GLUTATHIONE CAUSES CORONARY VASODILATION VIA A NITRIC OXIDE-DEPENDENTAND SOLUBLE GUANYLATE CYCLASE-DEPENDENT MECHANISM

The actions of thiols on coronary vascular tone in the intact heart ar e unknown. Glutathione (GSH), glutathione disulfide (GSSG), and L-cyst eine (10-1,000 mu M each) and GSH ethyl ester (8-300 mu M) were infuse d into isolated rat hearts perfused with Krebs buffer at a constant pr essure by the Langendorff method. GSH, GSSG, and GSH ethyl ester, but not L-cysteine, caused a concentration-dependent increase in coronary flow with the following order of potency: GSH ethyl eater > GSH = GSSG . The nitric oxide synthase inhibitor N-G-monomethyl-L-arginine (300 m u M), prevented the increase in coronary flow with GSH and attenuated that with GSSG (300 mu M each). The vasodilation with GSH or GSSG and the associated increase in myocardial guanosine 3',5'-cyclic monophosp hate were abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1- one (a specific inhibitor of soluble guanylate cyclase) at 1 and 3 mu M, res pectively. The vasodilator action of GSH was abolished by superoxide d ismutase (50 U/ml). Inhibition of GSH reductase abolished GSSG-induced vasodilation. Neither glibenclamide (1 mu M) nor indomethacin (4 mu M ) affected the vasodilator action of GSH and GSSG. We conclude that GS H and GSSG cause coronary vasodilation that is mediated by a nitric ox ide-and guanylate cyclase-dependent mechanism, possibly mediated by th e reaction between GSH and peroxynitrite to form S-nitrosoglutathione, a nitric oxide donor.