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-ε (PKCε) 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 PKCε 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 PKCε 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, PKCε and cGMP.