Cardioprotective effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on cardiac dysfunction induced by ischemia/reperfusion in isolated rat hearts.
Inhibition of fatty acid metabolite accumulation may be beneficial for treatment of cardiac dysfunction induced by ischemia. MET-88, 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, inhibits gamma-butyrobetaine hydroxylase which catalyzes conversion of gamma-butyrobetaine to carnitine. In this study, we investigated whether MET-88 has cardioprotective effects against cardiac dysfunction induced by ischemia/reperfusion. Rats were divided into four groups: (1) control; (2) MET-88 at 50 mg/kg; (3) MET-88 at 100 mg/kg; (4) nifedipine at 30 mg/kg. MET-88 was administered orally once a day for 10 days, and nifedipine was administered orally 30 min before the experiments. Cardiac functions (heart rate, left ventricular systolic pressure and coronary flow) were measured in rat working heart preparations for 30 min under ischemia followed by 20 min under reperfusion. Myocardial carnitine levels were measured at the end of the experiments. Before ischemia, MET-88 did not affect cardiac functions, but nifedipine significantly increased only coronary flow. Under the ischemic condition, cardiac functions were markedly decreased in all groups. During reperfusion, MET-88 and nifedipine promoted recovery of cardiac functions and decreased the incidence of ventricular fibrillation. MET-88 also prevented the accumulation of long-chain acylcarnitine induced by ischemia. These results indicated that MET-88 protected against cardiac dysfunction in ischemia/reperfusion, and preventing the accumulation of long-chain acylcarnitine may be responsible for the cardioprotective effects.
Hayashi
Y
Y
Pharmacology Research Laboratory, Taiho Pharmaceutical Co. Ltd., Tokushima, Japan. yucky@mail.netwave.or.jp
Tajima
K
K
Kirimoto
T
T
Miyake
H
H
Matsuura
N
N
D000818:Animals; D002331:Carnitine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006334:Heart Function Tests; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008763:Methylhydrazines / Q000627:therapeutic use*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014693:Ventricular Fibrillation / Q000188:drug therapy; D050563:gamma-Butyrobetaine Dioxygenase
D004791:Enzyme Inhibitors; D008763:Methylhydrazines; D019344:Lactic Acid; C050147:3-(2,2,2-trimethylhydrazine)propionate; D006899:Mixed Function Oxygenases; D050563:gamma-Butyrobetaine Dioxygenase; D009543:Nifedipine; D002331:Carnitine