We assessed the effects of the
angiotensin II (Ang II) type 1 receptor (AT1-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 (AT2-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) -B2 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, AT1-receptor/AT2-receptor
proteins and
PKC(epsilon) (immunoblots), and cyclic
guanosine 3', 5' monophosphate (cGMP, immunoassay). Compared with controls, CN inhibited the Ang II pressor response, reduced LV preload, improved LV systolic and diastolic function, limited LV remodelling, decreased
infarct size, and increased AT2-receptor and
PKC(epsilon)
proteins in the
infarct zone (IZ), and these responses were abrogated by
PD 123319,
chelerythrine,
L-NMMA and
HOE140. In addition, the increase in LV cGMP with CN was attenuated by
PD 123319,
L-NMMA and
HOE140. The overall results suggest that AT2-receptor activation and signalling via BK,
PKC(epsilon) and cGMP contribute to cardioprotection associated with AT1-receptor blockade during ischaemia-
reperfusion injury.