Protection by bepridil against myocardial ATP-catabolism is probably due to negative inotropy.
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 microM), to Langendorff rat hearts 10 or 15 min before ischemia (flow reduction approximately 80%). Vasodilation during normoxia was already observed with 0.3 microM DL-bepridil (flow increase 34%, p less than 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 microM bepridil, the ischemic purine efflux was suppressed by 55% (p less than 0.05), with negative inotropy (p greater than 0.05) during normoxia. At 3 and 10 microM, bepridil decreased normoxic contractility by 40 and 75%, respectively (p less than 0.001), concomitant with a decrease in ischemic purine release by 80 and 76%, respectively (p less than 0.01). At the end of ischemia, myocardial ATP and creatine phosphate had decreased by 22 and 55%, respectively (p less than 0.05), and ADP, AMP, and creatine had increased 1.5-3.5-fold (p less than 0.05). Bepridil (3 microM) 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.
D000241:Adenosine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D015764:Bepridil; D003864:Depression, Chemical; D004734:Energy Metabolism / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D007288:Inosine / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014664:Vasodilation / Q000187:drug effects; D019820:Xanthine; D014970:Xanthines / Q000378:metabolism
D007042:Hypoxanthines; D011759:Pyrrolidines; D014970:Xanthines; D019820:Xanthine; D019271:Hypoxanthine; D007288:Inosine; D015764:Bepridil; D000255:Adenosine Triphosphate; D000241:Adenosine