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 associated with decreases in blood pressure, an effect that could result from a direct action of metformin on arterial smooth muscle, Objective To determine the mechanisms responsible for arterial smooth muscle relaxation induced by acute application of metformin and to evaluate the effect of insulin pretreatment on intracellular [Ca2+] ([Ca2+](i)) and contraction in an intact artery, Methods We stimulated intact deendothelialized rat tail artery with phenylephrine, relaxed the tissue by adding increasing concentrations of metformin, and measured the membrane potential (E(m)), Mn2+ influx, Fura 2-estimated [Ca2+](i), and isometric force. We also evaluated the effect of insulin pretreatment on aequorin-estimated [Ca2+](i) in deendothelialized swine carotid artery, Results In rat tail artery we found that a high concentration of metformin-induced repolarization associated with proportional decreases in Mn2+ influx, Fura 2-estimated [Ca2+](i), and isometric force, Incubation 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 increases in [Ca2+]i or contraction. Conclusion These data suggest that acute administration of high concentrations of metformin induces rat tail artery relaxation primarily by repolarization. Additionally, we found 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.