Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs.
OBJECTIVE
We studied the effect of the angiotensin II type 1 (AT1)-receptor antagonist candesartan on infarct size resulting from regional myocardial ischemia in pigs.


BACKGROUND
The effects of AT1-receptor blockade on infarct size in different species remain controversial and its potential cardioprotective mechanisms are still unclear. In pigs, infarct development closely resembles that observed in humans.


METHODS
A total of 62 enflurane-anesthetized pigs underwent a protocol of 90-min low-flow ischemia and 120-min reperfusion. Systemic hemodynamics (micromanometer), regional myocardial function (sonomicrometry), regional myocardial blood flow (microspheres) and infarct size (TTC [triphenyl tetrazolium chloride]-staining) were determined.


RESULTS
Left ventricular peak pressure decreased with candesartan (1 mg/kg i.v.) from 97+/-2 standard error of the mean (SEM) to 86+/-5 mm Hg and was then readjusted by aortic banding. In placebo pigs (n=9), infarct size was 21.8+/-4.8% of the area at risk. Candesartan (n=7) reduced infarct size to 9.7+/-2.5% (p < 0.05). Pretreatment with the AT2-receptor antagonist PD123319 (3 microg/kg/min intracoronarily [i.c.]; n=8), the bradykinin B2-receptor antagonist HOE140 (0.01 microg/kg/min i.c.; n=8) or the cyclooxygenase inhibitor indomethacin (10 mg/kg i.v.; n= 8) per se did not affect infarct size but did abolish the reduction of infarct size achieved by candesartan (PD123319 + candesartan (n=7): 23.2+/-4.7%; HOE140 + candesartan (n=7): 18.2+/-4.0%; indomethacin + candesartan (n=8): 21.1+/-5.2%). Hemodynamics, regional myocardial blood flow during ischemia and the area at risk were comparable among all groups of pigs.


CONCLUSIONS
Reduction of infarct size by the AT1-receptor antagonist candesartan in pigs involves angiotensin II type 2 receptor (AT2) activation, bradykinin and prostaglandins.
Jalowy
A
A
Abteilung für Pathophysiologie, Zentrum für Innere Medizin des Universitätsklinikums Essen, Germany.
Schulz
R
R
Dörge
H
H
Behrends
M
M
Heusch
G
G
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001713:Biphenyl Compounds; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004338:Drug Combinations; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology*; D011453:Prostaglandins / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011945:Receptors, Angiotensin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine; D013556:Swine, Miniature; D013777:Tetrazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065168:Bradykinin Receptor Antagonists; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D007093:Imidazoles; D011453:Prostaglandins; D011725:Pyridines; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C073402:PD 123319; C065679:icatibant; C081643:candesartan; D001920:Bradykinin; D007213:Indomethacin