Biochemical and pharmacological interactions between nitroglycerin and thiols. Effects of thiol structure on nitric oxide generation and tolerance reversal

Co-administration of N-acetylcysteine (NAC) with nitroglycerin (NTG) has been shown to partially reverse nitrate tolerance and to potentiate the hypotensive effect of NTG in humans. However, a high clinical dose of NAC was required for this pharmacologic interaction resulting in the production of unwanted side-effects. Therefore, sulfhydryl compounds more active than NAC need to be identified if this interaction is to be exploited clinically. We previously suggested that the effect of sulfhydryl compounds on NTG may be mediated by the formation of S-nitrosothiol or nitric oxide (NO) extracellularly to the vascular smooth muscle cell (e.g. in plasma) (Fung et al., J. Pharmacol Exp Ther 245: 524-530, 1988). In an attempt to understand the structural features which govern this thiol-catalyzed NO generation from NTG, nineteen different aliphatic and ten aromatic sulfhydryl compounds were examined with respect to their catalytic activity to generate NO from NTG in plasma. Significantly enhanced production of NO was observed with most sulfhydryl compounds examined when compared to buffer control. Among the aliphatic thiols, only mercaptosuccinic acid was more potent than NAC (2x), whereas among the aromatic thiols, both thiosalicylic acid (TSA, 10x) and TSA-methyl ester (3x) were more potent than NAC. Comparative in vitro relaxation studies were carried out using isolated (and nitrate-tolerant) rat aortic rings with NTG/TSA and NTG/NAC, in the presence of 0.5% (v/v) plasma. Under these conditions, partial reversal of NTG tolerance could be achieved with TSA, but not with NAC. These data are consistent with the view that extracellular production of NO or S-nitrosothiol serves as a tolerance-reversing mechanism of thiols on NTG. TSA appears to be a more potent sulfhydryl compound than NAC in this biochemical and pharmacologic interaction.