Cardioprotective profile of MET-88, an inhibitor of carnitine synthesis, and insulin during hypoxia in isolated perfused rat hearts.
3-(2,2,2-trimethylhydrazinium) propionate (MET-88) is an inhibitor of carnitine synthesis. This study was carried out to investigate whether or not reduction of carnitine content could attenuate hypoxic damage in isolated perfused rat hearts. Rats were divided into four groups: 1) vehicle control; 2) pretreatment with MET-88 (MET-88); 3) application of insulin (500 muU/mL) in the perfusate (insulin); and 4) pretreatment with MET-88 and application of insulin (MET-88 + insulin). MET-88 (100 mg/kg) was orally administered once a day for 10 days until the day before the experiments. Hearts were initially perfused for a 10 min period under normoxia, followed by a 30 min period under hypoxia. Hearts were frozen at the end of hypoxia for the measurement of high-energy phosphates, carnitine derivatives, and glycolysis intermediates. In a separate series of untreated and MET-88 treated hearts, exogenous glucose and palmitate oxidation was measured. MET-88 decreased the extent of the depression of cardiac contractility (+dP/dt), and aortic flow during the hypoxic state. Insulin also improved cardiac function, and co-treatment of MET-88 and insulin additionally improved cardiac function during hypoxia. MET-88 prevented the decrease of high-energy phosphate and the increase of long-chain acylcarnitine after 30 min of hypoxic perfusion. In addition, MET-88 increased the steady state of glucose oxidation in hypoxic perfused rat hearts. These results indicate that MET-88 has cardioprotective effects on contractile function and energy metabolism of isolated perfused rat hearts in a hypoxic condition. Preventing the accumulation of long-chain acylcarnitine may serve to protect hypoxic hearts.
Asaka
N
N
Pharmacology Research Laboratory, Taiho Pharmaceutical Co Ltd, Tokushima, Japan.
Muranaka
Y
Y
Kirimoto
T
T
Miyake
H
H
D000284:Administration, Oral; D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002331:Carnitine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D003326:Coronary Circulation / Q000187:drug effects; D005947:Glucose / Q000032:analysis / Q000737:chemistry; D006019:Glycolysis / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D019344:Lactic Acid / Q000032:analysis / Q000378:metabolism; D008297:Male; D008763:Methylhydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D010084:Oxidation-Reduction; D010168:Palmitates / Q000032:analysis / Q000737:chemistry; D010710:Phosphates / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D002317:Cardiovascular Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D008763:Methylhydrazines; D010168:Palmitates; D010710:Phosphates; D019344:Lactic Acid; C050147:3-(2,2,2-trimethylhydrazine)propionate; D005947:Glucose; D002331:Carnitine