NITRATE TOLERANCE IMPAIRS NITRIC OXIDE-MEDIATED VASODILATION IN-VIVO

Objectives: Nitroglycerin (NTG) is metabolized to nitric oxide (NO) in vascular smooth muscle cells. It is currently not clear whether prolo nged exposure to NTG and tolerance development directly affects endoge nous NO-mediated vasodilation in vivo. This study investigates NO-medi ated vasodilation in conscious chronically catheterized rats before an d after development of nitrate tolerance. The effect of the thiol comp ound N-acetylcysteine (NAG), which may affect NTG responsiveness, was also studied. Methods: Nitrate tolerance was induced by a 72-h intrave nous infusion of NTG and confirmed by a 65-68% reduction in the hypote nsive response to NTG (P < 0.05). The hypotensive effects of acetylcho line (ACh) and sodium nitroprusside, (SNP) and possible NAG-mediated c hanges in the responses to these compounds were examined in nontoleran t and nitrate-tolerant rats, Furthermore, the hypertensive response to the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) was measured. Results: Nitrate tolerance was associated with a signifi cantly attenuated hypotensive response to ACh (before 24 +/- 1 mmHg; a fter 17 +/- 2 mmHg, n = 7, P < 0.05). Similarly, the response to SNP w as reduced from 32 +/- 1 mmHg to 26 +/- 3 mmHg (n = 7, P < 0.05). NTG- vehicle (placebo) did nor affect the response to ACh and SNP (P > 0.05 ). NAC augmented the effect of NTG, ACh and SNP in both nontolerant an d nitrate-tolerant animals (P < 0.05). The hypertensive response to L- NAME (n = 8), was reduced by 67% (from 34 +/- 6 mmHg to 11 +/- 1 mmHg, P < 0.05) after induction of nitrate tolerance. Conclusions: The resu lts suggest (1) that nitrate tolerance in vivo is associated with cros s tolerance to NO-mediated vasodilation produced by both exogenous and endogenous nitrovasodilators and (2) that also responses to nitrovaso dilator agents other than NTG are improved by the addition of NAG.