The chronically reserpinized rat as a possible model for cystic fibrosis. VI. Synergistic effects of isoproterenol on Ca++ and protein in the submaxillary gland.

Elevated calcium and protein concentration are a consistent abnormality in submaxillary saliva from patients with cystic fibrosis (CF) and from experimental animal models developed by the chronic administration of either isoproterenol (IPR) or reserpine. The possibility that the effects of the two drugs may be additive was investigated by assessing their combined effects on glandular and salivary C++ and protein in the rat submaxillary gland. Individually, their effects were also assessed in relation to the dose used. Results indicate that: (1) treatment for 7 days with 0.05, 0.50, and 5.0 mg/kg daily dose of reserpine caused, respectively, a 45%, 95%, and 120% increase in glandular Ca++ and a 9.3%, 16.5%, and 37.4% increase in glandular protein; (2) treatment for 7 days with a 5.0 mg/kg daily dose of isoproterenol caused a 138% increase in gland Ca++ and a 12.38% increase in gland protein. Treatment with a 5.0 mg/rat daily dose of this drug caused increases of 166% and 10.3% in gland Ca++ and protein; (3) in experiments involving a combination of the two drugs, isoproterenol was administered in a 5.0 mg/kg daily dose from days 1-7 and reserpine in a 0.5 mg/kg daily dose from days 4-10 of the treatment schedule. This procedure resulted in (a) a 217% increase in gland Ca++ and a 25.7% increase in gland protein; (b) a marked accumulation of a granular, basophilic material in acinar cells and the development of intraductal precipitates; (c) the secretion of turbid saliva with high Ca++ and protein concentrations after a secretory dose of isoproterenol (this type of stimulation also reduced the gland Ca++ (50%) and protein (20%) contents and produced vacuolization in the acinar cells); (d) the secretion of saliva with elevated Ca++ and protein in response to pilocarpine (these elevated concentrations were, however, one-fifth of those obtained after isoproterenol stimulation); (e) the secretion of smaller volume of saliva after both types of stimulation. These findings indicate that both IPR and reserpine have a dose-related and significant effect on submaxillary gland Ca++ and protein and that their individual effects are synergistic. The implications of this synergism for the physiologic state of the submaxillary gland and for the secretory abnormality of cystic fibrosis are discussed.