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Cardiovascular-Renal Mechanisms in Health and Disease

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

¹Department of Physiology and Functional Genomics, and McKnight Brain Institute; and ²Department of Pharmacodynamics, University of Florida, Gainesville, Florida

Submitted 30 August 2006 ; accepted in final form 27 October 2006

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 x 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.

hypertension; angiotensin II; angiotensin receptor blocker; adenovirus; gene transfer

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