Effects of MCI-176, a new quinazolinone calcium antagonist, on myocardial energy and carbohydrate metabolism in ischemic dog hearts

Abstract

The effect of 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-isopropoxy-4(3 H)-quinazolinone hydrochloride (MCI-176), a calcium antagonist, on ischemic myocardial metabolism was studied in dog hearts subjected to an occlusion of the left anterior descending coronary artery (LAD) for 3 or 30 min. MCI-176 (0.03 or 0.1 mg/kg), when injected i.v. 5 min before occlusion, increased coronary blood flow and decreased systematic aortic pressure. When the LAD was ligated, the levels of creatine phosphate, ATP, total adenine nucleotides and energy charge potential decreased in the ischemic myocardium. Three minutes after ischemia, MCI-176 (0.1 mg/kg) significantly (P < 0.05) diminished these impairments of energy metabolism. Even 30 min after ischemia, pretreatment with MCI-176 tended to lessen the depletion of ATP and total adenine nucleotides, although these effects were not statistically significant. Myocardial ischemia produced a breakdown of glycogen, an accumulation of lactate, and an inhibition of glycolytic flux through phosphofructokinase reaction. MCI-176 (0.1 mg/kg) significantly (P < 0.05) reduced these alterations of carbohydrate metabolism after 3 min of ischemia. These results suggest that pretreatment with MCI-176 reduces the impairments of myocardial energy and carbohydrate metabolism in ischemic dog hearts, suggesting that the drug is capable of improving the imbalance between oxygen supply and oxygen demand in the ischemic myocardium.