Many instances of salivary dysfunction in humans can be traced to the use of medications that have hyposalivary side-effects. In this study, atropine, a cholinergic antagonist, was administered chronically to rats by use of osmotic mini-pumps. Steady-state blood levels, similar to levels obtained in human multiple oral dosing, were thus maintained. Atropine delivered in this manner for 24 days was found to decrease protein concentration of parotid saliva (p<0.05) elicited by pilocarpine, and to increase smooth-surface caries scores (p<0.05) in rats fed a cariogenic diet.
Parotid saliva collected via ductal cannulation from rats subjected to chronic atropine administration (and stimulated to secrete by pilocarpine) exhibited increased levels of two basic proline-rich proteins (Peak A and SP-3), as evaluated by SDS-PAGE, compared with those observed in saliva from controls.
Cannulation of sublingual glands in animals receiving high doses of atropine produced no measurable secretion upon pilocarpine stimulation. Carbachol stimulation of dispersed cell aggregates of sublingual glands from sham-operated and high-dose atropine groups indicated that the glands responded similarly once the antagonist was washed from the system, implying that the lack of secretion in vivo was caused by antagonism of the cholinergic receptor by atropine.
Our observations suggest that this model system can be exploited for determination of the effects of chronic administration of hyposalivary drugs on salivary composition and caries rates.
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References
1.
Aaltonen, L.; Kanto, J.; Iisalo, E.; and Pihlajamaki, K. (1984): Comparison of Radioreceptor Assay and Radioimmunoassay for Atropine: Pharmacokinetics Application, Eur J Clin Pharmacol26:613-617.
2.
Abe, K. and Dawes, C. (1978): The Effects of Electrical and Pharmacological Stimulation on the Types of Proteins Secreted by Rat Parotid and Submandibular Glands, Arch Oral Biol23:367-372.
3.
Baum, B.J. (1987): Neurotransmitter Control of Secretion, J Dent Res66 :628-632.
4.
Bertram, U. (1976): Xerostomia: Clinical Aspects, Pathology and Pathogenesis , Copenhagen: Aarhus Stifts bogtrykkerie , pp. 31-59.
5.
Bertram, U.; Kragh-Sorensen, P.; Rafaelsen, O.; and Larsen, N. (1979): Saliva Secretion Following Long Term Antidepressant Treatment with Nortriptyline Controlled by Plasma Levels, Scand J Dent Res87:58-64.
6.
Bowen, W.H.; Madison, K.M.; and Pearson, S.K. (1988a): Influence of Desalivation in Rats on Incidence of Caries in Intact Cagemates, J Dent Res67:1316-1318.
7.
Bowen, W.H.; Pearson, S.K.; and Young, D.A. (1988b): The Effect of Desalivation on Coronal and Root Surface Caries in Rats, J Dent Res67 :21-23.
8.
Bowen, W.H.; Pearson, S.K.; Young, D.A.; and Thibodeau, E.A. (1985): The Effect of Partial Desalivation on Coronal and Root Surface Caries in the Rat. In: Factors Relating to Demineralisation of the Teeth, S.A. Leach , Ed., Oxford: IRL Press Ltd. , pp. 243-250.
9.
Carrier, O. (1972): Pharmacology of the Peripheral Autonomic Nervous System, Chicago: Year Book Medical Publishers, Inc., pp. 36-37, 50-56.
10.
Clark, B. and Smith, D. (1986): An Introduction to Pharmacokinetics, 2nd ed., London: Blackwell Scientific Publications, pp. 33-54.
11.
Conover, W.J. (1980): Practical Nonparametric Statistics, 2nd ed., New York: Wiley, pp. 229-239.
12.
Dreizen, S. and Brown, L.R. (1976): Xerostomia and Dental Caries. In: Microbial Aspects of Dental Caries, H.M. Stiles, W.J. Loesche, and T.C. O'Brien, Eds. (Sp Supp) Microbiology Abstracts, Washington, DC: Information Retrieval, pp. 263-274.
13.
Fairbanks, G.; Steck, T.L.; and Wallach, D.F.H. (1971): Electrophoretic Analysis of the Major Polypeptides of the Human Erythrocyte Membrane, Biochemistry10:2606-2617.
14.
Fernandez-Sorensen, A. and Carlson, D.M. (1974): Isolation of a "Proline-rich" Protein from Rat Parotid Glands Following Isoproterenol Treatment, Biochem Biophys Res Commun60:249-256.
15.
Handelman, S.L.; Baric, J.M.; Espeland, M.A.; and Berglund, K.L. (1986): Prevalence of Drugs Causing Hyposalivation in an Institutionalized Geriatric Population, Oral Surg Oral Med Oral Pathol62:26-31.
16.
Hedlund, B.; Abens, J.; and Bartfai, T. (1983): Vasoactive Intestinal Peptide and Muscarinic Receptors; Supersensitivity Induced by Long-Term Atropine Treatment, Science220:519-521.
17.
Humphreys-Beher, M.G. and Wells, D.J. (1984): Metachromatic Staining Patterns of Basic Proline-rich Proteins from Rat and Human Saliva in Sodium Dodecyl Sulfate-Polyacrylamide Gels, J Appl Biochem6:353-360.
18.
Johnson, D.A. (1984): Changes in Rat Parotid Salivary Proteins Associated with Liquid Diet-induced Gland Atrophy and Isoproterenol-induced Gland Enlargement , Arch Oral Biol29:215-221.
19.
