Abstract
We assessed the effects of die angiotensin II (Ang II) type 1 receptor (AT(1)-receptor) blocker, candesartan, (CN, 1 mg/kg i.v. over 30 minutes pre-ischaemia) alone or after intracoronary administration of Ang II type 2 receptor (AT(2)-receptor) blocker (PD 123319), protein kinase C (PKC) inhibitor (chelerythrine), endothelial nitric oxide (NO) synthase inhibitor (N-G-monomethyl-L-arginine or L-NMMA), and bradykinin (BK) -B-2 receptor inhibitor (HOE140) on in vivo left ventricular (LV) function and remodelling (echocardiograms/ Doppler) and haemodynamics in 30 dogs with reperfused anterior infarction (90 minutes ischaemia, 120 minutes reperfusion), and ex vivo infarct size, AT(1)-receptor/AT(2)-receptor proteins and PKCepsilon (immunoblots), and cyclic guanosine 3', 5' monophosphate (cGMP, immunoassay). Compared with controls, CN inhibited the Ang II pressor response, reduced IV preload, improved IV systolic and diastolic function, limited IV remodelling, decreased infarct size, and increased AT(2)-receptor and PKCepsilon proteins in the infarct zone (IZ), and these responses were abrogated by PD 123319, chelerythrine, L-NMMA and HOE140. In addition, the increase in IV cGMP with CN was attenuated by PD 123319, L-NMMA and HOE140. The overall results suggest that AT(2)-receptor activation and signalling via BK, PKCepsilon and cGMP contribute to cardioprotection associated with AT(1)-receptor blockade during ischaemia-reperfusion injury.