Protection by Bepridil Against Myocardial ATP-Catabolism Is Probably Due to Negative Inotropy

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Abstract
The protective effect of calcium antagonists on ischemic heart has been attributed to decreased energy expenditure. We administered one of the newer calcium antagonists, DL-bepridil (0.1–10 μM), to Langendorff rat hearts 10 or 15 min before ischemia (flow reduction ∼80%). Vasodilation during normoxia was already observed with 0.3 μM DL-bepridil (flow increase 34%. p < 0.005). This concentration decreased normoxic contractility and ischemic purine release, a marker for ATP breakdown. In the absence of bepridil. purine release of hearts that were made ischemic was 8.5-fold higher than that of normoxic control hearts. With 1 μM bepridil. the ischemic purine efflux was suppressed by 55% (p < 0.05), with negative inotropy (p > 0.05) during normoxia. At 3 and 10 μM, bepridil decreased normoxic contractility by 40 and 75%, respectively (p < 0.001), concomitant with a decrease in ischemic purine release by 80 and 76%. respectively (p < 0.01). At the end of ischemia, myocardial ATP and creatine phosphate had decreased by 22 and 55%. respectively (p < 0.05). and ADP. AMP. and creatine had increased 1.5–3.5-fold (p < 0.05). Bepridil (3 μM) normalized the adenine nucleotide values; creatine and creatine phosphate approached control levels. The dose-dependent protection of the ischemic heart by bepridil appears to arise from its negative inotropic action during normoxia.