Role of Free Radicals and Angiotensin II in Blood Pressure Regulation in a Renal Model of Hypertension in Rat
One kidney one clip (1K1C) or uninephrectomized controls were treated with either the SOD mimetic tempol (T) (0.5 mmol/kg/day), AT1 receptor inhibitor losartan (L) (50mM/kg/day), or both(L+T) (n=6/group), for 2 weeks. At the end of the study,systolic BP decreased on average by 21% in T- and 29% in L-treated compared to untreated 1K1C (217±4.4 mmHg) and was normalized in the L+T group (123.5±3.3 mmHg). Mean BP also decreased from 130±3.7 mmHg in 1K1C to 83±2.8mmHg in the L+T treated group. The differences were significant (p<0.003) as tested with Bonferroni multiple comparisons test. Also, aortic wall area was reduced by 18% in the L or T treated 1K1C and by 30% in the L+T rats, compared to 1K1C (0.548±0.03 mm2). Plasma renin activity was increased from 4.8±0.3 in 1K1C to 15.9±0.9 ng/ml/h in L - but not T- 1K1C. Superoxide generation by the isolated aortic rings assessed by lucigenin (25μM) chemiluminescence was significantly decreased by ∼40% in all L, T and L+T groups compared to 1K1C controls (1065±200 RLU/mg DNAx105). The nitrotyrosine ELISA assay in the kidney displayed a significant reduction from 59±13 ng/mg protein in 1K1C to 12.5±5 ng/mg protein in the L+T 1K1C rats. Western blotting for nNOS in the kidney cortex and medulla showed a protein increase in both fractions of 1K1C vs controls and was normalized by the L+T treatment. Collectively, data show a synergistic effect of L and T on the blood pressure reduction in 1K1C rats. The mechanism may involve the reduced superoxide production and decreased kidney nNOS expression in the treated animals. Also, the reduced nitrosylation of the proteins in the kidney might have an important effect on blood pressure regulation.