930-104 Nitrate Tolerance: Impaired Vascular Effects of Stimulation and Inhibition of Nitric Oxide Release in Vivo

Nitroglycerin (NTG) is metabolized to nitric oxide (NO) in vascular smooth muscle cells. It has been suggested that prolonged exposure to NO results in reduced vascular sensitivity to NO and/or down regulation of NO synthesis. Whether such changes contribute to the in vivodevelopment of nitrate tolerance is currently not clear. This study investigates NO-mediated vasodilation in conscious rats before and after development of nitrate tolerance. Tolerance was induced by a 72 hours iv. infusion of NTG and confirmed by a 68% reduction in the response to NTG (from 25±3 to 8±1mmHg, p<0.05, n=7). The hypotensive effects of acetylcholine (ACh, endothelium dependent NO release, 10 μg/kg), and sodium nitroprusside (SNP, releases NO spontaneously, 20 μg/kg), were examined before and after infusion of NTG. Nitrate tolerance was associated with a attenuated hypotensive response to ACh (before 24±3; after 17±2mmHg, n=7, P<0.05). Similarly, the response to SNP was reduced from 32±1 to 26±3mmHg, n=7, P<0.05). Infusion of placebo (NTG solvens, n=6) for 72 hours did not affect the response to ACh and SNP (p>0.05). An effect of NTG treatment on endogenous NO regulation was further substantiated by the finding of a 62% reduction in the hypertensive response to the NO synthase inhibitor, L-NAME (n=6), after induction of nitrate tolerance (from 29±6 to 11±1mmHg, p<0.05). The results suggest that prolonged infusion of NTG attenuates the vasodilator effects of NO, whether it is derived from the endothelium (ACh) or from exogenous sources (SNP) and that reduced vascular sensitivity to NO dependent vasodilation may contribute to the development of nitrate tolerance in vivo