Cardioprotection induced by AT1R blockade after reperfused myocardial infarction: association with regional increase in AT2R, IP3R and PKCepsilon proteins and cGMP.
BACKGROUND
We hypothesized that the cardioprotective effect of angiotensin II (AngII) type 1 receptor (AT(1)R) blockade during in vivo ischemia-reperfusion (IR) might be associated with an increase in AngII type 2 receptor (AT(2)R) protein, as well as 1,4,5-inositol trisphosphate type 2 receptor (IP(3)R) and protein kinase C(epsilon) (PKC(epsilon)) proteins and cyclic guanosine 3',5' monophosphate (cGMP).


RESULTS
We studied the effects of the AT(1)R blocker, candesartan, on in vivo left ventricular (LV) systolic and diastolic function and remodeling (echocardiogram/Doppler) and hemodynamics during canine reperfused anterior infarction (90-minute ischemia, 120-minute reperfusion), and ex vivo infarct size and AT(1)R/AT(2)R, IP(3)R, and PKC(epsilon) proteins (immunoblots), and cGMP (enzyme immunoassay). Compared with controls, candesartan (1 mg/kg intravenously over 30-minute preischemia) inhibited the AngII pressor response, decreased preload and afterload, improved LV systolic and diastolic function, limited LV remodeling, decreased infarct size (55% vs 27% risk; P <.000003), markedly increased AT(2)R, IP(3)R, and PKC(epsilon) proteins in the infarct zone, but not the AT(1)R protein, and increased infarct more than noninfarct cGMP.


CONCLUSIONS
The overall results suggest that cardioprotective effects of AT(1)R blockade on acute IR injury might involve AT(2)R activation and downstream signaling via IP(3)R, PKC(epsilon), and cGMP.
Jugdutt
B I
BI
Cardiology Division of the Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. bjugdutt@cha.ab.ca
Xu
Y
Y
Balghith
M
M
Moudgil
R
R
Menon
V
V
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006439:Hemodynamics; D007262:Infusions, Intravenous; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000150:complications*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007527:Isoenzymes; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D018160:Receptors, Cytoplasmic and Nuclear; D013777:Tetrazoles; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D006152:Cyclic GMP; C081643:candesartan