Hydrogen sul®de (H 2 S) has been traditionally viewed as a toxic gas. It is also, however, endogenously generated from cysteine metabolism. We attempted to assess the physiological role of H 2 S in the regulation of vascular contractility, the modulation of H 2 S production in vascular tissues, and the underlying mechanisms. Intravenous bolus injection of H 2 S transiently decreased blood pressure of rats by 12± 30 mmHg, which was antagonized by prior blockade of K ATP channels. H 2 S relaxed rat aortic tissues in vitro in a K ATP channel-dependent manner. In isolated vascular smooth muscle cells (SMCs), H 2 S directly increased K ATP channel currents and hyperpolarized membrane. The expression of H 2 S-generating enzyme was identi®ed in vascular SMCs, but not in endothelium. The endogenous production of H 2 S from different vascular tissues was also directly measured with the abundant level in the order of tail artery, aorta and mesenteric artery. Most importantly, H 2 S production from vascular tissues was enhanced by nitric oxide. Our results demonstrate that H 2 S is an important endogenous vasoactive factor and the ®rst identi®ed gaseous opener of K ATP channels in vascular SMCs.

Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H 2 S) is now receiving increasing attention. Here we show that H 2 S is physiologically generated by cystathionine γ-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H 2 S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H 2 S formation in response to vascular activation. These findings provide direct evidence that H 2 S is a physiologic vasodilator and regulator of blood pressure.Nitric oxide (NO) and carbon monoxide (CO) are established physiologic messenger molecules, and NO has an important role as an endothelial cell-derived relaxing factor (EDRF) and regulator of blood pressure (1,2). Indirect evidence has implicated another endogenous gasotransmitter, hydrogen sulfide (H 2 S), in similar functions (3-7). H 2 S can be produced by cystathionine γ-lyase (CSE) or cystathionine β-synthase (CBS) (3,4), but definitive evidence for either of these enzymes in the physiologic formation of H 2 S is lacking.To investigate the role of H 2 S as a physiologic vasorelaxant and determinant of blood pressure, we generated mice with a targeted deletion of the gene encoding CSE (8) (fig. S1, A to C). The homozygous (CSE −/− ) and heterozygous (CSE −/+ ) mutant mice were viable, fertile, and indistinguishable from their control wild-type littermates (CSE +/+ ) in terms of growth pattern.