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

Our previous studies demonstrated that peripheral overexpression of angiotensin II ( ANG II) type 2 receptors ( AT(2)R) prevents hypertension-induced cardiac hypertrophy and remodeling without altering high blood pressure. This, coupled with the observations that AT(2)R play a role in the antihypertensive actions of ANG II type 1 receptor ( AT(1)R) blockers ( ARBs), led us to propose that peripheral overexpression of AT(2)R 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 AT(2)R gene transfer to test this hypothesis. A single intracardiac injection of adenoviral vector containing genomic AT(2)R ( G-AT(2)R) DNA and enhanced green fluorescent protein ( EGFP) gene controlled by cytomegalovirus ( CMV) promoters ( Ad-G-AT(2)R-EGFP; 5 x 10(9) infectious units) into adult SD rats produced robust AT(2)R 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 AT(2)R 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 AT(2)R-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 AT(2)R and the proposal that combined AT(2)R agonist and ARB treatment may be an improved therapeutic strategy for controlling hypertension.