arteries. Amperometric recordings revealed that free [H2S] after addition to closed tubes of sodium hydrosulfide (NaHS), Na2S, and GYY4137 [P-(4-methoxyphenyl)-P-4-morpholinyl-phosphinodithioic acid] were, respectively, 14%, 17%, and 1% of added amount. The compounds caused equipotent relaxations in isometric myographs, but based on the measured free [H2S], GYY4137 caused more relaxation in relation to released free H2S than NaHS and Na2S in rat mesenteric small arteries. Simultaneous measurements of [H2S] and tension showed that 15 µM of free H2S caused 61% relaxation in superior mesenteric arteries. Simultaneous measurements of smooth muscle calcium and tension revealed that NaHS lowered calcium and caused relaxation of NE-contracted arteries, while high extracellular potassium reduced NaHS relaxation without corresponding calcium changes. In NE-contracted arteries, NaHS (1 mM) lowered the phosphorylation of myosin light chain, while phosphorylation of myosin phosphatase target subunit 1 remained unchanged. Protein kinase A and G, inhibitors of guanylate cyclase, failed to reduce NaHS relaxation, whereas blockers of voltage-gated KV7 channels inhibited NaHS relaxation, and blockers of mitochondrial complex I and III abolished NaHS relaxation. Our findings suggest that low micromolar concentrations of free H2S open K channels followed by lowering of smooth muscle calcium, and by another mechanism involving mitochondrial complex I and III leads to uncoupling of force, and hence vasodilation., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Hypoxic pulmonary vasoconstriction (HPV) is an adaptive response that diverts pulmonary blood flow from poorly ventilated and hypoxic areas of the lung to more well-ventilated parts. This response is important for the local matching of blood perfusion to ventilation and improves pulmonary gas exchange efficiency. HPV is an ancient and highly conserved response, expressed in the respiratory organs of all vertebrates, including lungs of mammals, birds, and reptiles; amphibian skin; and fish gills. The mechanism underlying HPV and how cells sense low Po(2) remains elusive. In perfused trout gills (Oncorhynchus mykiss), acute hypoxia, as well as H(2)S, caused an initial and transient constriction of the vasculature. Inhibition of the enzymes cystathionine-β-synthase and cystathionine-γ-lyase, which blocks H(2)S production, abolished the hypoxic response. Individually blocking the four complexes in the electron transport chain abolished both the hypoxic and the H(2)S-mediated constriction. Glutathione, an antioxidant and scavenger of superoxide, attenuated the vasoconstriction in response to hypoxia and H(2)S. Furthermore, diethyldithiocarbamate, an inhibitor of superoxide dismutase, attenuated the hypoxic and H(2)S constriction. This strongly suggests that H(2)S mediates the hypoxic vasoconstriction in trout gills. H(2)S may stimulate the mitochondrial production of superoxide, which is then converted to hydrogen peroxide (H(2)O(2)). Thus, H(2)O(2) may act as the "downstream" signaling molecule in hypoxic vasoconstriction.

Hydrogen sulfide (H(2)S), nitric oxide (NO) and nitrite (NO(2)(-)) are formed in vivo and are of crucial importance in the tissue response to hypoxia, particularly in the cardiovascular system, where these signaling molecules are involved in a multitude of processes including the regulation of vascular tone, cellular metabolic function and cytoprotection. This report summarizes current advances on the mechanisms by which these signaling pathways act and may have evolved in animals with different tolerance to hypoxia, as presented and discussed during the scientific sessions of the annual meeting of the Society for Experimental Biology in 2011 in Glasgow. It also highlights the need and potential for a comparative approach of study and collaborative effort to identify potential link(s) between the signaling pathways involving NO, nitrite and H(2)S in the whole-body responses to hypoxia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Recent research has shown that the endogenous gas hydrogen sulphide (H2S) is a signalling molecule of considerable biological potential and has been suggested to be involved in a vast number of physiological processes. In the vascular system, H2S is synthesized from cysteine by cystathionine-γ-lyase (CSE) in smooth muscle cells (SMC) and 3- mercaptopyruvate sulfuresterase (3MST) and CSE in the endothelial cells. In pulmonary and systemic arteries, H2S induces relaxation and/or contraction dependent on the concentration of H2S, type of vessel and species. H2S relaxes SMC through a direct effect on KATP-channels or Kv-channels causing hyperpolarization and closure of voltage-dependent Ca2+-channels followed by a reduction in intracellular calcium. H2S also relaxes SMC through the release of endothelium- derived hyperpolarizing factor (EDHF) and nitric oxide (NO) from the endothelium. H2S contracts SMC through a reduction in nitric oxide (NO) availability by reacting with NO forming a nitrosothiol compound and through an inhibitory effect on endothelial nitric oxide synthase (eNOS) as well as a reduction in SMC cyclic AMP concentration. Evidence supports a role for H2S in oxygen sensing. Furthermore, reduced endogenous H2S production may also play a role in ischemic heart diseases and hypertension, and treatment with H2S donors and cysteine analogues may be beneficial in treatment of cardiovascular disease.

