Membrane-Permeable Superoxide Dismutase Mimetic : Role of Nitric Oxide Normalization of Blood Pressure and Renal Vascular Resistance in SHR With a

Superoxide radical (O2 ) is increased in the vessel wall of spontaneously hypertensive rats (SHR) where its blockade potentiates endothelium-dependent vasodilation. The purpose of this study was to determine the role of O2 2 in the hypertension and renal vasoconstriction of SHR and its interaction with nitric oxide (NO). Baseline mean arterial pressure (MAP) and renal vascular resistance were markedly elevated in SHR (n56) compared with Wistar-Kyoto rats (WKY; n56) (14564 versus 11864 mm Hg, P,0.05, and 2463 versus 1761 mm Hg z mL z min, respectively; P,0.05). The stable membrane-permeable superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidine-1oxyl (tempol; 72 mmol/kg IV) normalized MAP (10369 versus 9666 mm Hg for SHR and WKY, respectively) and RVR (1762 versus 1561 mm Hg z mL z min) of SHR. The MAP of SHR was more sensitive and responsive to graded infusions of tempol (0, 1.8, 18, 180, and 1800 mmol z kg z h IV) than that of WKY. To determine whether O2 2 increases MAP by inactivation of NO, its synthesis was blocked in SHR with N-nitro-L-arginine methyl ester (L-NAME, 11 mmol z kg z min IV, n56). Whereas tempol alone significantly reduced MAP by 32% (184612 to 121618 mm Hg, P,0.05, n56), L-NAME infusion abolished the MAP response to tempol (18768 to 18664 mm Hg, n55). In contrast, tempol did reduce MAP of SHR (18867 to 16167 mm Hg, P,0.05) where MAP was elevated by norepinephrine (31 nmol z kg z min IV, n56). Finally, to determine the longer-term effect of O2 , tempol (1.5 mmol z kg z d IP) was given for 7 days. Tempol had no effect on MAP in WKY (9661 to 9761 mm Hg, n57) but significantly decreased MAP in SHR (13362 to 12063 mm Hg, P,0.05, n57). These data implicate O2 2 in the hypertension of SHR in vivo. The antihypertensive action of tempol depends on NO synthesis presumably because O2 2 inactivates NO and thus diminishes its vasodilatory actions. (Hypertension. 1998;32:59-64.)