Direct Renin Inhibition With Aliskiren Normalizes Blood Pressure in Cyp1a1-Ren2 Transgenic Rats With Inducible Angiotensin II-Dependent Malignant Hypertension

Introduction: Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1a1Ren2)], administered indole-3-carbinol (I3C) develop angiotensin (ANG) II-dependent hypertension due to hepatic expression of the Ren2 renin gene. Although AT 1 receptor blockade prevents the development of hypertension and normalizes the elevated arterial blood pressure of Cyp1-Ren2 rats, little information is available regarding the blood pressure and renal functional responses to direct inhibition of renin in this high circulating renin model of ANG II-dependent hypertension. This study was performed to determine the effects of acute direct renin inhibition with aliskiren on blood pressure and renal hemodynamics in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. Methods: Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital-anesthetized male Cyp1a1-Ren2 rats during control conditions and after administration of the renin inhibitor, aliskiren (10 mg/kg, intravenous). Results: Rats induced with I3C had higher MAP (194 +/- 7 versus 141 +/- 2 mmHg, P < 0.001), lower renal plasma flow (RPF; 2.47 +/- 0.23 versus 4.17 +/- 0.35 mL/min/g, P < 0.001) and lower glomerular filtration rate (GFR; 1.01 +/- 0.07 versus 1.34 +/- 0.06 mL/min/g, P = 0.01) than noninduced Cyp1a1-Ren2 rats (n = 5). Aliskiren administration decreased MAP (194 +/- 7 to 136 +/- 2mmHg, P < 0.001) and increased RPF (2.47 +/- 0.23 versus 4.31 +/- 0.20 mL/min/g, P < 0.001) in hypertensive but not in normotensive rats, without altering GFR. Conclusions: Acute renin inhibition with aliskiren normalizes MAP and RPF in Cyp1a1-Ren2 rats with malignant hypertension. The normalization of MAP and RPF after acute renin inhibition indicates that renin generated by expression of the Ren2 gene is responsible for the maintenance of malignant hypertension and the associated reduction in renal hemodynamic function in Cyp1a1-Ren2 rats.