Systemic vascular resistance (R(sys)) of freshwater turtles increases substantially during anoxia, but the underlying mechanisms are not fully understood. We investigated whether hydrogen sulfide (H(2)S), an endogenously produced metabolite believed to be an O(2) sensor/transducer of vasomotor tone, contributes to the increased R(sys) of anoxic red-eared slider turtles (Trachemys scripta). Vascular infusion of the H(2)S donor NaHS in anesthetized turtles at 21 degrees C and fully recovered normoxic turtles at 5 degrees C and 21 degrees C revealed H(2)S to be a potent vasoconstrictor of the systemic circulation. Likewise, wire myography of isolated turtle mesenteric and pulmonary arteries demonstrated H(2)S to mediate an anoxia-induced constriction. Intriguingly, however, NaHS did not exert vasoconstrictory effects during anoxia (6 h at 21 degrees C; 14 days at 5 degrees C) when plasma H(2)S concentration, estimated from the colorimetric measurement of plasma acid-labile sulfide concentration, likely increased by approximately 3- and 4-fold during anoxia at 21 degrees C, and 5 degrees C, respectively. Yet, blockade of endogenous H(2)S production by DL-propargylglycine or hydroxylamine (0.44 mmol/kg) partially reversed the decreased systemic conductance (G(sys)) exhibited by 5 degrees C anoxic turtles. These findings suggest that the signal transduction pathway of H(2)S-mediated vasoactivity is either maximally activated in the systemic circulation of anoxic turtles and/or that it is oxygen dependent.

O2 chemoreceptors elicit cardiorespiratory reflexes in all vertebrates, but consensus on O2-sensing signal transduction mechanism(s) is lacking. We recently proposed that hydrogen sulfide (H2S) metabolism is involved in O2 sensing in vascular smooth muscle. Here, we examined the possibility that H2S is an O2 sensor in trout chemoreceptors where the first pair of gills is a primary site of aquatic O2 sensing and the homolog of the mammalian carotid body. Intrabuccal injection of H2S in unanesthetized trout produced a dose-dependent bradycardia and increased ventilatory frequency and amplitude similar to the hypoxic response. Removal of the first, but not second, pair of gills significantly inhibited H2S-mediated bradycardia, consistent with the loss of aquatic chemoreceptors. mRNA for H2S-synthesizing enzymes, cystathionine beta-synthase and cystathionine gamma-lyase, was present in branchial tissue. Homogenized gills produced H2S enzymatically, and H2S production was inhibited by O2, whereas mitochondrial H2S consumption was O2 dependent. Ambient hypoxia did not affect plasma H2S in unanesthetized trout, but produced a PO2-dependent increase in a sulfide moiety suggestive of increased H2S production. In isolated zebrafish neuroepithelial cells, the putative chemoreceptive cells of fish, both hypoxia and H2S, produced a similar approximately 10-mV depolarization. These studies are consistent with H2S involvement in O2 sensing/signal transduction pathway(s) in chemoreceptive cells, as previously demonstrated in vascular smooth muscle. This novel mechanism, whereby H2S concentration ([H2S]) is governed by the balance between constitutive production and oxidation, tightly couples tissue [H2S] to PO2 and may provide an exquisitely sensitive, yet simple, O2 sensor in a variety of tissues.

