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Potentiation of the antihypertensive action of losartan by peripheral overexpression of the ANG II type 2 receptor. Am J Physiol Heart Circ Physiol 2007 Feb;292(2):H727-35

Date

11/07/2006

Pubmed ID

17085538

DOI

10.1152/ajpheart.00938.2006

Scopus ID

2-s2.0-33846977415   25 Citations

Abstract

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.

Author List

Li H, Gao Y, Grobe JL, Raizada MK, Katovich MJ, Sumners C

Author

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenoviridae
Angiotensin II
Angiotensin II Type 1 Receptor Blockers
Animals
Antihypertensive Agents
Blood Pressure
Cardiovascular System
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Fibroblasts
Genetic Vectors
Hypertension
Imidazoles
Losartan
Male
Myocardium
Pyridines
Rats
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 2
Time Factors
Transduction, Genetic
Up-Regulation