title: Metformin treatment corrects vascular insulin resistance in hypertension.
abstract: OBJECTIVE
  In states of insulin resistance, the vasorelaxant actions of insulin are blunted, which may contribute towards the development of increased vascular tone/hypertension and reduced glucose uptake. To examine whether treating insulin resistance in hypertension restores the vascular actions of insulin, we studied the long-term effects of metformin on the contractile responses of isolated aortas from control and insulin-resistant, hyperinsulinaemic fructose-hypertensive rats in the presence and absence of insulin.
  
  
  METHODS
  Sprague Dawley rats were divided into control, control metformin-treated, fructose and fructose metformin-treated groups (n = 8 per group). The treated groups received metformin (500 mg/kg per day for 6 weeks), following which isometric responses to noradrenaline (NA) and angiotensin II (A-II) were examined in thoracic aortas in the presence and absence of insulin (100 mU/ml for 2 h) using isolated organ-bath apparatus. In addition, endothelium-dependent and independent vascular responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were also studied.
  
  
  RESULTS
  Metformin treatment prevented the development of fructose-induced insulin resistance, hyperinsulinaemia and hypertension. Insulin attenuated the contractile responses to NA and A-II in control rat aortas; however, blood vessels from untreated fructose rats were refractory to insulin-induced vasodilation. Strikingly, long-term metformin treatment restored the vasodepressor actions of insulin in fructose rats. Metformin did not affect the contractile responses to NA or A-II in either control or fructose rats. In addition, metformin treatment restored ACh-induced endothelium-dependent vasorelaxation in aortas from fructose rats without affecting SNP-induced relaxation.
  
  
  CONCLUSIONS
  These data show, for the first time, that long-term metformin treatment corrects vascular insulin resistance and improves endothelium-dependent vasorelaxation in hypertension. These effects appear to be secondary to metformin-induced improvements in metabolic derangements (versus a direct vascular action of metformin). Improving the vascular effects of insulin may serve to decrease peripheral tone, attenuate blood pressure and improve insulin sensitivity.
authors.affiliation: Faculty of Medicine, The University of Calgary, Alberta, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Verma
authors.forename: L
authors.initials: L
authors.lastname: Yao
authors.forename: A S
authors.initials: AS
authors.lastname: Dumont
authors.forename: J H
authors.initials: JH
authors.lastname: McNeill
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D000804:Angiotensin II; D009569:Nitric Oxide; D008687:Metformin; D000109:Acetylcholine; D009638:Norepinephrine