title: A nonpeptide angiotensin II type 2 receptor agonist does not attenuate postmyocardial infarction left ventricular remodeling in mice.
abstract: Cardiac overexpression of the angiotensin II type 2 receptor (AT2 R) attenuates left ventricular (LV) remodeling after myocardial infarction (MI) in transgenic mice. We hypothesized that a novel nonpeptide AT2 R agonist, compound 21 (C21), would attenuate post-MI LV remodeling. Fifty-nine mice were studied for 28 days after 1-hour surgical occlusion-reperfusion of the left anterior descending coronary artery. Immediately thereafter, 23 mice received 0.3 mg·kg·d of C21 via Alzet osmotic minipump, 16 received 10 mg·kg·d of the AT1 R antagonist candesartan in drinking water, and 20 were untreated controls. Cardiac magnetic resonance imaging measured ejection fraction (EF), LV end-systolic, and end-diastolic volumes (ESVI and EDVI) indexed to weight serially post MI. Infarct size was measured on day 1 by late gadolinium-enhanced cardiac magnetic resonance imaging. At baseline, heart rate, blood pressure, EDVI, ESVI, and EF were similar between groups. Mean infarct size (42%-45% of LV mass) was similar between groups. C21-treated animals demonstrated adverse LV remodeling (increased EDVI and ESVI at all post-MI time points) compared with control. Candesartan therapy preserved left ventricular EF at day 28 compared with the C21-treated group. Thus, direct stimulation of the AT2 R by C21 at 0.3 mg·kg·d does not attenuate post-MI LV remodeling in reperfused MI in mice.
authors.affiliation: Departments of Medicine and Radiology, University of Virginia Health System, 1215 Lee St, Box 800170, Charlottesville, VA 22908, USA.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Jehle
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Xu
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Dimaria
authors.forename: Brent A
authors.initials: BA
authors.lastname: French
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Epstein
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Berr
authors.forename: Rene J
authors.initials: RJ
authors.lastname: Roy
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Kemp
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Kramer
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D054059:Coronary Occlusion / Q000150:complications; D004195:Disease Models, Animal; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C081643:candesartan