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 (AT2)-receptor activation associated with cardioprotection induced by Ang II type 1 (AT1)-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-ε (protein kinase C-ε) proteins and tissue cGMP (cyclic guanosine monophosphate), we measured in vivo left ventricular (LV) systolic and diastolic function and remodelling (echocardiogram/Doppler) and haemodynamics, and ex vivo infarct size, AT1-/AT 2receptor, IP3-receptor and PKC-ε 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 i.v. over 30-minute pre-ischaemia, n=6) effectively inhibited the Ang II pressor response (Δ%, -14±22% vs. -80±11, p<0.003) and decreased preload (122±35 vs. -2±16%, p<0.01), improved LV 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 LV 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) AT2 -receptor protein by 8-fold (but not AT1-receptor protein), IP3-receptor protein by 12-fold, PKC-ε protein by 5-fold and cGMP by 40%. Cardioprotective effects of AT1-receptor blockade on acute IR injury, LV function, and remodelling may also involve AT 2-receptor activation and downstream signalling via IP3-receptor, PKC-ε and cGMP.