Desensitization of nitrate-induced venodilation: Reversal with oral N-acetylcysteine in humans

The objective of this study was to determine whether the dorsal hand vein could be used as a model to study tolerance to oral nitrates, and whether oral N-acetylcysteine (NAC) could reverse tolerance if present. Dose-response curves to nitroglycerin were constructed for 11 normotensive volunteers before and during treatment with a sustained-release formulation of isosorbide dinitrate, 80 mg, three times daily for 7 days and followed by concurrent treatment with NAC at a mean dose of 150 mg/kg/day, in divided doses, for 2 days. In separate studies, dose-response curves were constructed for seven normotensive volunteers before and after treatment with oral NAC at the same dose for 2 days. Nitroglycerin's E_maxwas significantly attenuated from 115 ± 36 to 77 ± 22% after treatment with isosorbide dinitrate alone (p < 0.009). Concurrent treatment with NAC reversed this decrease, as nitroglycerin's E_maxof 108 ± 26% during coadministration of isosorbide dinitrate and NAC was not different from its E_maxin the control period. There was also no difference in the dose of phenylephrine required to cause 80% of maximal venoconstriction throughout the study. These studies demonstrate that smooth muscle tolerance to nitrates can be demonstrated in medium-sized veins in humans. In addition, high-dose oral NAC can reverse existing tolerance to oral nitrates in human veins. These results indicate that the dorsal hand vein compliance technique is a good model for the clinical investigation of tolerance to nitrates in humans.