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.
Li
Hongwei
H
Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610-0274, USA.
Gao
Yongxin
Y
Grobe
Justin L
JL
Raizada
Mohan K
MK
Katovich
Michael J
MJ
Sumners
Colin
C
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic; D015854:Up-Regulation
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; C073402:PD 123319; D019808:Losartan