title: Nitrate tolerance in epicardial arteries or in the venous system is not reversed by N-acetylcysteine in vivo, but tolerance-independent interactions exist.
abstract: N-acetylcysteine is assumed to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, but data on interactions of N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of N-acetylcysteine on nitrate responsiveness of epicardial arteries and of the venous system (assessed as changes in effective vascular compliance) in dogs (n = 12) during long-term nitroglycerin treatment (1.5 micrograms/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 micrograms/kg/min nitroglycerin. In vitro, the augmentation of purified guanylate cyclase activity by nitroglycerin (10-100 microM) 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 N-acetylcysteine-induced extracellular formation of a stimulant of guanylate cyclase from nitroglycerin.
authors.affiliation: Institute of Applied Physiology, University of Freiburg, FRG.
authors.forename: T
authors.initials: T
authors.lastname: Münzel
authors.forename: J
authors.initials: J
authors.lastname: Holtz
authors.forename: A
authors.initials: A
authors.lastname: Mülsch
authors.forename: D J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: E
authors.initials: E
authors.lastname: Bassenge
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D004347:Drug Interactions; D004361:Drug Tolerance; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000494:pharmacology*; D010496:Pericardium; D014664:Vasodilation / Q000187:drug effects; D014680:Veins / Q000187:drug effects*
chemical_list: D009566:Nitrates; D006162:Guanylate Cyclase; D000111:Acetylcysteine