The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener

Abstract

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.

Regulation of cardiovascular cell function by hydrogen sulfide (H2S)

“…21 Prolonged incubation of cultured vascular smooth muscle cells with NO donors produced an increase in the CSE mRNA and protein levels. 15 Conversely, circulating H 2 S levels, CSE gene expression and enzymatic activity in the cardiovascular system were reduced in rats chronically treated with a NOS inhibitor, highlighting the physiological significance of NO in the regulation of H 2 S production in the cardiovascular system. 25 Interestingly H 2 S (50-200 mM) has been shown to inhibit NO production and down regulate inducible NOS expression in lipopolysaccharide-stimulated macrophages via a mechanism that involves heme oxygenase expression and CO production.…”

“…Administration of H 2 S donor compounds in intact animals produces a transient hypotensive effect, whilst pharmacological inhibitors of enzymatic H 2 S production have no hemodynamic effect. 15 This is in contrast to NOS inhibitors which cause a significant vasoconstrictor effect in normal animals and increase the peripheral vascular resistance. 28 These findings suggest that under normal physiological conditions H 2 S may not be directly responsible for regulating blood pressure but does so via its interaction with the NO pathway.…”

“…23 H 2 S has been shown to both enhance 14 and attenuate 7 the relaxant effect of NO in the rat aorta, whilst NO has been shown to enhance the release of H 2 S in rat vascular tissues and increase the expression of CSE in cultured vascular smooth muscle cells. 15 There is evidence that NO and peroxynitrite react with H 2 S to form a novel nitrosothiol, which has been proposed to regulate the physiological effects of both NO and H 2 S. 24 In homogenates of rat aorta, NO donors increased CSE-dependent H 2 S generation in a cGMP-dependent manner. 21 Prolonged incubation of cultured vascular smooth muscle cells with NO donors produced an increase in the CSE mRNA and protein levels.…”

“…Zhao et al 15 subsequently reported that intravenous bolus injections of H 2 S caused a transient decrease in the blood pressure of rats. This hypotensive effect was mimicked by the K ATP channel opener pinacidil and blocked by glibenclamide, a K ATP channel blocker.…”

“…These effects were again blocked by glibenclamide and mimicked by pinacidil confirming the involvement of K ATP channel opening as a key mechanism of the vasorelaxant effect. 15 However, a study investigating the effect of H 2 S in aortic rings has questioned the role of K ATP channels 27 since glibenclamide did not inhibit the actions of H 2 S in mouse aortic rings. It is also uncertain whether endogenous H 2 S is a vasorelaxant under normal physiological conditions, since the vascular effect of H 2 S is dependent on tissue concentration.…”