Mechanisms for the pharmacologic interaction of organic nitrates with thiols. Existence of an extracellular pathway for the reversal of nitrate vascular tolerance by N-acetylcysteine.

Recent reports have shown that the coadministration of N-acetylcysteine (NAC) potentiated the hemodynamic actions of i.v. nitroglycerin (NTG) and reversed NTG tolerance in humans. This study has investigated the feasibility of various pharmacokinetic and biochemical mechanisms for the thiol-organic nitrate interaction, using the rat as an animal model. In order to establish that the potentiating interaction between NAC and NTG can be reproduced in the rat, NTG dose-blood pressure response curves were determined before and during concurrent thiol infusion. The hypotensive effect of NTG was enhanced significantly by NAC and glutathione, but not by N-acetylserine, showing clearly that the potentiating effect of NAC was due specifically to its thiol functional group. The systemic clearance of NTG was not affected significantly by NAC coinfusion. In addition, the intracellular metabolism of NTG in thoracic aorta segments from rats infused previously with NAC or N-acetylserine was similar, both with respect to total production of metabolites and their distribution. Thus, the enhancement of NTG action could not be attributed apparently to an effect of NAC on NTG systemic pharmacokinetics or vascular metabolism of NTG. Because glutathione, which does not enter cells readily, also potentiated the effects of NTG, the possibility of an extracellular pathway for the thiol-organic nitrate interaction was examined. In vitro degradation of NTG in plasma and blood was accelerated in the presence of NAC (or glutathione). NAC also promoted the formation of S-nitroso-N-acetylcysteine from NTG in rat and human plasma and human blood.(ABSTRACT TRUNCATED AT 400 WORDS)