Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity

Objective-Recent studies have demonstrated that hydrogen sulfide (H2S) is produced within the vessel wall from L-cysteine regulating several aspects of vascular homeostasis. H2S generated from cystathione gamma-lyase (CSE) contributes to vascular tone; however, the molecular mechanisms underlying the vasorelaxing effects of H2S are still under investigation. Methods and Results-Using isolated aortic rings, we observed that addition of L-cysteine led to a concentration-dependent relaxation that was prevented by the CSE inhibitors DL-propargylglyicine (PAG) and beta-cyano-L-alanine (BCA). Moreover, incubation with PAG or BCA resulted in a rightward shift in sodium nitroprusside-and isoproterenol-induced relaxation. Aortic tissues exposed to PAG or BCA contained lower levels of cGMP, exposure of cells to exogenous H2S or overexpression of CSE raised cGMP concentration. RNA silencing of CSE expression reduced intracellular cGMP levels confirming a positive role for endogenous H2S on cGMP accumulation. The ability of H2S to enhance cGMP levels was greatly reduced by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Finally, addition of H2S to a cell-free system inhibited both cGMP and cAMP breakdown. Conclusion-These findings provide direct evidence that H2S acts as an endogenous inhibitor of phosphodiesterase activity and reinforce the notion that this gasotransmitter could be therapeutically exploited. (Arterioscler Thromb Vasc Biol. 2010;30:1998-2004.)