title: Metformin improves vascular function in insulin-resistant rats.
abstract: This study assessed the effect of metformin treatment on insulin, mean arterial pressure (MAP), and endothelial function in insulin-resistant (IR) rats. In addition, we assessed the direct effect of metformin in vitro. Sprague-Dawley rats were randomized to control (n=28) or IR (n=28) groups. Rats were further randomized to receive metformin (300 mg/kg) or placebo for 2 weeks. MAP and insulin were measured. Subsequently, a third-order branch of the superior mesenteric artery was isolated, and endothelial function was assessed. Specifically, dose-response experiments of acetylcholine (ACh) with or without N-nitro-L-arginine (LNNA) were performed. For in vitro experiments, mesenteric arteries were removed from untreated control and IR rats and treated with metformin (100 micromol/L) before ACh+/-LNNA. MAP and insulin levels were improved in IR-metformin compared with IR-placebo rats. Maximal relaxation (E(max)) to ACh was enhanced in IR-metformin (92+/-2%) compared with 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 metformin in response to ACh produced results similar to those in the experiments with metformin-treated rats. Although metformin improves metabolic abnormality 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-dependent relaxation. These data suggest that metformin improves vascular function through a direct mechanism rather than by improving metabolic abnormalities.
authors.affiliation: University of Georgia Colleges of Pharmacy, Augusta VA Medical Center, Augusta, GA, USA.
authors.forename: P V
authors.initials: PV
authors.lastname: Katakam
authors.forename: M R
authors.initials: MR
authors.lastname: Ujhelyi
authors.forename: M
authors.initials: M
authors.lastname: Hoenig
authors.forename: A W
authors.initials: AW
authors.lastname: Miller
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000209:etiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D014280:Triglycerides; D019335:Nitroarginine; D009569:Nitric Oxide; D008687:Metformin; D000109:Acetylcholine