Transient induction of ANG II-dependent malignant hypertension causes sustained elevation of blood pressure and augmentation of the pressor response to ANG II in CYP1A1-REN2 transgenic rats.

INTRODUCTION Transgenic rats with inducible expression of the mouse Ren2 renin gene [strain name: TGR(Cyp1a1Ren2)] allow induction of various degrees of ANG II-dependent hypertension. Dietary administration of the aryl hydrocarbon indole-3-carbinol (I3C) at a dose of 0.15% induces a slowly developing form of ANG II-dependent hypertension, whereas dietary administration of a higher dose (0.3%) of I3C results in the development of ANG II-dependent malignant hypertension. Cessation of administration of 0.15% I3C results in the normalization of blood pressure, indicating the reversibility of hypertension induced by this dose of I3C. The present study was performed to determine if ANG II-dependent malignant hypertension is similarly reversible following cessation of dietary administration of 0.3% I3C. METHODS Cyp1a1-Ren2 rats (n = 6) were fed a normal diet containing 0.3% I3C for 11 days to induce malignant hypertension. RESULTS Cyp1a1-Ren2 rats induced with I3C exhibited pronounced increases in systolic blood pressure (SBP) (132 +/- 3-229 +/- 11 mm Hg, P < 0.001) and marked decreases in body weight (303 +/- 4-222 +/- 2 g, P < 0.001). When I3C administration was terminated, SBP decreased to 167 +/- 4 mm Hg (P < 0.01) and body weight increased to normal levels (309 +/- 2 g, P < 0.01) within 12 days. However, SBP remained significantly elevated (172 +/- 1 mm Hg, P < 0.01) for up to 3 weeks after termination of dietary administration of 0.3% I3C. In addition, the magnitude of the blood pressure response to intravenous bolus administration of 50 ng of ANG II (50 microL in volume) 3 weeks after cessation of dietary I3C administration was substantially higher than that observed in normotensive control rats (134 +/- 1 mm Hg, n = 6) not previously induced with 0.3% I3C (53 +/- 2 versus 38 +/- 3 mm Hg, P < 0.05). CONCLUSIONS The present findings demonstrate that transient induction of ANG II-dependent malignant hypertension results in prolonged elevations of arterial blood pressure and marked augmentation of the magnitude of the pressor response to ANG II in Cyp1a1-Ren2 transgenic rats.