Chlorpromazine-induced inhibition of catecholamine secretion by a differential blockade of nicotinic receptors and L-type Ca2+ channels in rat pheochromocytoma cells

Abstract

We investigated the effect of chlorpromazine (CPZ), a phenothiazine neuroleptic, on catecholamine secretion in rat pheochromocytoma (PC12) cells. CPZ inhibited [H-3]norepinephrine ([H-3]NE) secretion induced by 1,1 dimethyl-4-phenylpiperazinium iodide (DMPP), an agonist of nicotinic acetylcholine receptors (nAChRs) with an IC50 value of 1.0 +/- 0.2 mu M. The DMPP-induced rise in cytosolic free Ca2+ concentration [Ca2+], was inhibited by CPZ with an IC50 of 1.9 +/- 0.1 mu M. The DMPP induced increase in cytosolic free Nat concentration [Na+], was also inhibited by CPZ with a similar potency. Furthermore, the binding of [H-3]nicotine to PC12 cells was inhibited by CPZ with an IC50 value of 2.7 +/- 0.6 mu M, suggesting that the nAChRs themselves are inhibited by CPZ. In addition, both 70 mM K+-induced [H-3]NE secretion and [Ca2+](i) increase were inhibited by CPZ with IC50 of 7.9 +/- 1.1 and 6.2 +/- 0.3 mu M, respectively. Experiments with Ca2+ channel antagonists suggest that L-type Ca2+ channels are mainly responsible for the inhibition. We conclude that CPZ inhibits catecholamine secretion by blocking nAChRs and L-type Ca2+ channels, with the former being more sensitive to CPZ. (C) 1999 Elsevier Science Inc.