Effect of antioxidant treatments on nitrate tolerance development in normotensive and hypertensive rats
- 1 February 2000
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal Of Hypertension
- Vol. 18 (2), 187-196
- https://doi.org/10.1097/00004872-200018020-00009
Abstract
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). 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. 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. 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.Keywords
This publication has 30 references indexed in Scilit:
- New insights into mechanisms underlying nitrate toleranceThe American Journal of Cardiology, 1996
- Role of Superoxide in the Depressed Nitric Oxide Production by the Endothelium of Genetically Hypertensive RatsHypertension, 1995
- Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance.JCI Insight, 1995
- Decreased Superoxide Dismutase Activity and Increased Superoxide Anion Production in Cardiac Hypertrophy of Spontaneously Hypertensive RatsClinical and Experimental Hypertension, 1995
- Melatonin As a Free Radical Scavenger: Implications for Aging and Age‐Related DiseasesaAnnals of the New York Academy of Sciences, 1994
- [48] N-acetylcysteineMethods in enzymology, 1994
- Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitriteArchives of Biochemistry and Biophysics, 1992
- Angina Due to Coronary Microvascular Disease in Hypertensive Patients without Left Ventricular HypertrophyNew England Journal of Medicine, 1988
- Effect of In Vivo Nitroglycerin Therapy on Endothelium-Dependent and Independent Vascular Relaxation and Cyclic GMP Accumulation in Rat AortaJournal of Cardiovascular Pharmacology, 1987
- Oral Isosorbide dinitrate in angina pectoris: Comparison of duration of action and dose-response relation during acute and sustained therapyThe American Journal of Cardiology, 1982