The ability of chlorpromazine (CPZ) to inhibit muscarinic-cholinergic secretory events was studied in vitro in rat parotid acinar cells. CPZ inhibited carbachol-induced amylase release in a dose-dependent fashion but had no effect on that elicited by isoproterenol. The inhibition of parotid protein synthesis induced by carbachol, but not that induced by A23187, was blocked by CPZ. CPZ exhibited a dose-dependent inhibition of [3H]quinuclidinyl benzilate (QNB) binding to muscarinic receptors, and altered the KD of the receptor for the ligand. These results are consistent with an ability of CPZ to inhibit muscarinic-cholinergic-induced salivary secretion by complex interference with receptor binding. In addition, CPZ may block parotid-muscarinic responses by impeding a post-receptor signaling step which is proximal to Ca2+ mobilization.
Get full access to this article
View all access options for this article.
References
1.
Aub, D.L. and Putney, J.W., Jr. (1985): Properties of Receptor-controlled Inositol Triphosphate Formation in Parotid Acinar Cells, Biochem J225:263-266.
2.
Baum, B.J.; Freiberg, J.M.; Ito, H.; Roth, G.S.; and Fil-Burn, C. (1981): β-Adrenergic Regulation of Protein Phosphorylation and its Relationship to Exocrine Secretion in Dispersed Rat Parotid Gland Acinar Cells, J Biol Chem256:9731-9736.
3.
Bernfeld, P. (1955): Amylases a and β, Methods Enzymol1 :149-158.
4.
Blackmore, P.F.; El-Rafai, M.F.; Dehaye, J.-P.; Strick-Land, W.G.; Hughes, B.P.; and Exton, J.H. (1981): Blockade of Hepatic a-Adrenergic Receptors and Responses by Chlorpromazine and Trifluoperazine, FEBS Lett123:245-248.
5.
Curry, S.H. (1976): Plasma Level Studies in Psychotropic Drug Evaluation , Br J Clin Pharmac3(Suppl): 20-28.
6.
Curry, S.H.; Davis, J.M.; Janowsky, D.S.; and Marshall, J.H.L. (1970): Factors Affecting Chlorpromazine Plasma Levels in Psychiatric Patients, Arch Gen Psychiat22:209-215.
7.
Dartt, D.A.; Guerina, V.J.; Donowitz, M.; Taylor, L.; and Sharp, G.W.G. (1982): Ca2+ and Calmodulin-dependent Protein Phosphorylation in Rat Lacrimal Glands, Biochem J202:799-802.
8.
Dobkin, A.B. and Palko, D. (1960): The Antisialogogue Effect of Phenothiazine Derivatives , Anesthesiology21:260-262.
9.
Gilman, A.G.; Goodman, L.S.; and Gilman, A. (1980): The Pharmacologic Basis of Therapeutics, New York: Macmillan Co., pp. 391-447.
10.
Godfrey, P.P. and Putney, J.W., Jr. (1984): Receptor-mediated Metabolism of the Phosphoinositides and Phosphatidic Acid in Rat Lacrimal Glands, Biochem J218:187-195.
11.
Haigh, E. and Young, J.M. (1980): Persistent Effects of High Concentrations of Chlorpromazine on [3H]-Propylbenzilyl-Choline Mustard Binding to Muscarinic Receptors in Guinea Pig Intestinal Muscle Strips, Arch Int Pharmacodyn247:21-30.
12.
Hollister, L.E.; Curry, S.H.; Derr, J.E.; and Kanter, S.L. (1969): Studies of Delayed Action Medication. V. Plasma Levels and Urinary Excretion of Four Different Dosage Forms of Chlorpromazine , Clin Pharmacol Ther11:49-59.
13.
Hulme, E.C.; Birdsall, N.J.M.; Burgen, A.S.V.; and Mehta, P. (1978): The Binding of Antagonists to Brain Muscarinic Receptors, Molec Pharmacol14:737-750.
14.
Ito, H.; Baum, B.J.; and Roth, G.S. (1981): β-Adrenergic Regulation of Rat Parotid Gland Exocrine Protein Secretion During Aging, Mech Ageing Develop15:177-188.
15.
Ito, H.; Hoopes, M.T.; Baum, B.J.; and Roth, G.S. (1982): K+ Release From Rat Parotid Cells: An α1-Adrenergic Mediated Event, Biochem Pharmacol31:567-573.
