Volume 1, Number 2, June 2000

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.
Effect of UP269-6 and losartan on AT₁-and AT₂-receptor expression and IP₃ receptor and PKC_ε proteins
Yi Xu, Vijayan Menon, Bodh I Jugdutt

To determine whether cardioprotection after chronic angiotensin II (Ang II) type 1 (AT₁) receptor blockade involves Ang II type 2 (AT₂) receptor expression and protein kinase C-ε (PKC_ε) activation, we measured in vivo haemodynamics and left ventricular (LV) remodelling and dysfunction (echocardiogram/ Doppler) and ex vivo AT₁/AT₂-receptor expression, IP₃R (1, 4, 5-inositol trisphosphate type 2 receptor) and PKC_ε proteins in dogs with acutely reperfused (90 minutes ischaemia, 90 minutes reperfusion) myocardial infarction (MI) following seven days of AT₁-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 AT₁-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 AT₁-receptor antagonists decreased infarct size. Importantly, MI decreased AT₁-receptor and AT₂-receptor expression while MI after AT₁-receptor antagonism increased AT₁-receptor (mRNA, not protein) and AT₂-receptor (mRNA and protein) expression as well as IP₃R and PKC_ε proteins and cyclic guanosine 3', 5' monophosphate (cGMP). These results suggest that cardioprotection induced by chronic AT₁-receptor antagonism involves enhanced AT₂-receptor expression and possibly downstream signalling through IP₃R, PKC_ε and cGMP.

JRAAS 2000;1:184-195.

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