Cardioprotective effects of angiotensin II type 1 receptor blockade with candesartan after reperfused myocardial infarction: role of angiotensin II type 2 receptor

To determine whether angiotensin II (Ang II) type 2 (AT(2))-receptor activation associated with cardioprotection induced by Ang II type I (AT(1))-receptor blockade during ischaemia-reperfusion (IR) might be reflected in increased AT(2)-receptor, IP3-(1,4,5- inositol trisphosphate type 2) receptor and PKC-epsilon (protein kinase C-epsilon) proteins and tissue cGMP (cyclic guanosine monophosphate), we measured in vivo left ventricular (IV) systolic and diastolic function arid remodelling (echocardiogram/Doppler) and haemodynamics, and ex vivo infarct size, AT(1)-/AT(2)-receptor, IP3-receptor and PKC-epsilon proteins (immunoblots) and cGMP (enzyme immunoassay) in dogs with reperfused anterior acute myocardial infarction (MI) (90-minute ischaemia, 120-minute reperfusion). Compared with controls (C, n=6) in vivo, candesartan (1 mg/kg ix. over 30-minute pre-ischaemia, n=6) effectively inhibited the Ang H pressor response (Delta%, -14 +/- 22% vs. -80 +/- 11, p <0.003) and decreased preload (122 +/- 35 vs. -2 +/- 16%, p <0.01), improved IV systolic ejection fraction (-29 +/-4 vs. -11 +/-5, p <0.03) and diastolic function (E/A ratio, -25 +/-7 vs. 33 +/- 13, p <0.004), decreased the extent of IV asynergy (26 +/- 20 vs. -31 +/- 10% LV, p <0.05) and limited acute LV remodelling (expansion index 19 +/-6 vs. -3 +/-5, p <0.05; thinning ratio -22 +/-2 vs. -4 +/-2, p <0.0003). Ex vivo, candesartan decreased infarct size (55 +/-2 vs. 27 +/-2% risk, p <0.001) and increased infarct zone (IZ) AT(2)-receptor protein by 8-fold (but not ATI-receptor protein), IP3-receptor protein by 12-fold, PKC-epsilon protein by 5-fold and cGMP by 40%. Cardioprotective effects of AT(1)-receptor blockade on acute IR injury, IV function, and remodelling may also involve AT(2)-receptor activation and downstream signalling via IP3-receptor, PKC-epsilon and cGMP.