Postischemic apoptosis and functional recovery after angiotensin II type 1 receptor blockade in isolated working rat hearts.
OBJECTIVE
To determine whether chronic angiotensin (AngII) type I receptor (AT1R) blockade inhibits cardiomyocyte (CM) apoptosis and attenuates left ventricular (LV) dysfunction after ischemia-reperfusion (IR) in the isolated working rat heart.


METHODS
Postischemic recovery of LV developed pressure, the apoptotic index (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end labeling or TUNEL assay), and changes in expression of apoptotic markers Bcl-2, Bax, p53 and caspase-3 (Western immunoblots) were measured after IR (50 min aerobic perfusion; 25 min global ischemia; 40 min reperfusion) in working rat hearts that were randomized to five groups of six each along 1 week or 3 week pretreatment arms: sham (no drug, no perfusion); no drug, aerobic perfusion; and oral AT1R blockers losartan (30 mg/kg per day) or UP269-6 (3 mg/kg per day), or no drug before IR.


RESULTS
Compared to the no drug group after IR, losartan (not UP269-6) preserved functional recovery in 1 and 3 week groups. However, both losartan and UP269-6 reduced the apoptotic index and normalized the increase in Bax, decrease in Bcl-2 and increase in p53 and caspase-3 after IR. A bell-shaped relation between apoptosis and functional recovery after IR was flattened by AT1R blockade.


CONCLUSIONS
The results indicate that IR is associated with LV dysfunction and CM apoptosis involving activation of p53, caspase-3, and increased Bax/Bcl-2 ratio in the working rat heart. Importantly, chronic AT1R blockade inhibited the apoptosis and changes in expression of the markers without improving functional recovery, implying that decrease in apoptosis does not necessarily translate into decreased LV dysfunction.
Moudgil
R
R
Department of Medicine, University of Alberta, Edmonton, Canada.
Menon
V
V
Xu
Y
Y
Musat-Marcu
S
S
Kumar
D
D
Jugdutt
B I
BI
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein
D057911:Angiotensin Receptor Antagonists; C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C088791:UP 269-6; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D019808:Losartan