Normalization of blood pressure and renal vascular resistance in SHR with a membrane-permeable superoxide dismutase mimetic: role of nitric oxide.
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- 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 mmHg, P<0.05, and 24+/-3 versus 17+/-1 mmHg x mL(-1) x 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 micromol/kg i.v.) normalized MAP (103+/-9 versus 96+/-6 mm Hg for SHR and WKY, respectively) and RVR (17+/-2 versus 15+/-1 mm Hg x mL(-1) x 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 micromol x kg(-1) x h(-1) i.v.) than that of WKY. To determine whether O2- increases MAP by inactivation of NO, its synthesis was blocked in SHR with NW-nitro-L-arginine methyl ester (L-NAME, 11 micromol x kg(-1) x min(-1) i.v., 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 x kg(-1) x min(-1) i.v., n=6). Finally, to determine the longer-term effect of O2-, tempol (1.5 mmol x kg(-1) x d(-1) i.p.) was given for 7 days. Tempol had no effect on MAP in WKY (96+/-1 to 97+/-1 mmHg, n=7) but significantly decreased MAP in SHR (133+/-2 to 120+/-3 mm Hg, P<0.05, n=7). These data implicate O2- in the hypertension of SHR in vivo. The antihypertensive action of tempol depends on NO synthesis presumably because O2- inactivates NO and thus diminishes its vasodilatory actions.
Schnackenberg
C G
CG
Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC 20007, USA.
Welch
W J
WJ
Wilcox
C S
CS
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology*; D005609:Free Radicals; D007668:Kidney / Q000187:drug effects*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012079:Renal Circulation / Q000187:drug effects; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects*
D000975:Antioxidants; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D005609:Free Radicals; D013113:Spin Labels; D013481:Superoxides; D009569:Nitric Oxide; D013482:Superoxide Dismutase; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester