Selective blockade of AT1 angiotensin II receptors abolishes ischemic preconditioning in isolated rabbit hearts.
The aim of the present study was to assess the participation of angiotensin II receptors in the triggering mechanism of ischemic preconditioning. Isolated buffer-perfused rabbit hearts were subjected to 40 min of regional ischemia (37 degrees C) followed by 60 min of reperfusion. Ischemic preconditioning was induced with three cycles of 5-min ischemia and 10-min reperfusion given prior to the 40-min ischemic period. Infarct size and ventricular function were assessed. Ischemic preconditioning reduced infarct size to 5.2 +/- 1.2% of the area at risk (mean +/- S.E.M., P<0.001) when compared to controls (26.4 +/- 3.0%), but did not protect against ventricular dysfunction. Activation of angiotensin II receptors with angiotensin II (100 nM) also limited infarct size (9.6 +/- 2.2%, P<O.01 v control group). Inhibition of angiotensin II receptors with [Sar1, Val5, Ala8]-angiotensin II (saralasin, 1 microM) blocked the protection of ischemic preconditioning against necrosis (29.7 +/- 3.2%) while it did not increase infarct size in saralasin-treated control hearts (31.5 +/- 3.9%). Furthermore, inhibition of the AT1 subtype of the angiotensin II receptor with losartan (20 microM), but not inhibition of the AT2 subtype with PD-123,319 ditrifluoroacetate (10 microM), abolished the infarct size-limiting effect of ischemic preconditioning. We conclude that the AT1 angiotensin II receptor participates in ischemic preconditioning. Thus, in the isolated rabbit heart, activation of AT1 receptors must occur before prolonged ischemia for ischemic preconditioning to limit infarction.
Diaz
R J
RJ
Division of Cardiovascular Research, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Wilson
G J
GJ
D000704:Analysis of Variance; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use; D003326:Coronary Circulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D019808:Losartan; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology*; D015425:Myocardial Reperfusion; D011817:Rabbits; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012504:Saralasin / Q000627:therapeutic use; D013777:Tetrazoles / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D012504:Saralasin; D019808:Losartan