Interactions between Ca2+, PCA50941 and Bay K 8644 in bovine chromaffin cells

We describe here the effects of PCA50941 (a novel 1,4-dihydropyridine derivative) comparatively with Bay K 8644 on various parameters in bovine adrenal chromaffin cells. The binding of [3H](+)-isradipine to bovine adrenal medulla plasma membranes was inhibited similarly by PCA50941 and Bay K 8644 at various [Ca2+]o suggesting a common binding site for both compounds on the dihydropyridine receptor. In voltage-clamped chromaffin cells PCA50941 (1 microM) and Bay K 8644 (1 microM) shifted the I-V relationship of whole-cell Ca2+ currents by about 5-10 mV towards more hyperpolarizing potentials. At -20 mV, PCA50941 enhanced ICa by 195 +/- 16% and Bay K 8644 by 288 +/- 51%. Stimulation of fura 2-loaded chromaffin cell suspensions with 17.7 K+/0.5 Ca2+ increased 3-fold the basal [Ca2+]i. PCA50941 increased further the K(+)-evoked peak to 655 nM, and Bay K 8644 to 1129 nM. In the presence of 5 mM Ca2+, PCA50941 or Bay K 8644 increased the [Ca2+] peaks to 427 and 350 nM, respectively. PCA50941 potentiated the release of catecholamines from perfused bovine adrenal glands evoked by 30 s pulses of 17.7 mM K+ in a manner dependent on the [Ca2+]o. Thus at 1, 2.5, 5 and 10 mM Ca2+, secretion was 2.3-, 3.8-, 5- and 4-fold greater than in control glands. Bay K 8644 enhanced the K(+)-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.(ABSTRACT TRUNCATED AT 250 WORDS)