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

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. 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 to 229±11 mmHg, P<0.001) and marked decreases in body weight (303±4 to 222±2 g, P<0.001). When I3C administration was terminated, SBP decreased to 167±4 mmHg (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 mmHg, P<0.01) for up to 3 weeks following 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 μl in volume) 3 weeks following cessation of dietary I3C administration was substantially higher than that observed in normotensive control rats (134±1 mmHg, n=6) not previously induced with 0.3% I3C (53±2 vs. 38±3 mmHg, 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

Enhanced Urinary Angiotensinogen Excretion in Cyp1a1-Ren2 Transgenic Rats With Inducible ANG II-Dependent Malignant Hypertension

BACKGROUND: Previous studies have demonstrated that the urinary excretion of angiotensinogen is significantly increased in ANG II-infused hypertensive rats, which is associated with an augmentation of intrarenal ANG II levels. These findings suggest that urinary angiotensinogen excretion rates provide an index of intrarenal ANG II levels in ANG II-dependent hypertensive states. However, little information is available regarding the urinary excretion of angiotensinogen in ANG II-dependent malignant hypertension. METHODS: The present study was performed to determine if urinary angiotensinogen excretion is increased in Cyp1a1-Ren2 transgenic rats [strain name: TGR(Cyp1aRen2)] with inducible 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. RESULTS: Rats induced with I3C exhibited pronounced increases in systolic blood pressure (SBP) (208±7 vs. 127±3 mmHg, P<0.001), marked proteinuria (29.4±3.6 vs. 5.9±0.3 mg/day, P<0.001), and augmented urinary angiotensinogen excretion (996±186 vs. 241±31 ng/day, P<0.01). Chronic administration of the AT(1) receptor antagonist, candesartan (25 mg/L in drinking water, n=6), prevented the I3C-induced increases in SBP (125±5, P<0.001), proteinuria (7.3±1.0 mg/day, p<0.001) and urinary angiotensinogen excretion (488±51 ng/day, P<0.01). CONCLUSIONS: These data demonstrate that the urinary excretion of angiotensinogen is markedly augmented in ANG II-dependent malignant hypertension. Such increased urinary angiotensinogen excretion may contribute to augmented intrarenal ANG II levels and, thereby, to the increased blood pressure in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

Angiotensin-converting enzyme Ii a modifier of hypertensive end organ damage

Severe forms of hypertension are characterized by high blood pressure combined with end organ damage. Through the development and refinement of a transgenic rat model of malignant hypertension incorporating the mouse renin gene, we previously identified a quantitative trait locus on chromosome 10, which affects malignant hypertension severity and morbidity. We next generated an inducible malignant hypertensive model where the timing, severity, and duration of hypertension was placed under the control of the researcher, allowing development of and recovery from end organ damage to be investigated. We have now generated novel consomic Lewis and Fischer rat strains with inducible hypertension and additional strains that are reciprocally congenic for the refined chromosome 10 quantitative trait locus. We have captured a modifier of end organ damage within the congenic region and, using a range of bioinformatic, biochemical and molecular biological techniques, have identified angiotensin-converting enzyme as the modifier of hypertension-induced tissue microvascular injury. Reciprocal differences between angiotensin-converting enzyme and the anti-inflammatory tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro in the kidney, a tissue susceptible to end organ damage, suggest a mechanism for the amelioration of hypertension-dependent damage