Metformin improves vascular function in insulin-resistant rats

This study assessed the effect of metformin treatment on insulin, mean arte rial pressure (MAP), and endothelial function in insulin-resistant (IR) rat s. In addition, we assessed the direct effect of metformin in vitro. Spragu e-Dawley rats were randomized to control (n=28) or IR (n=28) groups. Rats w ere further randomized to receive metformin (300 mg/kg) or placebo for 2 we eks. MAP and insulin were measured. Subsequently, a third-order branch of t he superior mesenteric artery was isolated, and endothelial function was as sessed. Specifically, dose-response experiments of acetylcholine (ACh) with or without N-nitro-L-arginine (LNNA) were performed. For in vitro experime nts, mesenteric arteries were removed iom untreated control and IR rats and treated with metformin (100 mu mol/L) before ACh+/-LNNA. MAP and insulin l evels were improved in IR-metformin compared with IR-placebo lars. Maximal relaxation (E-max) to ACh was enhanced in IR-metformin (92+/-2%) compared w ith IR-placebo rats (44+/-4%) (P<0.05), Relaxation in response to ACh+LNNA was greater in IR-metformin (33+/-4%) than in IR-placebo rats (12+/-4%) but remained depressed compared with control rats (E-max=68+/-5%). The control group was not affected by metformin. In vitro treatment of arteries with m etformin in response to ACh produced results similar to those in the experi ments with metformin-treated rats. Although metformin improves metabolic ab normality in IR rats, this action does not appear to mediate its effect on vascular function. Both in vivo and in vitro metformin improved ACh-induced relaxation in IR rats to control levels, apparently through nitric oxide-d ependent relaxation. These data suggest that metformin improves vascular fu nction through a direct mechanism rather than by improving metabolic abnorm alities.