Selective inhibition of cholinergic receptor-mediated 45Ca++ uptake and catecholamine secretion from adrenal chromaffin cells by taxol and vinblastine.
We have characterized the actions of taxol, a novel drug promoting microtubule formation, on 45Ca++ uptake and catecholamine release by isolated and cultured bovine adrenal chromaffin cells. The effects of taxol are compared with corresponding actions of vinblastine. We also have measured the effects of microtubule-active drugs on the dynamic pattern of release by means of column perifusion of isolated chromaffin cells. Taxol inhibits acetylcholine-stimulated catecholamine secretion (IC50: approximately 1 microM) and 45Ca++ uptake. The inhibitory effects of both taxol and vinblastine on secretion are rapid in onset (approximately 1 min) and reversible. Taxol and vinblastine (5 microM) exert little or no inhibitory effect on catecholamine secretion induced by 1) the nonreceptor mediated secretagogues K+, Ba++ or veratridine or by 2) the receptor-mediated secretagogues histamine or bradykinin. Similarly, taxol and vinblastine had no effect on K+-induced 45Ca++ uptake into chromaffin cells. The inhibitory effects of taxol and vinblastine during a secretory challenge are specific for cholinergic receptor-mediated 45Ca++ uptake and catecholamine release and prevent receptor-mediated membrane depolarization. These results do not support a role for microtubules either in the exocytosis event or in granule transport during an initial secretory challenge. The results would be consistent with either an interaction of microtubule protein with the acetylcholine receptor or a direct action of the drugs on the acetylcholine receptor.
D000109:Acetylcholine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D002838:Chromaffin System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008870:Microtubules / Q000502:physiology; D017239:Paclitaxel; D011188:Potassium / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects*; D014747:Vinblastine / Q000494:pharmacology*
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D002132:Calcium Radioisotopes; D002395:Catecholamines; D011950:Receptors, Cholinergic; D014747:Vinblastine; D000109:Acetylcholine; D017239:Paclitaxel; D011188:Potassium; D002118:Calcium