Direct Inhibition with Aliskiren Normalizes Blood Pressure in Cyp1a1‐Ren2 Transgenic Rats with Inducible ANG II‐Dependent Malignant Hypertension

Abstract

The present study was performed to determine the effects of acute direct renin inhibition with aliskiren on blood pressure and renal hemodynamics in Cyp1a1‐Ren2 transgenic rats with ANG II‐dependent malignant hypertension. Male Cyp1a1‐Ren2 rats (n=6) were fed a normal diet containing 0.3% I3C for 9–11 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital‐anesthetized male Cyp1a1‐Ren2 rats during control conditions and following administration of the renin inhibitor, aliskiren (10 mg/kg, iv). Rats induced with I3C had higher MAP (196±4 vs. 142±3 mmHg, P<0.01) and lower renal plasma flow (RPF; 1.98±0.32 vs. 3.86±0.26 ml/min.g, P<0.01) than non‐induced rats (n=6). There were no differences in glomerular filtration rate (GFR) between the two groups (1.22±0.13 vs. 0.85±0.15 ml/min.g). Aliskiren administration decreased MAP (196±4 to 126±6 mmHg, P<0.001) and increased RPF (1.98±0.32 to 2.67±0.46 ml/min.g, P<0.05) in the hypertensive rats. GFR remained unaltered following renin inhibition in the hypertensive rats. Aliskiren administration did not alter MAP or GFR, but increased RPF (3.86±0.26 to 4.53±0.33 ml/min.g, P<0.05) in the normotensive rats. The present data demonstrate that acute renin inhibition with aliskiren normalizes MAP and improves RPF in Cyp1a1‐Ren2 transgenic rats with malignant hypertension. The normalization of MAP and the increased RPF following acute renin inhibition with aliskiren indicate that renin generated as a consequence of expression of the Ren2 gene is responsible for the development of malignant hypertension and the associated reduction of renal hemodynamic function in Cyp1a1‐Ren2 transgenic rats.