Effects of peroxynitrite on the reactivity of diabetic rat aorta. Pharmacology 63: 58–64

Abstract Endogenous nitric oxide (NO) reacts with superoxide to form peroxynitrite, which is capable of either oxidizing or nitrating various biological substrates. We compared the vasodilatory effect of exogenous peroxynitrite with the effects of decomposed peroxynitrite or sodium nitrite in precontracted aorta isolated from streptozotocin-induced diabetic and age-matched control rats. Peroxynitrite (10 nmol/l to 300 Ìmol/l) produced a concentrationdependent relaxation in aortic rings with or without endothelium. Relaxation was also observed with a higher concentration of its decomposition product or sodium nitrite, although these relaxations were considerably slower and with reduced sensitivity. Endothelium-containing rings were less sensitive to the vasorelaxant effect of peroxynitrite than the endothelium-denuded rings in control (pD 2 was 5.19 B 0.06 in rings with endothelium and 5.86 B 0.03 in rings without endothelium, p ! 0.01) but not in diabetic aorta (pD 2 was 5.97 B 0.05 in rings with endothelium and 6.12 B 0.06 in rings without endothelium, p 1 0.05). The maximum relaxation to peroxynitrite also increased in diabetics, but did not change by removal of the endothelium either in diabetic or control rings. Diabetes did not alter the relaxations elicited by both decomposed peroxynitrite and sodium nitrite. Peroxynitrite-induced relaxation was not inhibited by diethylenetriaminepentaacetic acid, an inhibitor of hydroxyl radical formation. Pretreatment with peroxynitrite (1 Ìmol/l, 15 min) significantly suppressed the phenylephrine-induced tone and acetylcholine-stimulated endothelium-dependent relaxation, both effects were more pronounced in diabetic than in control aorta. The increased responsiveness of diabetic vessels to exogenous peroxynitrite seems to be related to depressed basal NO bioavailability and may be considered as a compensatory way against activated contractile mechanisms of diabetic vascular smooth muscle