Johnson, D.A. (1988): Changes in Rat Parotid Saliva Protein Composition Following Chronic Reserpine Treatment and Their Relation to Inanition, Arch Oral Biol33:463-466.
20.
Johnson, D.A. and Cortez, J.E. (1988): Chronic Treatment with Beta Adrenergic Agonists and Antagonists Alters the Composition of Proteins in Rat Parotid Saliva, J Dent Res67:1103-1108.
21.
Keller, P.J.; Robinovitch, M.; Iverson, J.; and Kauffman, D.L. (1975): The Protein Composition of Rat Parotid Saliva and Secretory Granules, Biochim Biophys Acta379:562-570.
22.
Keyes, P.H. (1958): Dental Caries in the Molar Teeth of Rats, I. Distribution of Lesions Induced by High Carbohydrate Low-fat Diets, J Dent Res37 :1077-1087.
23.
Keyes, P.H. (1959): Dental Caries in the Syrian Hamster. VIII. The Induction of Rampant Caries Activity in Albino and Golden Animals, J Dent Res38 :525-533.
24.
Laemmli, U.K. (1970): Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4, Nature227:680-685.
25.
Larson, R.M. (1981): Merits and Modifications of Scoring Rat Dental Caries by Keyes' Method. In: Animal Models in Cariology, J.M. Tanzer, Ed., Washington, DC: IRL Press, pp. 195-203.
26.
Lowry, O.H.; Rosebrough, N.J.; Farr, A.L.; and Randall, R.J. (1951): Protein Measurement with the Folin Phenol Reagent , J Biol Chem193:265-275.
27.
Martinez, J.R.; Bylund, D.B.; and Camden, J. (1982): Characterization of Autonomic Receptors in the Rat Sublingual Gland by Biochemical and Radioligand Assays, Naunyn Schmiedebergs Arch Pharmacol318:313-318.
28.
McBride, R.K. and Siegel, I.A. (1988): The Influence of Plasma Catecholamines on Methotrexate-enhanced Rat Salivary Gland Protein Secretion, Arch Oral Biol33:575-578.
29.
Miller, R.G. (1981): Simultaneous Statistical Inference, 2nd ed., New York: Springer-Verlag, pp. 67-70, 254-255.
30.
Mornstad, H.; Von Knorring, L.; Forsgren, L.; and Holmgren, S. (1986): Long-term Effects of Two Principally Different Antidepressant Drugs on Saliva Secretion and Composition, Scand J Dent Res94:461-470.
31.
Oppenheim, F.G.; Hay, D.I.; and Franzblau, C. (1971): Proline-rich Proteins from Human Parotid Saliva. I. Isolation and Partial Characterization, Biochemistry10:4233-4238.
32.
Quissell, D.O. and Redman, R.S. (1979): Functional Characteristics of Dispersed Rat Submandibular Cells, Proc Natl Acad Sci USA76:2789-2793.
33.
Robinovitch, M.R.; Keller, P.J.; Johnson, D.A.; Iversen, J.M.; and Kauffman, D.L. (1977): Changes in Rat Parotid Salivary Proteins Induced by Chronic Isoproterenol Administration, J Dent Res56:290-303.
34.
Robinovitch, M.R. and Sreebny, L.M. (1969): Separation and Identification of Some of the Protein Components of Rat Parotid Saliva, Arch Oral Biol14 :935-949.
35.
Rundegren, J.; Van Dijken, J.; Mornstad, H.; and Von Knorring, L. (1985): Oral Conditions in Patients Receiving Long-term Treatment with Cyclic Antidepressant Drugs, Swed Dent J9:55-64.
36.
Schneyer, C.A. (1965): Modification of the Action of Pilocarpine by Adrenergic Blocking Agents, Proc Soc Exp Biol Med120:230-232.
37.
Schneyer, C.A. and Hall, H.D. (1966): Autonomic Pathways Involved in a Sympathetic-Like Action of Pilocarpine on Salivary Composition, Proc Soc Exp Biol Med121:96-100.
38.
Schwartz, A. and Shaw, J.H. (1953): Studies on the Effect of Selective Desalivation on the Dental Caries Incidence of Albino Rats, J Dent Res34 :239-247.
39.
Shaw, J.H. and Weisberger, D. (1949): Carious Lesions in Cotton Rat Molars. II. Effect of Removal of Principal Salivary Glands, Proc Soc Exp Biol NY70:103-105.
40.
Snedecor, G.W. and Cochran, W.G. (1980): Statistical Methods, 7th ed., Ames, Iowa: Iowa State University Press, pp. 215-237.
41.
Spiers, R.L. and Hodgson, C. (1976): Control of Amylase Secretion in the Rat Parotid Gland During Feeding, Arch Oral Biol21:539-544.
42.
Suddick, R.P. and Shannon, I.L. (1970): Salivary Na, K., and CI Secretion Rates: Relationship to a Fluid Generation Mechanism, Jpn J Physiol20 :540-549.
43.
Ukai, Y.; Taniguchi, N.; Ishima, T.; and Kimura, K. (1989): Muscarinic Supersensitivity and Subsensitivity Induced by Chronic Treatment with Atropine and Diisopropylfluorophosphate in Rat Submaxillary Glands, Arch Int Pharmacodyn297 :148-157.
44.
Weber, K. and Osborn, M. (1975): Proteins and Sodium Dodecyl Sulfate: Molecular Weight Determination on Polyacrylamide Gels and Related Procedures. In: The Proteins, Vol. 1, H. Neurath and R.L. Hill, Eds., New York: Academic Press, pp. 179-223.
