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)
Montiel
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Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
de la Fuente
M T
MT
Vinet
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del Valle
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Gandía
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Artalejo
A R
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García
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AG
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D016257:Fura-2 / Q000378:metabolism; D066298:In Vitro Techniques; D017275:Isradipine / Q000493:pharmacokinetics; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*
D002120:Calcium Channel Agonists; D015220:Calcium Channels; D002395:Catecholamines; D004095:Dihydropyridines; D013844:Thiazoles; C084781:PCA 50941; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011188:Potassium; D002118:Calcium; D016257:Fura-2; D017275:Isradipine