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

Abstract

Abstract —Superoxide radical (O 2 − ) 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 O 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 (n=6) compared with Wistar-Kyoto rats (WKY; n=6) (145±4 versus 118±4 mm Hg, P <0.05, and 24±3 versus 17±1 mm Hg · mL −1 · min −1 , respectively; P <0.05). The stable membrane-permeable superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (tempol; 72 μmol/kg IV) normalized MAP (103±9 versus 96±6 mm Hg for SHR and WKY, respectively) and RVR (17±2 versus 15±1 mm Hg · mL −1 · min −1 ) of SHR. The MAP of SHR was more sensitive and responsive to graded infusions of tempol (0, 1.8, 18, 180, and 1800 μmol · kg −1 · h −1 IV) than that of WKY. To determine whether O 2 − increases MAP by inactivation of NO, its synthesis was blocked in SHR with N w -nitro- l -arginine methyl ester (L-NAME, 11 μmol · kg −1 · min −1 IV, n=6). Whereas tempol alone significantly reduced MAP by 32% (184±12 to 121±18 mm Hg, P <0.05, n=6), L-NAME infusion abolished the MAP response to tempol (187±8 to 186±4 mm Hg, n=5). In contrast, tempol did reduce MAP of SHR (188±7 to 161±7 mm Hg, P <0.05) where MAP was elevated by norepinephrine (31 nmol · kg −1 · min −1 IV, n=6). Finally, to determine the longer-term effect of O 2 − , tempol (1.5 mmol · kg −1 · d −1 IP) was given for 7 days. Tempol had no effect on MAP in WKY (96±1 to 97±1 mm Hg, n=7) but significantly decreased MAP in SHR (133±2 to 120±3 mm Hg, P <0.05, n=7). These data implicate O 2 − in the hypertension of SHR in vivo. The antihypertensive action of tempol depends on NO synthesis presumably because O 2 − inactivates NO and thus diminishes its vasodilatory actions.