Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity

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. CONCLUSIONS: 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.