Antioxidant pre-treatment with melatonin or NAC prevented the increase in lipid peroxidation and improved vascular responses to SNP and 5-HT during nitrate tolerance development in rats.
Do antioxidant treatments (NAC or melatonin) prevent the development of nitrate tolerance in normotensive and hypertensive rats?
Antioxidant therapy may prevent nitrate tolerance by reducing oxidative stress, with differential efficacy depending on the presence of hypertension.
OBJECTIVES: To investigate the effect of chronic antioxidant treatments on the development of nitrate tolerance in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats by evaluating (i) coronary vascular reactivity, (ii) lipid peroxidation (malondialdehyde), and (iii) peroxynitrite 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 pre-treated (2-weeks) with antioxidants: N-acetyl-L-cysteine (NAC) or melatonin. Effects of serotonin (5-HT) and sodium nitroprusside (SNP) perfusion were tested in isolated Langendorff-perfused hearts. 3-Nitrotyrosine levels were measured in coronary sinus effluent and malondialdehyde in plasma. RESULTS: Nitrate tolerance reduced SNP-induced dilation in both strains. This alteration was differently improved by antioxidants: melatonin was effective in SHR, whereas NAC was effective in WKY. Tolerance also reduced 5-HT-mediated vasodilation in WKY, which was reversed by both antioxidants. By contrast, nitrate tolerance enhanced the vasoconstriction to 5-HT in SHR and both antioxidants prevented this response. Furthermore, tolerance was associated with higher malondialdehyde levels in both strains and with higher 3-nitrotyrosine levels in SHR. These changes were reversed by both antioxidants. CONCLUSIONS: A participation of oxidative stress was suggested during nitrate 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 suggest distinct mechanisms of tolerance development in hearts from hypertensive and normotensive rats. An increased peroxynitrite generation, expressed by higher 3-nitrotyrosine levels, could contribute to nitrate tolerance in the coronary circulation of SHR.
Cabassi et al. (Tue,) conducted a other in Nitrate tolerance. N-acetyl-L-cysteine (NAC) or melatonin vs. Nitrate tolerance without antioxidant pre-treatment was evaluated on Coronary vascular reactivity, lipid peroxidation, and peroxynitrite formation. Antioxidant pre-treatment with melatonin or NAC prevented the increase in lipid peroxidation and improved vascular responses to SNP and 5-HT during nitrate tolerance development in rats.
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