Endothelial dysfunction and peroxynitrite formation are early events in angiotensin‐induced cardiovascular disorders

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Abstract

Angiotensin II (ANG II) is a well-established participant in many cardiovascular disorders, but the mechanisms involved are not clear. Vascular cell experiments suggest that ANG II is a potent stimulator of free radicals such as superoxide anion, an agent known to inactivate nitric oxide and promote the formation of peroxynitrite. Here we hypothesized that ANG II reduces the efficacy of NO-mediated vascular relaxation and promotes vascular peroxynitrite formation in vivo. ANG II was infused in rats at sub-pressor doses for 3 days. Systolic blood pressure and heart rate were unchanged on day 3 despite significant reductions in plasma renin activity. Thoracic aorta was isolated for functional and immunohistochemical evaluations. No difference in isolated vascular contractile responses to KCI (125 mM), phenylephrine, or ANG II was observed between groups. In contrast, relaxant response to acetylcholine (ACh) was decreased sixfold without a change in relaxant response to sodium nitroprusside. Extensive prevalence of 3-nitrotyrosine (3-NT, a stable biomarker of tissue peroxynitrite formation) immunoreactivity was observed in ANG II-treated vascular tissues and was specifically confined to the endothelium. Digital image analysis demonstrated a significant inverse correlation between ACh relaxant response and 3-NT immunoreactivity. These data demonstrate that ANG II selectively modifies vascular NO control at sub-pressor exposures in vivo. Thus, endothelial dysfunction apparently precedes other established ANG II-induced vascular pathologies, and this may be mediated by peroxynitrite formation in vivo. Wattanapitayakul, S., Weinstein, D. M., Holycross, B. J., Bauer, J. A. Endothelial dysfunction and peroxynitrite formation are early events in angiotensin-induced cardiovascular disorders.

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