Cardioprotection by metformin is abolished by a nitric oxide synthase inhibitor in ischemic rabbit hearts

Hypertens Res. 2003 Jan;26(1):107-10. doi: 10.1291/hypres.26.107.


We investigated the effects of metformin on myocardial metabolism during ischemia by 31P-nuclear magnetic resonance (NMR) in isolated rabbit hearts. Metformin was administered 60 min prior to induction of global ischemia, or in combination with a nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), at 5 min or 60 min prior to the ischemia. Normothermic global ischemia was then carried out for 45 min. Twenty-eight hearts were divided into 4 experimental groups consisting of 7 hearts each: a control (C) group; an M group receiving metformin treatment alone; an M+L (5) group receiving metformin treatment with L-NAME at 5 min before ischemia; and an M+L (60) group receiving metformin treatment with L-NAME at 60 min before ischemia. During ischemia, the decrease in adenosine triphosphate (ATP) was significantly inhibited in the M group in comparison with the C group (p < 0.01). However, this preservation of ATP in the M group was inhibited in the M+L (5) group during ischemia. In contrast, in the M+L (60) group, this preservation of ATP in the M group was not inhibited during, but not at the end of, ischemia. These results suggest that metformin has a significant beneficial effect for improving the myocardial energy metabolism during myocardial ischemia. This cardioprotection may be more dependent on nitric oxide synthase during ischemia than during pre-ischemia.

MeSH terms

  • Animals
  • Cardiotonic Agents / pharmacology*
  • Drug Interactions
  • Energy Metabolism / drug effects
  • Enzyme Inhibitors / pharmacology
  • Hypoglycemic Agents / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Male
  • Metformin / pharmacology*
  • Myocardial Ischemia / diagnostic imaging
  • Myocardial Ischemia / drug therapy*
  • Myocardial Ischemia / metabolism
  • Myocardium / metabolism
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Phosphorus Radioisotopes
  • Rabbits
  • Radionuclide Imaging


  • Cardiotonic Agents
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Phosphorus Radioisotopes
  • Nitric Oxide
  • Metformin
  • Nitric Oxide Synthase
  • NG-Nitroarginine Methyl Ester