Selective activation of A3 adenosine receptors with N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide protects against myocardial stunning and infarction without hemodynamic changes in conscious rabbits.
To examine the cardioprotective role of A3 adenosine receptors during myocardial ischemia/reperfusion injury, we tested the effect of N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), a potent and selective A3 adenosine receptor agonist, in models of myocardial stunning and infarction in chronically instrumented conscious rabbits. In phase I (studies of myocardial stunning), rabbits were subjected to six 4-minute coronary occlusions, each separated by 4-minute reperfusion periods, after which the recovery of systolic wall thickening was measured (ultrasonic crystals). In phase II (studies of myocardial infarction), rabbits were subjected to a 30-minute coronary occlusion followed by 3 days of reperfusion. In both phases, IB-MECA was administered as an intravenous bolus (100 micrograms/kg) 10 minutes before the first coronary occlusion. This dose of IB-MECA was determined in pilot studies to have no effect on heart rate, arterial blood pressure, or plasma histamine concentration in rabbits. In phase I, IB-MECA markedly improved the recovery of wall thickening after the six occlusion/reperfusion cycles, and this effect was sustained throughout the 5-hour observation period; the total deficit of wall thickening (a measure of the overall severity of myocardial stunning) was reduced by 68% (control, 129 +/- 16 arbitrary units, n = 7; IB-MECA, 41 +/- 6 arbitrary units, n = 6; P < .01). The protective effects of IB-MECA against stunning were completely blocked by pretreatment with the nonselective adenosine receptor antagonist 8-p-sulfophenyl theophylline or the specific protein kinase C inhibitor chelerythrine. In phase II, IB-MECA reduced myocardial infarct size by 61%; infarct size (tetrazolium staining) was 41 +/- 4% of the risk region in control animals (n = 8) and 16 +/- 6% in IB-MECA-treated animals (n = 8, P < .01). These results demonstrate that in conscious rabbits the A3 adenosine receptor agonist IB-MECA confers a powerful protection against both reversible (stunning) and irreversible (infarction) injury during acute myocardial ischemia and reperfusion by a protein kinase C-mediated pathway, suggesting that selective activation of A3 receptors is an effective means of protecting the ischemic myocardium without hemodynamic changes.
Auchampach
J A
JA
Division of Cardiology, University of Louisville, KY 40292, USA.
Rizvi
A
A
Qiu
Y
Y
Tang
X L
XL
Maldonado
C
C
Teschner
S
S
Bolli
R
R
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects*; D006632:Histamine / Q000097:blood; D008297:Male; D009203:Myocardial Infarction / Q000517:prevention & control*; D017682:Myocardial Stunning / Q000517:prevention & control*; D011817:Rabbits; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000502:physiology
D018047:Receptors, Purinergic P1; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D006632:Histamine; D000241:Adenosine