METFORMIN RELAXES RAT TAIL ARTERY BY REPOLARIZATION AND RESULTANT DECREASES IN CA2+ INFLUX AND INTRACELLULAR [CA2+]

Background Metformin treatment of type II diabetes is frequently assoc iated with decreases in blood pressure, an effect that could result fr om a direct action of metformin on arterial smooth muscle, Objective T o determine the mechanisms responsible for arterial smooth muscle rela xation induced by acute application of metformin and to evaluate the e ffect of insulin pretreatment on intracellular [Ca2+] ([Ca2+](i)) and contraction in an intact artery, Methods We stimulated intact deendoth elialized rat tail artery with phenylephrine, relaxed the tissue by ad ding increasing concentrations of metformin, and measured the membrane potential (E(m)), Mn2+ influx, Fura 2-estimated [Ca2+](i), and isomet ric force. We also evaluated the effect of insulin pretreatment on aeq uorin-estimated [Ca2+](i) in deendothelialized swine carotid artery, R esults In rat tail artery we found that a high concentration of metfor min-induced repolarization associated with proportional decreases in M n2+ influx, Fura 2-estimated [Ca2+](i), and isometric force, Incubatio n of swine carotid artery in 100 mU/ml insulin for 30 min or overnight (16-22 h) did not significantly alter histamine or high-K+-induced in creases in [Ca2+]i or contraction. Conclusion These data suggest that acute administration of high concentrations of metformin induces rat t ail artery relaxation primarily by repolarization. Additionally, we fo und that insulin was not vasoactive in the swine carotid artery, It is possible that insulin may alter [Ca2+](i) handling in other arteries, in other species, or only in cultured smooth muscle.