Metformin improves cardiovascular outcomes in patients with
type 2 diabetes compared with other
glucose-lowering drugs. Experimental studies have shown that
metformin can increase the intracellular concentration of
adenosine monophosphate, which is a major determinant of the intracellular formation of
adenosine. We hypothesize that
metformin, given at reperfusion, can limit
myocardial infarct size due to increased
adenosine receptor stimulation. Isolated perfused hearts from Sprague-Dawley rats were subjected to 35 minutes of regional
ischemia and 120 minutes of reperfusion. Perfusion with
metformin (50 microM) for the first 15 minutes of reperfusion reduced
infarct size (percent area at risk) from 42% +/- 2% to 19% +/- 4% (n >or= 6; P < 0.01), which was blocked by a concomitant perfusion with the
adenosine receptor antagonist 8-p-sulfophenyltheophylline (100 microM; 43% +/- 3%) or nitrobenzylthioinosine (a blocker of transmembranous
adenosine transport; 1 microM; 45% +/- 5%). In addition,
intravenous administration of
metformin (5 mg/kg) reduced
infarct size in a rat in situ model of
myocardial infarction (34% +/- 6% vs. 62% +/- 5%; P < 0.01), which was completely abolished by 8-p-sulfophenyltheophylline (61% +/- 3%). We conclude that
metformin, given at reperfusion, reduces
infarct size in a rat model of
myocardial infarction, which is critically dependent on
adenosine receptor stimulation, probably via increased intracellular formation of
adenosine.