The Journal of Pathology

Vol. 124 No. 4

THE EFFECTS O F LONG-TERM PROPRANOLOL O N T H E SALIVARY GLANDS AND INTESTINAL SEROSA O F THE MOUSE

BARBARA SMITH AND MURIEL BUTLER Department of Pathology, St Bartholomew’s Hospital, London EClA 7BE

PLATES CXIII AND CXIV

THE adrenergic blocking agent practolol (BP) has recently been withdrawn from use because of unacceptable side-effects. Among these side-effects were ocular damage and sclerosing peritonitis (Brown et al., 1974; Rahi et al., 1976).

We have been studying the long-term effects of another adrenergic blocker, propranolol hydrochloride injection (BP), for a different purpose, but on routine examination of the organs we found changes in the salivary glands and the intestine, which we report here.

METHODS Thirty-five Porton mice, initially weighing about 25 g were given propranolol hydrochloride

added to their drinking water. The dose was 5.0 mgm/litre and they drank approximately 25 ml/week. They were killed, together with 15 litter-mate controls, after varying periods. Ten animals were killed between 2 and 6 mth, 15 between 6 mth and 1 year and ten between 1 year and 18 mth after onset of treatment.

Histology was done on most available organs including the small and large intestine and the submandibular, sublingual and in some cases the parotid salivary gland. In addition to haematoxylin and eosin, the alcian blue/periodic acid-Schiff (AB/PAS) stain was done on the salivary glands. This stains neutral polysaccharides red and acid mucopolysaccharides blue.

RESULTS The histology of the salivary glands in man and the mouse is not identical,

but the type of secretion produced is histochemically similar. The sublingual gland contains an acidic much which stains blue with AB/PAS and appears relatively unaffected by adrenergic drugs in the mouse. The parotid gland produces a neutral seromucinous secretion staining red with AB/PAS and the

Received 5 Sept. 1911; accepted 27 Sept. 1977. J. PATH.-VOL. 124 (1978) 185 0

186 BARBARA S M P H AND MURIEL BUTLER

submandibular gland produces a mixture of the two. In man, the lacrimal gland produces a neutral secretion with a very small amount of acidic mucin.

The first change seen histologically after only 2 months’ treatment was loss of staining of the neutral mucopolysaccharide in the submandibular and, where taken, the parotid gland. There was also some apparent decrease of epithelial height, making the gland lumina appear larger (fig. 2). Between 6 and 18 mth, these changes became more pronounced and one animal showed some necrosis of epithelial cells. The most striking feature seen in 16 out of 25 animals was infiltration of the gland by lymphocytes. In less severely affected animals, the lymphocytes were seen only around the ducts, but later they infiltrated the gland parenchyma destroying the epithelial cells (fig. 3).

Changes in the serosa of the intestinal mucosa were seen in six animals, The earliest change appeared to be in the serosal cells themselves; the nuclei became plump (fig. 4) and increased in numbers. A few macrophages became adherent and in two animals there were granulomas on the serosal surface of the colon and duodenum (fig. 5).

DISCUSSION It has been known for some time that adrenergic stimulation of the salivary

glands produces hypertrophy and hyperplasia (Selye et al., 1961). These effects occur quickly, being apparent within a week of starting treatment. Over a similar period of time Fukinda (1968) reported a decrease in weight of the rat submandibular gland after administration of propranolol. Long-term effects in animals have not been recorded.

The main findings consisted of a reduction in stainable seromucin in the salivary gland which probably represents a reduction in secretion. If the thicker acid muck remains normal, the saliva would become more viscid. After longer periods of administration there was a lymphocytic infiltration with gland destruction.

The lacrimal glands were not examined in this study but they produce a similar secretion to the submandibular glands with lysozyme instead of amylase. The lacrimal and salivary glands are also subject to similar pathology such as Mickulicz disease, primary biliary cirrhosis and Sjogren’s disease. Rahi et al. (1976) have reported post-mortem evidence of lymphocytic infiltration of the lacrimal gland in a patient who had been given practolol.

B blockers suppress secretion and in this study this eventually resulted in some irreversible damage.

The changes in the intestine were seen in six animals and were only severe in two. The small granulomata are similar to the changes seen in sclerosing peritonitis but in that condition they are, of course, accompanied by gross fibrosis not seen in our mice. This study would suggest that if such abdominal complications occur in propranolol therapy, the drug would have to be taken for a very long time before significant pathology was seen and even then it might affect only a small proportion of patients taking it.

Salivary gland secretion is influenced by adrenergic drugs.

SMITH AND BUTLER

PROPRANOLOL

PLATE CXlII

FIG. 1 .-Normal mouse submandibular salivary gland. The epithelial cells contain neutral sero- much and in between the acini are collections of acidic much appearing darker. AB/PAS. x 120.

FIG. 2.--A submandibular salivary gland from a mouse treated for 6 mth with propranolol. The epithelium has reduced in height giving a larger lumen. The neutral serornucin is reduced and concentrated at the edge. The acid mucin is unaffected. AB/PAS. x 120.

SMITH AND BUTLER

PROPRANOLOL

PLATE CXIV

FIG. 3.-A parotid salivary gland from a mouse There is

FIG. 4.-The intestinal wall from a mouse treated treated for 6 mth with propranolol. for 6 mth with propranolol. The serosal nuclei lymphocytic infiltration of the gland with are plump and perpendicular to the muscle destruction of the parenchyma. Haematoxylin rather than flattened. HE. x 240. and eosin HE. x 120.

FIG. 5.-The colonic wall from a mouse treated for 6 mth with propranolol. There is a small granu- loma on the serosal surface. HE. x 240.

PROPRANOLOL 187

S W Y Long-term propranolol produces damage to salivary glands in mice and

occasional serosal granulomata.

REFERENCES BROWN, P., BADDELY, H., READ, A. E., DAVIES, J. D., AND MCGARRY, J. 1974. Sclerosing

peritonitis, an unusual reaction to a adrenergic blocking drug (practolol). Lancet, 2, 1477.

FUKINDA, M. 1968. The influence of isoprenaline and propranolol on the submaxillary gland of the rat. Jap. J. Pharmacol., 18, 185.

practolol-induced ocular toxicity. Br. J. Ophthalmol., 60, 312.

salivary glands induced by chronic treatment with isoproterenol. Growth, 2§, 243.

RAW, A. H. S., CHAPMAN, c. M., GARNER, A., AND WRIGHT, P. 1976. Pathology of

SELYE, H., CANTIN, M., AND VEILLEUX, R. 1961. Abnormal growth and sclerosis of the