Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-epsilon in acutely reperfused myocardial infarction in the dog. Effect of UP269-6 and losartan on AT1 and AT2-receptor expression and IP3 receptor and PKCepsilon proteins.
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.
Xu
Y
Y
Department of Medicine and the Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada.
Menon
V
V
Jugdutt
B I
BI
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001810:Blood Volume / Q000187:drug effects; D015220:Calcium Channels / Q000378:metabolism; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007527:Isoenzymes / Q000378:metabolism*; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D011743:Pyrimidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013777:Tetrazoles / Q000627:therapeutic use; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D015220:Calcium Channels; D002316:Cardiotonic Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007527:Isoenzymes; D011743:Pyrimidines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D018160:Receptors, Cytoplasmic and Nuclear; D013777:Tetrazoles; C088791:UP 269-6; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D006152:Cyclic GMP; D019808:Losartan