16.
Joseph, S.K. (1985): Receptor-stimulated Phosphoinositide Metabolism : A Role for GTP-binding Proteins?, Trends Biochem Sci10:297-298.
17.
Kanagasuntheram, P. and Lim, S.C. (1978): Calcium-dependent Inhibition of Protein Synthesis in Rat Parotid Gland, Biochem J176:23-29.
18.
Kanagasuntheram, P. and Teo, T.S. (1982): Calmodulin Sensitive ATP-dependent Calcium Transport by the Rat Parotid Endoplasmic Reticulum, FEBS Lett141:233-236.
19.
Ku, K.Y. and Butcher, F.R. (1980): Detection of a Calmodulin-sensitive Cyclic Nucleotide Phosphodiesterase in Rat Parotid Gland, Biochim Biophys Acta631:70-78.
20.
Manalan, A.S. and Klee, C.B. (1984): Calmodulin, Adv Cyclic Nucleotides and Prot Phosphor Res18:227-278.
21.
Mauduit, P.; Herman, G.; and Rossignol, B. (1983): Effect of Trifluoperazine on [3H]-labeled Protein Secretion Induced by Pentoxifylline, Cholinergic or Adrenergic Agonists in Rat Lacrimal Gland. A Possible Role of Calmodulin?, FEBS Lett152 :207-210.
22.
Morgan, N.G.; Charest, R.; Blackmore, P.F.; and Exton, J.H. (1984): Potentiation of α1-adrenergic Responses in Rat Liver by a cAMP-dependent Mechanism, Proc Natl Acad Sci USA81:4208-4212.
23.
Putney, J.W., Jr.; Weiss, S.J.; Leslie, B.A.; and Marier, S.H. (1977): Is Calcium the Final Mediator of Exocytosis in the Rat Parotid Gland?, J Pharm Exp Ther203:144-155.
24.
Putney, J.W., Jr. and Van DerWalle, C.M. (1980): The Relationship Between Muscarinic Receptor Binding and Ion Movements in Rat Parotid Cells, J Physiol (Lond)299:521-531.
25.
Richards, G.M. (1974): Modifications of the Diphenylamine Reaction Giving Increased Sensitivity and Simplicity in the Estimation of DNA, Anal Biochem57:369-376.
26.
Salhab, A.S. and Dujovne, C.A. (1979): Chlorpromazine Uptake by Isolated Rat Hepatocytes , Proc Soc Exp Biol Med161 :270-274.
27.
Scatchard, G. (1949): The Attractions of Proteins for Small Molecules and Ions, Ann NY Acad Sci51:660-672.
28.
Schramm, M. and Selinger, Z. (1975): Enzyme Secretion and K+ Release Mediated by Beta and Alpha Adrenergic Receptors in Rat Parotid Slices, Methods Enzymol34:461-466.
29.
Scopp, I.W.; Heyman, R.A.; Goldberg, M.A.; and Croy, D.J. (1965): Dryness of the Mouth with Use of Tranquilizers: Chlorpromazine, J Amer Dent Assoc71:66-69.
30.
Seeman, P.M. (1966): Membrane Stabilization by Drugs: Tranquilizers, Steroids and Anesthetics, Int Rev Neurobiol9:145-221.
31.
Takuma, T.; Kuyatt, B.L.; and Baum, B.J. (1984): α1-Adrenergic Inhibition of Protein Synthesis in Rat Submandibular Cells, Am J Physiol247:G284-G289.
32.
Watkins, D.T. and Cooperstein, S.J. (1983): Role of Calcium and Calmodulin in the Interaction Between Islet Cell Secretion Granules and Plasma Membranes , Endocrinology112:766-768.
33.
Yamamura, H.I.; Manian, A.A.; and Snyder, S.H. (1976): Muscarinic Cholinergic Receptor Binding: Influence of Pimozide and Chlorpromazine Metabolites, Life Sci18:685-692.
34.
Zavoico, G.B.; Halenda, S.P.; Sha'Afi, R.I.; and Fein-Stein, M.B. (1985): Phorbol Myristate Acetate Inhibits Thrombin-stimulated Ca2+ Mobilization and Phosphatidylinositol 4, 5-Bisphosphate Hydrolysis in Human Platelets, Proc Natl Acad Sci USA82:3859-3862.
