Inhibition of nicotinic acetylcholine receptors and calcium channels by clozapine in bovine adrenal chromaffin cells.
The effects of clozapine on the activities of nicotinic acetylcholine receptors (nAChRs) and voltage-sensitive calcium channels (VSCCs) were investigated and compared with those of chlorpromazine (CPZ) in bovine adrenal chromaffin cells. [(3)H]Norepinephrine ([(3)H]NE) secretion induced by activation of nAChRs was inhibited by clozapine and CPZ with half-maximal inhibitory concentrations (IC(50)) of 10.4 +/- 1.1 and 3.9 +/- 0.2 microM, respectively. Both cytosolic calcium increase and inward current in the absence of extracellular calcium induced by nicotinic stimulation were also inhibited by clozapine and CPZ, but the greater inhibition was achieved by CPZ. In addition, [(3)H]nicotine binding to chromaffin cells was inhibited by clozapine and CPZ with IC(50) values of approximately 19 and 2 microM, respectively. On the other hand, [(3)H]NE secretion induced by high K(+) was inhibited by clozapine and CPZ with similar IC(50) values of 15.5 +/- 3.8 and 17.1 +/- 3.9 microM, respectively. Our results suggest that clozapine, as well as CPZ, inhibits nAChRs and VSCCs, thereby causing inhibition of catecholamine secretion, and that clozapine is much less potent than CPZ in inhibiting nAChRs.
Park
T
T
Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, 31, Pohang 790-784, San, South Korea.
Bae
S
S
Choi
S
S
Kang
B
B
Kim
K
K
D000311:Adrenal Glands / Q000166:cytology / Q000187:drug effects; D000475:Alkenes / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism* / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002746:Chlorpromazine / Q000494:pharmacology; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D003024:Clozapine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D004594:Electrophysiology; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D009538:Nicotine / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D014316:Tritium
C420384:1-(3',4'-dimethoxyphenyl)propene; D000475:Alkenes; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002395:Catecholamines; D018492:Dopamine Antagonists; D018756:GABA Antagonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D014316:Tritium; D009538:Nicotine; D003024:Clozapine; D011188:Potassium; D002118:Calcium; D002746:Chlorpromazine; D009638:Norepinephrine