AT(1) receptor blockade is superior to conventional triple therapy in protecting against end-organ damage in Cyp1a1 Ren-2 transgenic rats with inducible hypertension
Abstract
Objective In the present study we compared the effects of treatment with the AT(1) receptor antagonist candesartan and of 'triple therapy' (hydralazine, hydrochlorothiazide, reserpine) on the course of blood pressure, cardiac hypertrophy and angiotensin II concentrations after induction of hypertension in transgenic rats with inducible expression of the mouse renin gene (Cyp1a1-Ren-2 rats). Methods Hypertension was induced in Cyp1a1-Ren-2 rats through dietary administration of the natural xenobiotic indole-3-carbinol (l3C, 0.3%) for 4 days.
Starting on the day before administration of l3C, rats were treated either with candesartan or received triple therapy for 9 days. Systolic blood pressure was measured in conscious animals.
Rats were decapitated and angiotensin II levels in plasma and in whole kidney and left ventricular tissues were determined by radioimmunoassay. Results Administration of l3C resulted in the development of severe hypertension and cardiac hypertrophy that was accompanied by marked elevations of plasma and tissue angiotensin II concentrations.
Candesartan treatment prevented the development of hypertension and cardiac hypertrophy and was associated with a reduction of tissue angiotensin II concentrations. In contrast, triple therapy, despite maintaining systolic blood pressure in the normotensive range, did not prevent the development of cardiac hypertrophy and tissue angiotensin II augmentations.
Conclusions Our findings indicate that hypertension in Cyp1a1-Ren-2 rats is a clearly angiotensin II-dependent model of hypertension with elevated circulating and tissue angiotensin II concentrations, and that anti hypertensive treatment with AT(1) receptor blockade is superior to conventional triple therapy in effective protection against hypertension-induced end-organ damage in this rat model.