Nitrate action on epicardial coronary arteries and tolerance: new aspects based on longterm glyceryl trinitrate infusions in dogs.
Continuous application of organic nitrates in patients causes a well-documented attenuation of their antianginal efficacy. N-acetylcysteine (NAC) is assumed to reverse this nitrate tolerance by replenishing depleted intracellular sulphydryl groups, but data on NAC application in patients are controversial. Therefore, we studied the effect of NAC on epicardial artery vasomotion under nitrate tolerance, and we examined under these conditions the epicardial artery dilations induced by glyceryl trinitrate (GTN) and those mediated by the endothelium, since the activation of soluble guanylate cyclase is a common mechanism of these two reactions. Tolerance was induced in chronically instrumented dogs by long-term GTN infusion (1.5 micrograms kg-1 min-1 i.v. for 5 to 6 days) and shifted the GTN dose response curve of epicardial arteries to 17- to 20-fold higher doses. However, there was no alteration of epicardial artery dilations induced by SIN-1, another activator of guanylate cyclase, or of endothelium-mediated dilations. Furthermore, NAC (100 mg kg-1 i.v.) did not alter the dose-response relation of GTN under tolerance. In vitro, however, NAC potentiated the activation of purified soluble guanylate cyclase by GTN, while NAC without GTN was ineffective. In non-tolerant dogs, NAC slightly (1.5- to 2-fold) augmentated dilations induced by 0.5-1.5 micrograms kg-1 min-1 GTN, and a similar small augmentation of GTN dilations by NAC is observed in patients, regardless whether they are tolerant to nitrates or not. We conclude: (1) a step prior to the guanylate cyclase activation is responsible for GTN-specific tolerance of epicardial arteries in vivo. (2) NAC does not reverse GTN-specific tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
Holtz
J
J
Institute of Applied Physiology, University of Freiburg, F.R.G.
Münzel
T
T
Stewart
D J
DJ
Bassenge
E
E
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D005996:Nitroglycerin / Q000008:administration & dosage / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D005996:Nitroglycerin; D000111:Acetylcysteine