Metformin treatment corrects vascular insulin resistance in hypertension

J Hypertens. 2000 Oct;18(10):1445-50. doi: 10.1097/00004872-200018100-00012.

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.

Design and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Angiotensin II / pharmacology
  • Animals
  • Hypertension / drug therapy*
  • Hypertension / physiopathology
  • Hypoglycemic Agents / pharmacology*
  • Insulin / blood
  • Insulin Resistance*
  • Male
  • Metformin / pharmacology*
  • Metformin / therapeutic use
  • Nitric Oxide / physiology
  • Norepinephrine / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Vasoconstriction / drug effects*

Substances

  • Hypoglycemic Agents
  • Insulin
  • Angiotensin II
  • Nitric Oxide
  • Metformin
  • Acetylcholine
  • Norepinephrine