title: Failure of the sulfhydryl donor N-acetylcysteine (NAC) to reverse nitrate tolerance in large epicardial arteries and the venous capacitance system of the dog.
abstract: NAC has been thought to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, however data on interactions between N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of NAC 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 nitroglycerine (GTN)-treatment (1.5 micrograms/kg/min for 5 to 6 days). In dogs with GTN-specific tolerance (shift of venous or epicardial artery dilation with 15- to 17-fold higher dosages), NAC (100 mg/kg i.v.) had no dilator effect and did not alter the dose response relations of nitroglycerin. However, in nontolerant dogs (n = 7) NAC augmented (1.5- to 2-fold) the reduction of peripheral vascular resistance induced by 0.5-1.5 microgram/kg/min GTN. In vitro, the augmentation of purified guanylate cyclase activity by GTN (100 microM) was potentiated by NAC (0.01-1.0 mM) in saline or in canine plasma, whereas NAC alone was ineffective. Therefore, NAC does not restore GTN-responsiveness in epicardial arteries or veins in vivo and a small, tolerance-independent augmentation of GTN-induced dilation may result from NAC-induced extracellular formation of a stimulant of guanylate cyclase from GTN.
authors.affiliation: Institute of Applied Physiology, 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; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D005996:Nitroglycerin / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects*; D014690:Venous Pressure / Q000187:drug effects*
chemical_list: D013438:Sulfhydryl Compounds; D005996:Nitroglycerin; D000111:Acetylcysteine