Cardioprotection by metformin is abolished by a nitric oxide synthase inhibitor in ischemic rabbit hearts.
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.
Kawabata
Hitoshi
H
Department of Cardiology, Kinki University School of Medicine, Ohnohigashi, Osakasayama, Japan. int1@med.kindai.ac.jp
Ishikawa
Kinji
K
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004347:Drug Interactions; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010761:Phosphorus Radioisotopes; D011817:Rabbits; D011877:Radionuclide Imaging
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010761:Phosphorus Radioisotopes; D009569:Nitric Oxide; D008687:Metformin; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester