Effect of chlorpromazine (CPZ) on cholecystokinin-induced gallbladder contraction: the role of calcium.
Smooth muscle contraction is initiated by a rise in intracellular calcium, which binds to calmodulin resulting in myosin phosphorylation. CPZ impairs smooth muscle contraction by either interfering with calcium influx at low concentrations (less than 1.25 x 10(-5) M) or inactivating calcium-calmodulin at higher levels. This chlorpromazine effect was used to determine if gallbladder agonists act through different intracellular mechanisms. Guinea pig gallbladders were mounted in an organ bath and auxotonic contractions induced by bethanechol, KCl and the octapeptide of cholecystokinin (CCK). Bethanechol and KCl-induced contractions were profoundly inhibited by 1.25 x 10(-5) M CPZ throughout the dose-response curve. In contrast, CPZ did not affect CCK-mediated contractions at CCK concentrations less than 5.7 x 10(-8) M. At maximal CCK doses (3 x 10(-7) M), CPZ had only a modest inhibitory effect of 20%, compared with tension losses of 62 and 80% for bethanechol and KCl, respectively. This inhibition with high-dose CCK was offset by increasing extracellular calcium in the organ bath. The resistance of CCK to CPZ inhibition at low doses within the physiologic range implies that CCK acts independently of extracellular Ca2+ unlike the other agonists. Higher CPZ concentrations, greater than or equal to 1.25 x 10(-4) M, markedly suppressed CCK throughout the dose-response curve. Cholecystokinin may act via myosin phosphorylation, but unlike other agonists any rise in cytoplasmic calcium likely originates from an intracellular site.
D000818:Animals; D018723:Bethanechol; D001626:Bethanechol Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002746:Chlorpromazine / Q000494:pharmacology*; D002766:Cholecystokinin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D005704:Gallbladder / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology
D001626:Bethanechol Compounds; D018723:Bethanechol; D011189:Potassium Chloride; D002766:Cholecystokinin; D002118:Calcium; D002746:Chlorpromazine