Reversed by N-Acetylcysteine In Vivo, but Tolerance-Independent Interactions Exist

as changes in effective vascular compliance) in dogs (n=12) during long-term nitroglycerin treatment (1.5 ,g/kg/min i.v. for 5-6 days). In dogs with nitroglycerin-specific tolerance (shift of venous or epicardial artery dilation to 15-17-fold higher dosages), N-acetylcysteine (100 mg/ kg i.v.) had no dilator effect and did not alter the dose-response relations of nitroglycerin. Yet, in nontolerant dogs (n=17), N-acetylcysteine augmented (1.5-2.0-fold) the dilation of epicardial arteries and the reduction of peripheral vascular resistance induced by 0.5-1.5 ,ug/kg/min nitroglycerin. In vitro, the augmentation of purified guanylate cyclase activity by nitroglycerin (10-100 ,M) was potentiated by N-acetylcysteine (0.01-1.0 mM) in saline or in canine plasma, but N-acetylcysteine alone was ineffective. We conclude that 1) N-acetylcysteine does not restore nitroglycerin responsiveness in tolerant epicardial arteries or veins in vivo, 2) a small, tolerance-independent augmentation of nitroglycerin-induced dilation may result from Nacetylcysteine-induced extracellular formation of a stimulant of guanylate cyclase from nitroglycerin. (Circulation 1989;79:188-197)