Role of angiotensin II and free radicals in blood pressure regulation in a rat model of renal hypertension.
One-kidney, 1-clip rats (1K1C) or uninephrectomized controls were treated with either the superoxide dismutase mimetic tempol (0.5 mmol. kg(-1). d(-1)), angiotension type 1 receptor inhibitor losartan (50 mmol. L(-1). kg(-1). d(-1)), or both (n=6 per group) for 2 weeks. At the end of the study, systolic blood pressure (BP) decreased on average by 21% in tempol-treated and 29% in losartan-treated versus untreated 1K1C (217+/-4.4 mm Hg) and was normalized in the losartan plus tempol group. Mean BP also decreased from 159+/-3.7 mm Hg in 1K1C to 93+/-2.8 mm Hg in the losartan plus tempol group. Also, aortic wall area was reduced by 18% in losartan- or tempol-treated 1K1C and by 30% in losartan plus tempol rats compared with untreated 1K1C. Plasma renin activity was increased from 4.8+/-0.3 in untreated 1K1C to 15.9+/-0.9 ng. mL(-1). h(-1) in losartan-treated but not tempol-treated 1K1C. Superoxide generation by the isolated aortic rings assessed by lucigenin chemiluminescence was significantly decreased (by approximately 40%) in all losartan, tempol, and losartan plus tempol groups compared with untreated 1K1C. Nitrotyrosine ELISA in the kidney displayed a significant reduction, from 59+/-13 ng/mg of protein in 1K1C to 12.5+/-5 ng/mg of protein in the losartan plus tempol 1K1C. Western blotting for nNOS in kidney cortex and medulla showed a protein increase in both fractions of 1K1C versus controls and was normalized by losartan plus tempol treatment. Collectively, data show a synergistic effect of losartan and tempol on BP reduction in 1K1C rats. The mechanism may involve reduced superoxide production and nitrotyrosine formation in kidney and decreased kidney neuronal-type NO synthase expression in treated animals. This status in the oxidative balance seems to affect BP in the renal hypertensive rats.
Dobrian
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AD
Eastern Virginia Medical School, Department of Physiological Sciences, Norfolk 23507, USA. dobriaad@evms.edu
Schriver
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SD
Prewitt
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RL
D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006978:Hypertension, Renovascular / Q000378:metabolism / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009392:Nephrectomy; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012077:Renal Artery / Q000187:drug effects / Q000473:pathology; D012083:Renin / Q000097:blood / Q000187:drug effects; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013599:Systole; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000187:drug effects / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D005609:Free Radicals; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013113:Spin Labels; D013481:Superoxides; D000804:Angiotensin II; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D012083:Renin; D019808:Losartan; C001803:tempol