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For more than a century, hydrogen sulfide (H(2)S) has been regarded as a toxic gas. This review surveys the growing recognition of the role of H(2)S as an endogenous signaling molecule in mammals, with emphasis on its physiological and pathological pathways in the cardiovascular system. In biological fluids, H(2)S gas is a weak acid that exists as about 15% H(2)S, 85% HS(-), and a trace of S(2-). Here, we use "H(2)S" to refer to this mixture. H(2)S has been found to influence heart contractile functions and may serve as a cardioprotectant for treating ischemic heart diseases and heart failure. Alterations of the endogenous H(2)S level have been found in animal models with various pathological conditions such as myocardial ischemia, spontaneous hypertension, and hypoxic pulmonary hypertension. In the vascular system, H(2)S exerts biphasic regulation of a vascular tone with varying effects based on its concentration and in the presence of nitric oxide. Over the past decade, several H(2)S-releasing compounds (NaHS, Na(2)S, GYY4137, etc.) have been utilized to test the effect of exogenous H(2)S under different physiological and pathological situations in vivo and in vitro. H(2)S has been found to promote angiogenesis and to protect against atherosclerosis and hypertension, while excess H(2)S may promote inflammation in septic or hemorrhagic shock. H(2)S-releasing compounds and inhibitors of H(2)S synthesis hold promise in alleviating specific disease conditions. This comprehensive review covers in detail the effects of H(2)S on the cardiovascular system, especially in disease situations, and also the various underlying mechanisms.

This study aimed to test these hypotheses: cystathionine ␥-lyase (CSE) is expressed in a human artery, it generates hydrogen sulfide (H 2 S), and H 2 S relaxes a human artery. H 2 S is produced endogenously in rat arteries from cysteine by CSE. Endogenously produced H 2 S dilates rat resistance arteries. Although CSE is expressed in rat arteries, its presence in human blood vessels has not been described. In this study, we showed that both CSE mRNA, determined by reverse transcription-polymerase chain reaction, and CSE protein, determined by Western blotting, apparently occur in the human internal mammary artery (internal thoracic artery). Artery homogenates converted cysteine to H 2 S, and the H 2 S production was inhibited by DL-propargylglycine, an inhibitor of CSE. We also showed that H 2 S relaxes phenylephrine-precontracted human internal mammary artery at higher concentrations but produces contraction at low concentrations. The latter contractions are stronger in acetylcholine-prerelaxed arteries, suggesting inhibition of nitric oxide action. The relaxation is partially blocked by glibenclamide, an inhibitor of K ATP channels. The present results indicate that CSE protein is expressed in human arteries, that human arteries synthesize H 2 S, and that higher concentrations of H 2 S relax human arteries, in part by opening K ATP channels. Low concentrations of H 2 S contract the human internal mammary artery, possibly by reacting with nitric oxide to form an inactive nitrosothiol. The possibility that CSE, and the H 2 S it generates, together play a physiological role in regulating the diameter of arteries in humans, as has been demonstrated in rats, should be considered.

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