Hydrogen sulfide (H(2)S) is rapidly emerging as a biologically significant signaling molecule. Studies published before 2000 report low or undetectable H(2)S (usually as total sulfide) levels in blood or plasma, whereas recent work has reported sulfide concentrations between 10 and 300 microM, suggesting it acts as a circulating signal. In the first series of experiments, we used a recently developed polarographic sensor to measure the baseline level of endogenous H(2)S gas and turnover of exogenous H(2)S gas in real time in blood from numerous animals, including lamprey, trout, mouse, rat, pig, and cow. We found that, contrary to recent reports, H(2)S gas was essentially undetectable (<100 nM total sulfide) in all animals. Furthermore, exogenous sulfide was rapidly removed from blood, plasma, or 5% bovine serum albumin in vitro and from intact trout in vivo. To determine if blood H(2)S could transiently increase, we measured oxygen-dependent H(2)S production by trout hearts in vitro and in vivo. H(2)S has been shown to mediate ischemic preconditioning (IPC) in mammals. IPC is present in trout and, unlike mammals, the trout myocardium obtains its oxygen from relatively hypoxic systemic venous blood. In vitro, myocardial H(2)S production was inversely related to Po(2), whereas we failed to detect H(2)S in ventral aortic blood from either normoxic or hypoxic fish in vivo. These results provide an autocrine or paracrine mechanism for myocardial coupling of hypoxia to H(2)S in IPC, i.e., oxygen sensing, but they fail to provide any evidence that H(2)S signaling is mediated by the circulation.

Hydrogen sulfide (H2S) is rapidly emerging as a biologically significant signaling molecule. Studies published before 2000 report low or undetectable H2S (usually as total sulfide) levels in blood or plasma, whereas recent work has reported sulfide concentrations between 10 and 300 µM. suggesting it acts as a circulating signal. In the first series of experiments, we used a recently developed polarographic sensor to measure the baseline level of endogenous H2S gas and turnover of exogenous H2S gas in real time in blood from numerous animals, including lamprey, trout, mouse, rat, pig, and cow. We found that, contrary to recent reports, H2S gas was essentially undetectable (<100 nM total sulfide) in all animals. Furthermore, exogenous sulfide was rapidly removed from blood, plasma, or 5% bovine serum albumin in vitro and from intact trout in vivo. To determine if blood H2S could transiently increase, we measured oxygen-dependent H25 production by trout hearts in vitro and in vivo. H2S has been shown to mediate ischemic preconditioning (IPC) in mammals. IPC is present in trout and, unlike mammals, the trout myocardium obtains its oxygen from relatively hypoxic systemic venous blood. In vitro, myocardial H2S production was inversely related to Po2, whereas we failed to detect H2S in ventral aortic blood from either normoxic or hypoxic fish in vivo. These results provide an autocrine or paracrine mechanism for myocardial coupling of hypoxia to H2S in IPC, i.e., oxygen sensing, but they fail to provide any evidence that H2S signaling is mediated by the circulation. [ABSTRACT FROM AUTHOR]

Background and purpose Hydrogen sulfide (H 2 S) is an endogenously produced gas with many physiological functions including involvement in regulation of the blood pressure. The present study was designed to investigate the effect of H 2 S in small arteries and the mechanisms underlying H 2 S-induced vasodilation. Experimental approach Mesenteric and pulmonary small arteries from rats were isolated and mounted in microvascular myographs for isometric tension recordings. The endogenous production of H 2 S was blocked with enzyme inhibitors dl-propargylglycine (PPG) and amino-oxyacetate (AOA) with and without the presence of blockers of nitric oxide (NO) synthase (nitro- l -arginine) and cyclooxygenase (indomethacin). NaHS (a H 2 S donor) was applied in arteries with and without endothelium as well as in the presence of different blockers. Simultaneous measurements of intracellular calcium concentration and force were conducted by fura-2 AM fluorescence. Key results In mesenteric arteries acetylcholine (ACh)-induced vasodilation was reduced in the presence of PPG and AOA both in the absence and the presence of indomethacin and nitro- l -arginine. In pulmonary arteries, the combination of indomethacin and nitro- l -arginine inhibited ACh-induced vasodilation, and there was no further effect by adding PPG and AOA. Application of NaHS relaxed mesenteric arteries with an EC 50 of 385 μM. Removing endothelium, inhibition of K ATP -channels or NO synthase did not affect H 2 S-induced vasodilation in mesenteric or pulmonary arteries. Simultaneous measurements of calcium and relaxation revealed that NaHS induces relaxation without changes in smooth muscle calcium. Conclusions and implications H 2 S induces vasodilation in both rat mesenteric and pulmonary arteries, but is only involved in ACh-induced vasodilatation in rat mesenteric arteries. H 2 S-induced vasodilation was endothelium-independent and may involve desensitization of the contractile apparatus in the vascular smooth muscle. [ABSTRACT FROM AUTHOR]