INTERACTIONS BETWEEN CA2-K-8644 IN BOVINE CHROMAFFIN CELLS(, PCA50941AND BAY)

We describe here the effects of PCA50941 (a novel 1,4-dihydropyridine derivative) comparatively with Bay K 8644 on various parameters in bov ine adrenal chromaffin cells. The binding of [H-3](+)-isradipine to bo vine adrenal medulla plasma membranes was inhibited similarly by PCA50 941 and Bay K 8644 at various [Ca2+](o) suggesting a common binding si te for both compounds on the dihydropyridine receptor. In voltage-clam ped chromaffin cells PCA50941(1 mu M) and Bay K 8644 (1 mu M) Shifted the I-V relationship of whole-cell Ca2+ currents by about 5-10 mV towa rds more hyperpolarizing potentials. At -20 mV, PCA50941 enhanced I-ca by 195 +/- 16% and Bay K 8644 by 288 +/- 51%. Stimulation of fura 2-l oaded chromaffin cell suspensions with 17.7 K+/0.5 Ca2+ increased 3-fo ld the basal [Ca2+](i). PCA50941 increased further the Kf-evoked peak to 655 nM, and Bay K 8644 to 1129 nM. In the presence of 5 mM Ca2+, PC A50941 or Bay K 8644 increased the [Ca2+] peaks to 427 and 350 nM, res pectively. PCA50941 potentiated the release of catecholamines from per fused bovine adrenal glands.evoked by 30 s pulses of 17.7 mM K+ in a m anner dependent on the [Ca2+](o). Thus at 1, 2.5, 5 and 10 mM Ca2+, se cretion was 2.3-, 3.8-, 5- and 4-fold greater than in control glands. Bay K 8644 enhanced the Kf-induced response 3- and 9-fold at [Ca2+](o) of 0.25 or 0.5 mM, respectively; at higher [Ca2+](o) the potentiation was similar to that of PCA50941. The results support the idea that Ba y K 8644 and the novel dihydropyridine derivative PCA50941 potentiates the K+-evoked release of catecholamines from bovine chromaffin cells by enhancing Ca2+ entry through L-type Ca2+ channels.