Temporal reduction in size of salivary acinus in rats induced by theophylline

Toxicol Pathol. 2005;33(2):218-24. doi: 10.1080/01926230590896118.


Repeated administration of theophylline, a phosphodiesterase inhibitor, induces the enlargement of the salivary glands in rats. Time-course changes after a single administration of theophylline were examined in the salivary glands, including phosphodiesterase enzyme activity, and the expression of aquaporin 5 (AQP5), a water channel. We also examined the contribution of beta-adrenergic receptors to theophylline-induced salivary changes. Male F344 rats were given 50 mg/kg of theophylline intraperitoneally either alone or concurrently with a 10 mg/kg subcutaneous injection of propranolol. After treatment with theophylline alone, the weight and histology of the submaxillary and parotid glands were examined. Phosphodiesterase activity and AQP5 were detected by enzyme- and immuno-histochemistry, respectively. At 4 hours, 8 hours, or both, organ weights were decreased with depletion of secretory vesicles in the acinar cells. In the submaxillary glands, reduced activity of phosphodiesterase and increased expression of AQP5 in the intercalated ducts were observed at 4 hours. When co-administered, propranolol partially abolished theophylline-induced glandular reduction. These results suggest that the theophylline-induced transient reduction in size of the salivary glands is attributable not only to phosphodiesterase inhibition but also to beta-adrenergic receptor activation and that the intercalated ducts in submaxillary glands play a role in the production of saliva.

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Aquaporin 5
  • Aquaporins / metabolism
  • Drug Therapy, Combination
  • Immunohistochemistry
  • Injections, Intraperitoneal
  • Male
  • Membrane Proteins / metabolism
  • Organ Size / drug effects
  • Parotid Gland / drug effects*
  • Parotid Gland / enzymology
  • Parotid Gland / pathology
  • Phosphodiesterase Inhibitors / toxicity*
  • Phosphoric Diester Hydrolases / metabolism
  • Propranolol / pharmacology
  • Rats
  • Rats, Inbred F344
  • Salivary Ducts / drug effects
  • Salivary Ducts / enzymology
  • Salivary Ducts / pathology
  • Submandibular Gland / drug effects*
  • Submandibular Gland / enzymology
  • Submandibular Gland / pathology
  • Theophylline / toxicity*
  • Time Factors


  • Adrenergic beta-Antagonists
  • Aqp5 protein, rat
  • Aquaporin 5
  • Aquaporins
  • Membrane Proteins
  • Phosphodiesterase Inhibitors
  • Propranolol
  • Theophylline
  • Phosphoric Diester Hydrolases