© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
NADPH oxidase and enhanced superoxide generation in intrauterine undernourished rats: involvement of the renin–angiotensin system
aLaboratory of Hypertension, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1524, São Paulo, SP 05508-900, Brazil
bLaboratory of Nephrology, UNIFESP, São Paulo, SP, Brazil
mdcfranco{at}yahoo.com
* Corresponding author. Tel./fax: +55-11-3091-7317.
Objective: We previously reported that intrauterine undernutrition increased the oxidative stress by decreasing superoxide dismutase activity. In the present study, we tested whether NADPH oxidase, xanthine oxidase, cyclooxygenase or nitric oxide synthase are responsible for the increased O2– generation observed in rats submitted to intrauterine undernutrition. In addition, we investigated the effect of angiotensin II (ANG II) on O2– production via activation of NADPH oxidase. Methods: Female pregnant Wistar rats were fed either normal or 50% of the normal intake diets, during the whole gestational period. At 16 weeks of age, the rats were used for the study of intravital fluorescence microscopy; microvascular reactivity, local ANG II concentration and AT1, p22phox and gp91phox gene expression. In this study only the male offspring was used. Results: Treatment of mesenteric arterioles with the xanthine oxidase inhibitor oxypurinol, the nitric oxide synthase inhibitor L-NAME or the cyclooxygenase inhibitor diclofenac did not significantly change superoxide production. Thus, these vascular sources of superoxide were not responsible for the increased superoxide concentration. In contrast, treatment with the NADPH oxidase inhibitor apocynin significantly decreased superoxide generation and improved vascular function. On the other hand, intrauterine undernutrition did not alter the gene expression for p22phox and gp91phox. The fact that the local ANG II concentration was increased and the attenuation of oxidative stress by blocking AT1 receptor with losartan, led us to suggest that ANG II induces O2– generation in intrauterine undernourished rats. Conclusion: Our study shows that NADPH oxidase inhibition attenuated superoxide anion generation and ameliorated vascular function in rats submitted to intrauterine undernutrition. Although it is not clear which mechanisms are responsible for the increase in NADPH oxidase activity, a role for ANG II-mediated superoxide production via activation of NADPH oxidase is suggested.
KEYWORDS Angiotensin; Endothelial function; Gene expression; Hypertension; Nutrition
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