Metformin but not glyburide prevents high glucose-induced abnormalities inrelaxation and intracellular Ca2+ transients in adult rat ventricular myocytes

We have recently demonstrated that adult rat ventricular myocytes maintaine d in a high glucose (HG) culture medium exhibit abnormalities in excitation -contraction coupling similar to myocytes from diabetic rats. Metformin, an insulin-sensitizing biguanide, enhances peripheral insulin action and lowe rs blood pressure in hyperinsulinemic animals, but its direct impact on car diac function is not fully understood. To examine the role of metformin on HG-induced cardiac dysfunction at the cellular level, normal adult ventricu lar myocytes were cultured for 1 day in a serum-free insulin-containing med ium with either normal glucose (5.5 mmol/l glucose) or HG (25.5 rmnol/l glu cose) in the presence or absence of metformin or the sulfonylurea glyburide , Mechanical properties were evaluated using a high-speed video-edge detect ion system, and intracellular Ca2+ transients were recorded in fura-a-loade d myocytes, As previously reported, culturing myocytes in HG depresses peak shortening, prolongs time to 90% relengthening, and slows Ca2+ transient d ecay. Culturing cells with metformin (50 mu mol/l) prevented the HG-induced abnormalities in relaxation without ameliorating depressed peak-shortening amplitudes, Incubation of the cells with metformin also prevented slower i ntracellular Ca2+ clearing induced by HG, Ho vr ever, the HG-induced relaxa tion defects were not improved by glyburide (50-300 mu mol/l). Interestingl y, metformin also improved HG-induced relaxation abnormalities in the absen ce of insulin, whereas it failed to protect against HG in the presence of t he tyrosine kinase inhibitor genistein (50 mu mol/l). These data demonstrat e that, unlike glyburide, metformin provides cardioprotection against HG-in duced abnormalities in myocyte relaxation, perhaps through tyrosine kinase- dependent changes in intracellular Ca2+ handling, independent of its insuli n sensitizing action.