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

Abstract

aObjectives 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 ef¯uent 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-HTmediated 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.

Infiltrating T lymphocytes in the kidney increase oxidative stress and participate in the development of hypertension and renal disease

“…Increased levels of oxidative stress have been described in experimental models of hypertension (2,6,20) and hypertensive patients (22,35). Treatment with a variety of antioxidants has been shown to decrease arterial blood pressure in several experimental and genetic models of hypertension (4,7,30,40,48). Several groups also demonstrated the association between elevated levels of intrarenal ROS and renal damage (44), and the deleterious effects that deficiencies in catalase (21,24) or superoxide dismutase (26,37) have on renal function.…”

“…Moreover, treatment with a variety of antioxidants reduces blood pressure in several genetic and experimental models of hypertension (4,7,30,40,48). One of the most important biological mechanisms for the production of ROS results from the generation of superoxide (O 2 ·Ϫ ) from O 2 by the enzyme NADPH oxidase (14).…”

Determination of 3-nitrotyrosine in human urine at the basal state by gas chromatography–tandem mass spectrometry and evaluation of the excretion after oral intake

“…These values are more than 1000 times higher than those measured by GC-tandem MS in the present study in healthy humans. The HPLC-UV method applied in that study has been originally developed to measure 3-nitrotyrosine in coronary sinus effluent in rats [19]. This HPLC-UV method has not been validated for this matrix or urine and plasma from humans [16].…”

BIOMARKERS OF APOPTOSIS: RELEASE OF CYTOCHROME c, ACTIVATION OF CASPASE-3, INDUCTION OF 8-HYDROXY-2'-DEOXYGUANOSINE, INCREASED 3-NITROTYROSINE, AND ALTERATION OF p53 GENE

“…Pannala et al (1998) reported that hydroxycinnamates antioxidants decreased peroxynitrite-mediated nitration of tyrosine in vitro. Cabassi et al (2000) showed that the antioxidants N-acetyl-L-cysteine and melatonin reversed the formation of 3-nitrotyrosine in rat heart. The addition of 7-nitroindazole, a nitric oxide synthase inhibitor, suppressed the formation of 3-nitrotyrosine to below the detection limits in the early phase following reperfusion of mouse brain (Hirabayashi et al, 1999).…”