Hydrogen sulfide (H₂S) is a gaseous mediator synthesized from cysteine by cystathionine γ lyase (CSE) and other naturally occurring enzymes. Pharmacological experiments using H₂S donors and genetic experiments using CSE knockout mice suggest important roles for this vasodilator gas in the regulation of blood vessel caliber, cardiac response to ischemia/reperfusion injury, and inflammation. That H₂S inhibits cytochrome c oxidase and reduces cell energy production has been known for many decades, but more recently, a number of additional pharmacological targets for this gas have been identified. H₂S activates K(ATP) and transient receptor potential (TRP) channels but usually inhibits big conductance Ca²(+)-sensitive K(+) (BK(Ca)) channels, T-type calcium channels, and M-type calcium channels. H₂S may inhibit or activate NF-κB nuclear translocation while affecting the activity of numerous kinases including p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and Akt. These disparate effects may be secondary to the well-known reducing activity of H₂S and/or its ability to promote sulfhydration of protein cysteine moieties within the cell.

Background-The potential biological significance of hydrogen sulfide (H 2 S) has attracted growing interest in recent years. The aim of this study was to characterize a novel, water-soluble, slow-releasing H 2 S compound [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137)] and evaluate its use as a tool to investigate the cardiovascular biology of this gas. Methods and Results-The acute vasorelaxant effect of drugs was assessed in rat aortic rings and perfused rat kidney in vitro and in the anesthetized rat in vivo. The chronic effect of GYY4137 on blood pressure in normotensive and spontaneously hypertensive rats was determined by tail-cuff plethysmography. GYY4137 released H 2 S slowly both in aqueous solution in vitro and after intravenous or intraperitoneal administration in anesthetized rats in vivo. GYY4137 caused a slow relaxation of rat aortic rings and dilated the perfused rat renal vasculature by opening vascular smooth muscle K ATP channels. GYY4137 did not affect rat heart rate or force of contraction in vitro. GYY4137 exhibited antihypertensive activity as evidenced by ability to reduce N G -nitro-L-arginine methyl ester-evoked hypertension in the anesthetized rat and after chronic (14-day) administration in spontaneously hypertensive rats. Conclusions-These results identify GYY4137 as a slow-releasing H 2 S compound with vasodilator and antihypertensive activity. GYY4137 is likely to prove useful in the study of the many and varied biological effects of H 2 S. GYY4137 may also prove of therapeutic value in cardiovascular disease.

Hydrogen sulfide (H2S) is synthesized in the body from L-cysteine by several enzymes including cystathionine-gamma-lyase (CSE). To date, there is little information about the potential role of H2S in inflammation. We have now investigated the part played by H2S in endotoxin-induced inflammation in the mouse. E. coli lipopolysaccharide (LPS) administration produced a dose (10 and 20 mg/kg ip)- and time (6 and 24 h)-dependent increase in plasma H2S concentration. LPS (10 mg/kg ip, 6 h) increased plasma H2S concentration from 34.1 +/- 0.7 microM to 40.9 +/- 0.6 microM (n=6, P<0.05) while H2S formation from added L-cysteine was increased in both liver and kidney. CSE gene expression was also increased in both liver (94.2+/-2.7%, n=6, P<0.05) and kidney (77.5+/-3.2%, n=6, P<0.05). LPS injection also elevated lung (148.2+/-2.6%, n=6, P<0.05) and kidney (78.8+/-8.2%, n=6, P<0.05) myeloperoxidase (MPO, a marker of tissue neutrophil infiltration) activity alongside histological evidence of lung, liver, and kidney tissue inflammatory damage. Plasma nitrate/nitrite (NOx) concentration was additionally elevated in a time- and dose-dependent manner in LPS-injected animals. To examine directly the possible proinflammatory effect of H2S, mice were administered sodium hydrosulfide (H2S donor drug, 14 micromol/kg ip) that resulted in marked histological signs of lung inflammation, increased lung and liver MPO activity, and raised plasma TNF-alpha concentration (4.6+/-1.4 ng/ml, n=6). In contrast, DL-propargylglycine (CSE inhibitor, 50 mg/kg ip), exhibited marked anti-inflammatory activity as evidenced by reduced lung and liver MPO activity, and ameliorated lung and liver tissue damage. In separate experiments, we also detected significantly higher (150.5+/-43.7 microM c.f. 43.8+/-5.1 microM, n=5, P<0.05) plasma H2S levels in humans with septic shock. These findings suggest that H2S exhibits proinflammatory activity in endotoxic shock and suggest a new approach to the development of novel drugs for this condition.

Objective: Hydrogen sulfide (H 2 S) has been reported to be a gasotransmitter which regulates cardiovascular homeostasis. The present study aims to examine the hypothesis that hydrogen sulfide is able to promote angiogenesis. Methods: Angiogenesis was assessed using in vitro parameters (i.e. endothelial cell proliferation, adhesion, transwell migration assay, scratched wound healing and formation of tube-like structure) and in vivo by assessing neovascularization in mice. Phosphorylation of Akt was measured using Western blot analysis. Results: Exogenously administered NaHS (H 2 S donor) concentration-dependently (10-20 μmol/l) increased cell growth, migration, scratched wound healing and tube-like structure formation in cultured endothelial cells. These effects of NaHS on endothelial wound healing and tube-like structure formation were prevented by either the phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002 (5 μmol/l) or transfection of a dominant-negative mutant of Akt. NaHS increased Akt phosphorylation and this effect was also blocked by either LY 294002 or wortmannin (25 nmol/l). NaHS did not significantly alter the levels of vascular endothelial growth factor, mRNA expression of fibroblast growth factor and angiopoietin-1, or nitric oxide metabolites. NaHS treatment (10 and 50 μmol kg − 1 day − 1 ) significantly promoted neovascularization in vivo in mice. Conclusion:The present study reports a novel proangiogenic role of H 2 S which is dependent on activation of Akt.