Cardioprotection Induced by AT1R Blockade After Reperfused Myocardial Infarction: Association With Regional Increase in AT2R, IP3R and PKCε Proteins and cGMP

Abstract

Background: We hypothesized that the cardioprotective effect of angiotensin II (AngII) type 1 receptor (AT,R) blockade during in vivo ischemia-reperfusion (IR) might be associated with an increase in AngII type 2 receptor (AT2R) protein, as well as 1,4,5-inositol trisphosphate type 2 receptor (IP3R) and protein kinase C ε, (PKCε) proteins and cyclic guanosine 3',5' monophosphate (cGMP). Methods and Results: We studied the effects of the AT1R blocker, candesartan, on in vivo left ventricular (LV) systolic and diastolic function and remodeling (echocardiogram/Doppler) and hemodynamics during canine reperfused anterior infarction (90-minute ischemia, 120-minute reperfusion), and ex vivo infarct size and AT1R/AT2R, IP3R, and PKCε proteins (immunoblots), and cGMP (enzyme immunoassay). Compared with controls, candesartan (1 mg/kg intravenously over 30-minute preischemia) inhibited the AngII pressor response, decreased preload and afterload, improved LV systolic and diastolic function, limited LV remodeling, decreased infarct size (55% vs 27% risk; P < .000003), markedly increased AT2R, IP3R, and PKCε proteins in the infarct zone, but not the AT,R protein, and increased infarct more than noninfarct cGMP. Conclusions: The overall results suggest that cardioprotective effects of AT1R blockade on acute IR injury might involve AT2R activation and downstream signaling via IP3R, PKCε, and cGMP.