Dual effects of nobiletin, a citrus polymethoxy flavone, on catecholamine secretion in cultured bovine adrenal medullary cells

Nobiletin, a compound of polymethoxy flavones found in citrus fruits, possesses a wide range of pharmacological activities. Here we report the effects of nobiletin on catecholamine secretion in cultured bovine adrenal medullary cells. Nobiletin (1.0-100 mu M) concentration-dependently stimulated catecholamine secretion and Ca-45(2+) influx. Its stimulatory effect of nobiletin on catecholamine secretion was abolished by deprivation of extracellular Ca2+ and partially inhibited by specific inhibitors of voltage-dependent Ca2+ channels and Na+/Ca2+ exchangers. On the other hand, nobiletin suppressed catecholamine secretion and Na-22(+) and Ca-45(2+) influx induced by acetylcholine, an agonist of nicotinic acetylcholine receptors, in a concentration-dependent manner. It also inhibited catecholamine secretion, Na-22(+) influx and/or Ca-45(2+) influx induced by veratridine, an activator of voltage-dependent Na+ channels, and 56 mM K+, an activator of voltage-dependent Ca2+ channels. In Xenopus oocytes expressing alpha 3 beta 4 neuronal acetylcholine receptors, nobiletin directly inhibited the current evoked by acetylcholine in a concentration-dependent manner similar to that observed in catecholamine secretion. The present findings suggest that nobiletin, by itself, stimulates catecholamine secretion via activation of voltage-dependent Ca2+ channels or Na+/Ca2+ exchangers, whereas it inhibits catecholamine secretion induced by acetylcholine through the suppression of Na+ influx and Ca2+ influx in cultured bovine adrenal medullary cells.