Chronic Renin Inhibition Normalizes Blood Pressure in Cyp1a1‐Ren2 Transgenic Rats with ANG II‐Dependent Malignant Hypertension

Abstract

The present study was performed to determine if chronic renin inhibition can normalize blood pressure in Cyp1a1-Ren2 transgenic rats with ANG II-dependent malignant hypertension. Adult male Cyp1a1-Ren2 rats (n=6) were fed a normal diet containing 0.3% indole-3-carbinol (I3C) for 10 days to induce ANG II-dependent malignant hypertension. Subsequently, the rats were treated chronically for 10 days with the renin inhibitor, aliskiren (60 mg/kg/day, sc), while maintaining dietary I3C administration. Systolic blood pressure (SBP) was measured daily by tail-cuff plethysmography and rats were placed in metabolic cages for determination of 24-hr urine flow and electrolyte excretion. Dietary I3C increased SBP (135±3 to 207±10 mmHg, P<0.001) and urine flow (5.6±0.7 to 37.2±10.8 ml/day, P<0.001). Subsequent chronic aliskiren administration normalized SBP within 1 day (108±1 mmHg, P<0.001). SBP remained at normotensive levels throughout the 10 days of chronic aliskiren treatment (125±7 mmHg, P<0.001). Urine flow and sodium excretion increased (from 37.2±10.8 to 56.3±6.1 ml/day, P<0.05, and from 0.89±0.28 to 2.06±0.32 mmol/day, P<0.01, respectively) by day 10 of aliskiren treatment. These findings demonstrate that chronic renin inhibition with aliskiren is highly effective in normalizing the elevated arterial pressure, and increases renal excretory function in ANG II-dependent malignant hypertension.