Background 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 AT1 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. 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 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 following administration of the renin inhibitor, aliskiren (10 mg/kg, iv). Results Rats induced with I3C had higher MAP (194±7 vs. 141±2 mmHg, P<0.001), lower renal plasma flow (RPF; 2.47±0.23 vs. 4.17±0.35 ml/min.g, P<0.001), and lower glomerular filtration rate (GFR; 1.01±0.07 vs. 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±2 mmHg, P<0.001) and increased RPF (2.47±0.23 vs. 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 following 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.

Background-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.

Angiotensin (ANG) II-dependent hypertension is characterized by increases in intrarenal ANG II levels, derangement in renal hemodynamics, and augmented tubular sodium reabsorptive capability. Increased nephron expression of renin-angiotensin system components, such as angiotensinogen by proximal tubule cells and renin by collecting duct principal cells, has been associated with an augmented ability of the kidney to form ANG II in hypertensive states. However, the contribution of de novo intrarenal ANG II production to the development and maintenance of ANG II-dependent hypertension remains unclear. The present study was performed to determine the effects of selective intrarenal renin inhibition on whole kidney hemodynamics and renal excretory function in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension in the absence of the confounding influence of associated reductions in mean arterial pressure (MAP). Male Cyp1a1-Ren2 transgenic rats were induced to develop malignant hypertension, anesthetized, and surgically prepared for intrarenal administration of the direct renin inhibitor aliskiren (0.01 mg/kg). Following acute aliskiren treatment, urine flow and sodium excretion increased (10.5 ± 1.1 to 15.9 ± 1.9 μl/min, P < 0.001; 550 ± 160 to 1,370 ± 320 neq/min, P < 0.001, respectively) and ANG II excretion decreased (120 ± 30 to 63 ± 17 fmol/h, P < 0.05). There were no significant changes in MAP, glomerular filtration rate, estimated renal plasma flow, plasma ANG II levels, or protein excretion. The present findings demonstrate that selective renal renin inhibition elicits diuretic and natriuretic responses in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension. Elevated intraluminal ANG II levels likely act to augment tubular reabsorptive function and, thereby, contribute to the elevated blood pressure in Cyp1a1-Ren2 rats with ANG II-dependent malignant hypertension.

Introduction The present study was performed to determine if chronic direct renin inhibition can prevent the development of slowly progressive ANG II-dependent hypertension and the associated derangements in renal function in Cyp1a1-Ren2 transgenic rats with inducible expression of the Ren2 gene. Methods Male Cyp1a1-Ren2 rats (n=6) were fed a normal diet containing 0.15% indole-3-carbinol (I3C) for 16 days to induce slowly progressive ANG II-dependent hypertension. Conscious systolic blood pressure (SBP) was measured daily using tail-cuff plethysmography. The rats were then anesthetized with pentobarbital sodium and surgically prepared for the measurement of mean arterial pressure (MAP) and renal hemodynamics and excretory function. Results In rats induced with I3C, SBP increased by day 3 (130±7 to 160±5 mmHg, P<0.01) and continued to increase to 191±6 mmHg (P<0.001) by day 16. In a separate group of rats (n=6), chronic administration of the direct renin inhibitor, aliskiren (30 mg/kg/day, sc), prevented the development of hypertension (113±5 vs. 114±5 mmHg, NS). Rats treated with aliskiren exhibited significantly lower MAP (138±4 vs. 201±6 mmHg, P<0.001), RVR (23±4 vs. 38±3 mmHg/ml/min.g, P<0.01), urine flow (17.6±1.4 vs. 25.1±2.9 µL/min, P<0.05), and urinary sodium excretion (1.11±0.32 vs. 2.35±0.28 µEq/min, P<0.05), and higher RPF (4.22±0.23 vs. 2.56±0.21 ml/min.g, P<0.01) and GFR (1.19±0.07 vs. 0.78±0.08 ml/min.g, P<0.01), compared with induced rats not treated chronically with aliskiren. Conclusions The present findings demonstrate that chronic direct renin inhibition with aliskiren prevents the development of ANG II-dependent hypertension and the associated derangements in renal hemodynamics and excretory function in Cyp1a1-Ren2 transgenic rats.

The present study was performed to determine whether dietary sodium restriction attenuates the development of hypertension and the impairment in renal hemodynamics that occur during the induction of the Ren2 gene in Cyp1a1‐Ren2 rats. Male Cyp1a1‐ Ren2 rats (n=5–6/group) were fed either a normal salt (0.6%) or salt‐deficient diet (<0.01%) containing indole‐3‐carbinol (I3C; 0.15%, wt/wt) for 16 days to induce slowly progressive ANG II‐dependent hypertension. The rats were then anesthetized with pentobarbital sodium and surgically prepared for measurement of mean arterial pressure (MAP), renal hemodynamics and renal excretory function. There were no significant differences between the induced normal salt group and the induced salt‐deficient group regarding MAP (183±4 vs. 181±5 mmHg), RVR (33.7±2.4 vs. 31.1±3.8 mmHg/mL/min.g), RPF (2.78±0.20 vs. 2.91±0.35 mL/min.g), or GFR (0.90±0.06 vs. 0.91±0.08 mL/min.g). Both groups had similar urine flows (41.1±1.3 vs. 39.0±6.9 μL/min), urinary sodium excretions (2.9±0.5 vs. 2.4±0.9 μEq/min) and fractional sodium excretions (0.94±0.15 vs. 0.76±0.22%). These data demonstrate that a sodium‐deficient diet does not attenuate the increase in arterial blood pressure or the associated renal functional derangements in Cyp1a1‐Ren2 transgenic rats with slowly progressive ANG II‐dependent hypertension.Support: NHLBI, Tulane COBRE in Hypertension and Renal Biology.