Effect of Adrenergic Agents on Salivary Composition 1. D. MANDEL, A. ZENGO, R. KATZ, and S. WOTMAN Division of Preventive Dentistry, School of Dental and Oral Surgery, Columbia University, New York, New York 10032, USA, and Department of Anesthesiology, University of California, Los Angeles, California 90007

Goodman and Gillman's classical textbook of pharmacology,' in dealing with salivary glands, considers the sympathetic system as affecting the submaxillary but not the parotid gland and operating via alpha rather than beta adrenergic stimulation. Surprisingly, this view is not based on direct observations on human subjects, which are limited, but rather on extrapolation from experiments on the cat.2 Quite different results have been noted in the rat and rabbit where direct sympathetic stimulation or introduction of beta adrenergic agents affect the parotid gland to a greater extent than the submaxillary gland.3,4 In the dog, the submaxillary gland is strongly affected by beta (not alpha) adrenergic agents5; the situation in the dog parotid gland is not clear.6 Obviously, differences among species are so great that one cannot readily extrapolate from animals to man. The most comparable species to man seems to be the rat.7 In view of the increasing use of adrenergic drugs in the treatment of a number of diseases and the paucity of direct data on the role of the sympathetic system in human salivary secretion, there is need for systematic examination of the effects of adrenergic drugs on human salivary secretion and composition. This report is concerned with the effect of intravenously administered isoproterenol as compared to effects observed with administration of epinephrine, norepinephrine, and phenylephrine. The agonists are used alone and after alpha or beta adrenergic blockade, or both. In addition to the human studies, experiments were conducted with rats to compare the effects on saliva of high doses of isoproThis study was supported by Grants No. DE-01554 and GM-09069 from the National Institutes of Health, Bethesda, Md.

terenol, epinephrine, and terbutaline, alone and after injection of an alpha blocking agent.

Materials and Methods HUMAN STUDIES.-In the initial experi-

ments with isoproterenol,8,9 five volunteers, ranging in age from 24 to 53 years and weighing 62 to 76 kg, were studied in an operating room area. They had been previously familiarized with the environment and the recording systems involved in order to diminish psychic factors. Studies were usually carried out at 5 PM, four hours postprandial for the volunteers. With the subject in a sitting position, ten-minute control samples of parotid and submaxillary saliva were collected without exogenous stimulation. Parotid saliva was collected from one gland with a modified Lashley cup and submaxillary saliva from both glands with a basic plastic collector modified for each subject with rubber base impression material. A continuous intravenous infusion of 5% dextrose in water was then started. The rate of infusion was 1 to 2 ml/kg/hr. The following drugs were injected into a side port of the infusion tubing: physiologic saline, 0.5 jug/ kg of isoproterenol, and 70 pg/kg of phentolamine (alpha blocker) or 50 jig/kg of H56/28 (beta blocker). With two of the subjects, individual experiments were repeated on several occasions. The volunteers were unaware of which drug or combination of drugs they were to receive on any given occasion. They also aided in the collection of their own samples so as to occupy their time and diminish psychic influences. They had previously participated in other salivary studies and were familiar with the effects of parasympathetic and sympathetic stimulating drugs.

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J Dent Res Special Issue B

MANDEL ET AL

method),"1 and calcium (atomic absorption spectrophotometry). In several situations, chloride, phosphorus, sodium, potassium, urea, hexose, and fucose were also quantitated using standard procedures.8

With control samples and those elicited by the various drugs, 2-ml portions were collected for determination of flow rate and subsequent chemical analysis. Samples were collected for at least ten minutes following each maneuver in order to ensure an adequate volume for flow rate measurement and chemical analysis. Heart rate and lead 2 of the electrocardiograph were continuously monitored on an oscilloscope and recorded on a polygraph. Arterial blood pressure was measured by auscultation. Similar procedures were used for epinephrine (0.5 pg/kg), norepinephrine (0.5 jug/kg), and phenylephrine (0.5 pg/kg). In several experiments, the control samples were unstimulated but were collected with a sour lemon candy as a gustatory stimulus. In these experiments, an identical gustatory stimulus was used while the experimental sample was collected; these latter samples represented a reflex sample modified by the various adrenergic agents. All samples were analyzed for amylase (Caraway method),10 protein (Biuret

ANIMAL STUDIES.-Male Sprague-Dawley rats, weighing approximately 225 to 250 gm each, were separated into groups of five or more animals and treated by subcutaneous injections (except where otherwise noted) with the drugs as specified: Series 1.-Group 1, control rats, 0.25 ml isotonic saline; group 2, 1 mg/kg epinephrine; group 3, 10 mg/kg phenoxybenzamine as an alpha blocking agent 45 minutes before the injection of 1 mg/kg epinephrine; group 4, .1 mg/kg isoproterenol; group 5, 10 mg/kg phenoxybenzamine as an alpha blocking agent 45 minutes before injection of I mg/kg isoproterenol. Series 2-In this series, groups of five rats were treated as those in series 1, except that 1 mg/kg terbutaline sulfate was substituted for epinephrine in groups 2 and 3 and an

PAROTID units/ml A M y L A

S E

T

0 T A L p R

Soline Isoproterenol

2000

0

4000

SUBMAXILLARY

6000

8000

10,0100

units/ml

0

200

Saline Isoproterenol

159 335

H 56/28 Isoproterenol

H 56/28 Isoproterenol

IB4

Phentolamine 12471 Isoproterenol 10,093

Phentolamine Isoproterenol

I

3796

mg %

1

400 1

1

800

1200

1600

1

1

2000

mg %

Soline

H 56/28

H 56/28 Isoproterenol

0

Isoproterenol Phentolamine

N

Isoproterenol

Isoproterenol

17

600

800

|

11

I

I

0

200

400

600

i

Saline Isoproterenol

T E

400

isoproterenol

407

489

FIG. 1. Salivary effects of isoproterenol and their modification by alpha and beta adrenergic blockade. Mean responses are reported and are the values obtaining following the injection of the agent listed: saline, H56/28 (50 ,ug/kg), phentolamine (70 ,g/kg), isoproterenol (0.5 ug/kg). Isoproterenol significantly (p