The biguanide, metformin, is widely used for the treatment of type 2 diabetes mellitus. In the recently published United Kingdom Prospective Diabetes Study (UKPDS), it was shown that the use of metformin was associated with a reduction of macrovascular complications compared to other blood glucose-lowering strategies. The present study was aimed at determining whether metformin has direct beneficial effects on the heart. We tested the effects of metformin on cardiac functional recovery after a mild ischemic incident (stunning) in our isolated, erythrocyte perfused, rat working-heart model. Three groups were tested: vehicle, 50 and 500 micromol/l metformin (total n = 6). In diabetic rats, a concentration of 50 microM has been shown to reduce the blood glucose concentration. Slight metformin-induced increases in coronary blood flow during normoxia (pre-ischemically) and during reperfusion (post-ischemically) were observed and compared to vehicle (p < 0.05). Both metformin concentrations significantly reduced cardiac functional loss induced by the 12-min global ischemic incident compared with vehicle (3.4 +/- 1.0 % and 3.5 +/- 0.6 % loss during metformin versus 10.7 +/- 0.8 % during vehicle, p < 0.001). This study clearly shows that metformin acutely improves cardiac function after a mild ischemic incident (stunning) in rats.

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Glibenclamide preserves postischaemic myocardial function in the isolated, erythrocyte perfused, working rat heart model. This study addresses the possible involvement of K ATP channels in this beneficial action of glibenclamide. We hypothesized that if glibenclamide improved postischaemic cardiac function by blocking of K ATP channels, opening of these K ATP channels should result in the opposite, namely detrimental effects on postischaemic heart function. Postischaemic functional loss and coronary blood flow were recorded during treatment with glibenclamide (4 mmol.l ª1 ; nΩ5), the K ATP channel openers pinacidil (1 mmol.l ª1 ; nΩ5) and diazoxide (30 mmol.l ª1 ; nΩ5), the combination of glibenclamide with pinacidil (nΩ5) and glibenclamide with diazoxide (nΩ5), and vehicle (nΩ8). Both pinacidil and diazoxide significantly increased coronary blood flow 2-3 times, which was abolished by glibenclamide pre-and postischaemically. This confirms that under both flow conditions glibenclamide significantly blocks K ATP channels in the coronary vasculature. The 12 min. global ischaemic incident resulted in a cardiac functional loss of 22.2∫2.9% during vehicle.

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