Metformin Prevents Myocardial Reperfusion Injury by Activating the Adenosine Receptor

Abstract

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.

Short-term treatment with metformin suppresses toll like receptors (TLRs) activity in isoproterenol-induced myocardial infarction in rat: Are AMPK and TLRs connected?

“…Metformin has beneficial effects on ischemic heart decreasing cardiac risk factors and improving clinical outcomes in human as well as recovering left ventricular functions in experimental animals [26][27][28]. However, the mechanisms by which metformin exerts these cardioprotective effects remain unclear.…”

Metformin: From Mechanisms of Action to Therapies

“…In a working-heart perfusion model where metformin is administered before a mild ischemic episode, the antidiabetic drug improved rat cardiac functional postischemic recovery (Legtenberg et al, 2002). It has been also shown that metformin given at the time of reperfusion reduced myocardial infarct size in both nondiabetic and diabetic hearts (Bhamra et al, 2008;Paiva et al, 2009). In these two last studies, the protective action of metformin was associated with a PI3K-mediated inhibition of the mitochondrial permeability transition pore opening and with increased intracellular formation of adenosine.…”

IGF-1 and atherothrombosis: relevance to pathophysiology and therapy

“…In addition, adenosine produced during cardiac ischaemia [144] and drugs interacting with the adenosine receptor, such as metformin [145], are able to block mitogenic effects and MAPK activity downstream of IGF-1, rather promoting the PI3K pathway and its favourable antiischaemic and anti-atherogenic effects.…”