Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-ε in acutely reperfused myocardial infarction in the dog

To determine whether cardioprotection after chronic angiotensin II (Ang II) type 1 (AT(1)) receptor blockade involves Ang II type 2 (AT(2)) receptor expression and protein kinase C-epsilon (PKC(epsilon)) activation, we measured in vivo haemodynamics and left ventricular (LV) remodelling and dysfunction (echocardiogram/ Doppler) and ex vivo AT(1)/AT(2)-receptor expression, IP(3)R (1, 4, 5-inositol trisphosphate type 2 receptor) and PKC(epsilon) proteins in dogs with acutely reperfused (90 minutes ischaemia, 90 minutes reperfusion) myocardial infarction (MI) following seven days of AT(1)-receptor blockade with oral losartan or UP269-6. The animals were randomised to sham; sham + losartan or UP269-6; MI alone; MI + losartan; MI + UP269-6. More marked AT(1)-receptor blockade with UP269-6 (greater inhibition of Ang II pressor responses) was associated with a smaller increase in preload, less systolic and diastolic dysfunction, less infarct expansion, and smaller LV diastolic and systolic volumes. However, both AT(1)-receptor antagonists decreased infarct size. Importantly, MI decreased AT(1)-receptor and AT(2)-receptor expression while MI after AT(1)-receptor antagonism increased AT(1)-receptor (mRNA, not protein) and AT(2)-receptor (mRNA and protein) expression as well as IP(3)R and PKC(epsilon) proteins and cyclic guanosine 3', 5' monophosphate (cGMP). These results suggest that cardioprotection induced by chronic AT(1)-receptor antagonism involves enhanced AT(2)-receptor expression and possibly downstream signalling through IP(3)R, PKC(epsilon) and cGMP.