Enhanced regional AT(2)-receptor and PKC(epsilon) expression during cardioprotection induced by AT(1)-receptor blockade after reperfused myocardial infarction.
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.
Jugdutt
B I
BI
Walter Mackenzie Health Sciences Centre, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. bjugdutt@ualberta.ca
Balghith
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M
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure; D002316:Cardiotonic Agents / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D006339:Heart Rate; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000201:enzymology; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000096:biosynthesis* / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D002316:Cardiotonic Agents; D007527:Isoenzymes; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D006152:Cyclic GMP