Potentiation of the antihypertensive action of losartan by peripheral overexpression of the ANG II type 2 receptor

Abstract

Our previous studies demonstrated that peripheral overexpression of angiotensin II (ANG II) type 2 receptors (AT2R) prevents hypertension-induced cardiac hypertrophy and remodeling without altering high blood pressure. This, coupled with the observations that AT2R play a role in the antihypertensive actions of ANG II type 1 receptor (AT1R) blockers (ARBs), led us to propose that peripheral overexpression of AT2R would improve the antihypertensive action of losartan (Los) in Sprague-Dawley (SD) rats made hypertensive via chronic infusion of ANG II. Here we utilized adenoviral vector-mediated AT2R gene transfer to test this hypothesis. A single intracardiac injection of adenoviral vector containing genomic AT2R (G-AT2R) DNA and enhanced green fluorescent protein (EGFP) gene controlled by cytomegalovirus (CMV) promoters (Ad-G-AT2R-EGFP; 5 × 109 infectious units) into adult SD rats produced robust AT2R overexpression in cardiovascular tissues (kidney, lung, heart, aorta, mesenteric artery, and renal artery) that persisted for 3–5 days postinjection. By 7 days post viral injection, the overexpressed AT2R are reduced toward basal values in certain tissues (lung, kidney, and heart) and are undetectable in others (kidney and blood vessels). In two separate protocols, we demonstrated that the hypotensive effect of Los (0.125, 0.5, and 1.0 mg/kg iv) was significantly greater in the AT2R-overexpressing animals (−40.7 ± 4.3, −41.8 ± 4.8, and −48.1 ± 2.6 mmHg, respectively) compared with control vector (Ad-CMV-EGFP)-treated rats (−12.4 ± 2.2, −20.2 ± 3.4, and −27.3 ± 3.4 mmHg, respectively). These results provide support for a depressor role of AT2R and the proposal that combined AT2R agonist and ARB treatment may be an improved therapeutic strategy for controlling hypertension.