The diphenylbutylpiperidine(DPBP) antipsychotic pimozide was identified as a potent new Ca2 channel antagonist in heart. In whole-cell patch-clamp experiments, pimozide blocked Ca2 current through L type channels of rat ventricular myocytes, in a voltage-dependent manner. At holding potentials positive to-40 mV, approximately 90% of current was blocked by 200 nri pimozide. Nearly half of this block, 48±5%(mean±SE, n= 5), was relieved by 5-mm hyperpolarization to-1 00 mV. In quin2-loaded myocytes, pimozide blocked 50 m KCI-induced increases in intracellular Ca2 concentration([Ca2]) half maximally at a concentration of 75±15 n(n= 5). Two other DPBPs, penfluridol and fluspirilene, also blocked the KCI-induced re-sponse at similar concentrations. The contractile force of cardiac tissue was also depressed by pimozide. One micromolar pimo-zide reduced twitch tension in rat papillary muscles by an average of 36±8%(n= 3). These results demonstrate that the DPBPs comprise a potent new class of Ca2 antagonists in heart, which will be useful in studying cardiac Ca2 channels. They also suggest that these agents may have therapeutic value outside the field of psychiatry.

Excitable neural, endocrine, and muscle cells express one on more of several distinct types of voltage-gated Ca2 channels. These Ca2 channels are differentially sensitive to the major groups of organic Ca2 antagonists(1-5). Several years ago, it was proposed that DPBP antipsychotics comprise a potent new class of Ca2 channel blocker. This claim was based on the observation that these agents inhibited both the specific binding ofthe dihydropyridine Ca2 channel ligand [3Hjnitrendipine to neuronal membranes and depolarization-stimulated contractions in smooth muscle (6). More direct evidence has been obtained in voltage-clamp studies on two separate types of excitable cells. The DPBP fluspinilene at nanomolar concentrations blocked Ca2 current through high threshold, slowly inactivating, L type Ca2 channels in rat skeletal muscle myoballs (7). We found that the antipsychotic pimozide potently blocked Ca2 current through similar channels in the GH4C1 pituitary cell line (8).