Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity

Abstract

Objective—Recent studies have demonstrated that hydrogen sulfide (H 2 S) is produced within the vessel wall from l-cysteine regulating several aspects of vascular homeostasis. H 2 S generated from cystathione γ-lyase (CSE) contributes to vascular tone; however, the molecular mechanisms underlying the vasorelaxing effects of H 2 S 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 β-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 H 2 S or overexpression of CSE raised cGMP concentration. RNA silencing of CSE expression reduced intracellular cGMP levels confirming a positive role for endogenous H 2 S on cGMP accumulation. The ability of H 2 S to enhance cGMP levels was greatly reduced by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Finally, addition of H 2 S to a cell-free system inhibited both cGMP and cAMP breakdown. Conclusion—These findings provide direct evidence that H 2 S acts as an endogenous inhibitor of phosphodiesterase activity and reinforce the notion that this gasotransmitter could be therapeutically exploited.