Cardiac hypertrophy and fibrosis in chronic L-NAME-treated AT2 receptor-deficient mice

Background The role of angiotensin II type 1 (AT(1)) and type 2 (AT(2)) receptors in cardiac hypertrophy and fibrosis is incompletely understood. The availability of AT(2) receptor-deficient mice (AT(2) -/y) makes it possible to study the effects of AT, receptors without the confounding influence of AT(2) receptor activity. Objective To test the hypothesis that the AT(2) receptor affords protection from left ventricular hypertrophy and fibrosis in chronic hypertension induced by N-omega-nitro-L-arginine methyl ester (L-NAME). Design Four groups of mice were studied over a period of 3 weeks: AT(2) -/y mice with and without L-NAME, and AT(2) +/y mice with and without L-NAME. Methods Blood pressure and heart rate were monitored by telemetry in groups of AT(2) +/y and AT(2) -/y mice for 4 weeks. L-NAME groups received the compound in drinking water for the last 3 weeks. We determined left ventricular AT, receptor expression, cardiac hypertrophy and fibrosis, with and without L-NAME treatment. We used a miniaturized conductance-manometer system to measure pressure-volume loops at the time when the animals were killed. Results AT(2) -/y mice treated with L-NAME showed worse left ventricular hypertrophy, more perivascular fibrosis and greater concentrations of brain natriuretic peptide than did AT(2) +/y mice treated with L-NAME. The end-systolic pressure-volume relationship, an index of left ventricular contractility, was decreased in AT(2) -/y mice treated with L-NAME. Conclusions The AT(2) receptor is not essential for development of L-NAME-induced cardiac hypertrophy, fibrosis and concomitant changes in left ventricular performance. In contrast, the AT(2) receptor offers a protective effect. (C) 2004 Lippincott Williams Wilkins.