title: AT2 receptor and apoptosis during AT1 receptor blockade in reperfused myocardial infarction in the rat.
abstract: We assessed whether upregulation of the angiotensin II (AngII) type 2 receptor (AT2R) during AngII type 1 receptor (AT1R) blockade might induce apoptosis in the in vivo rat model of reperfused myocardial infarction (RMI) and whether addition of an AT2R blocker abolishes that effect. We measured in vivo hemodynamics and left ventricular (LV) systolic and diastolic function (echocardiograms/Doppler), and ex vivo infarct size (triphenyl tetrazolium chloride), regional AT1R and AT2R proteins (immunoblots), and apoptosis (TUNEL assay and DNA ladder) after regional anterior RMI (60 min ischemia, 90 min reperfusion) in Sprague-Dawley rats randomized to intravenous AT1R blockade with candesartan (1 mg/kg, n = 9) or saline (controls, n = 14) over 30 min before RMI, and sham (n = 8). We also assessed the effect of AT2R blockade (PD123319, 10 mg/kg i.v.) plus candesartan on infarct size and apoptosis. Compared to controls, candesartan significantly (p < 0.001) limited increases in left atrial pressure, improved positive LV dP/dtmax and negative dP/dtmin, normalized LV ejection fraction, improved LV diastolic function, limited infarct expansion, decreased infarct size and apoptosis, and increased AT2R protein (not AT1R) in the reperfused ischemic zone. There were no changes in sham hearts. PD123319 abolished the candesartan-induced decrease in infarct size and LV dysfunction but not the decrease in apoptosis. Thus, during AT1R blockade in the in vivo rat model of RMI, regional AT2R upregulation contributes to the beneficial effect on infarct size and LV dysfunction but not on apoptosis, suggesting that the apoptosis is AT1R not AT2R-mediated.
authors.affiliation: Division of Cardiology, Department of Medicine and the Cardiovascular Research Group, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada. bjugdutt@ualberta.ca
authors.forename: Bodh I
authors.initials: BI
authors.lastname: Jugdutt
authors.forename: Vijayan
authors.initials: V
authors.lastname: Menon
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D006439:Hemodynamics; D007093:Imidazoles / Q000494:pharmacology; D009203:Myocardial Infarction / Q000473:pathology*; D015425:Myocardial Reperfusion; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C073402:PD 123319; C081643:candesartan