Effect of antioxidant treatments on nitrate tolerance development in normotensive and hypertensive rats

Objectives To investigate the effect of chronic antioxidant treatments on t he development of nitrate tolerance in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats by evaluating (i) coronary vascular r eactivity, (ii) lipid peroxidation (malondialdehyde), end (iii) peroxynitri te formation (3-nitrotyrosine). Methods Tolerance was induced in 16-week-old male SHR and WKY, by 4 days of continuous treatment with nitroglycerin patches. Two groups were orally pr e-treated (2-weeks) with antioxidants: N-acetyl-L-cysteine (NAC) or melaton in. Effects of serotonin (5-HT) and sodium nitroprusside (SNP) perfusion we re tested in isolated Langendorff-perfused hearts. 3-nitrotyrosine levels w ere measured in coronary sinus effluent and malondialdehyde in plasma. Results Nitrate tolerance reduced SNP-induced dilation in both strains. Thi s alteration was differently improved by antioxidants: melatonin was effect ive in SHR, whereas NAC was effective in WKY. Tolerance also reduced 5-HT-m ediated vasodilation in WKY, which was reversed by both antioxidants, By co ntrast, nitrate tolerance enhanced the vasoconstriction to 5-HT in SHR and both antioxidants prevented this response. Furthermore, tolerance was assoc iated with higher malondialdehyde levels in both strains and with higher 3- nitrotyrosine levels in SHR, These changes were reversed by both antioxidan ts, Conclusions A participation of oxidative stress was suggested during nitrat e tolerance development, since antioxidants prevented the increase in lipid peroxidation and improved vascular responses to SNP and 5HT. Differential effects of antioxidants on SNP-induced vasodilation in SHR and WKY may sugg est distinct mechanisms of tolerance development in hearts from hypertensiv e and normotensive rats. An increased peroxynitrite generation, expressed b y higher 3-nitrotyrosine levels, could contribute to nitrate tolerance in t he coronary circulation of SHR, J Hypertens 2000, 18:187-196 (C) Lippincott Williams & Wilkins.