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. 