title: Early radiation effects on muscarinic receptor-induced secretory responsiveness of the parotid gland in the freely moving rat.
abstract: Although the salivary glands have a low rate of cell turnover, they are relatively radiosensitive. To study the possible mechanism behind this inherent radiosensitivity, a rat model was developed in which saliva can be collected after local irradiation of the parotid gland without the use of anesthetics or stressful handling. Saliva secretion was induced by the partial muscarinic receptor agonist pilocarpine (0.03-3 mg/kg) with or without pretreatment with the beta-adrenoceptor antagonist propranolol (2.5 mg/kg), or the full muscarinic receptor agonist methacholine (0.16-16 mg/min), and measured during 5 min per drug dose before and 1, 3, 6 and 10 days after irradiation. The maximal secretory response induced by pilocarpine plus propranolol was increased compared to that with pilocarpine alone but did not reach the level of methacholine-induced secretion, which was about five times higher. One day after irradiation a decrease in maximal pilocarpine-induced secretion was observed (-22%) using the same dose of pilocarpine that induces 50% of the maximal response (ED(50)), in both the absence and presence of propranolol, indicating that the receptor-drug interaction was not affected by the radiation at this time. The secretory response to methacholine 1 day after irradiation, however, was normal. At day 3 after irradiation, the maximal methacholine-induced secretion was also affected, whereas pilocarpine (+/-propranolol)-induced maximal secretion decreased further. At day 6 after irradiation, maximal secretory responses had declined to approximately 50% regardless of the agonist used, whereas ED(50) values were still unaffected. No net acinar cell loss was observed within the first 10 days after irradiation, and this therefore could not account for the loss in function. The results indicate that radiation does not affect cell number or receptor-drug interaction, but rather signal transduction, which eventually leads to the impaired response. We hypothesize that the early radiation effect, within 3 days, may be membrane damage affecting the receptor-G-protein signaltransfer. Later critical damage, however, is probably of a different nature and may be located in the second-messenger signal transduction pathway downstream from the G protein, not necessarily involving cellular membranes.
authors.affiliation: Department of Radiobiology University of Groningen, Groningen, The Netherlands.
authors.forename: R P
authors.initials: RP
authors.lastname: Coppes
authors.forename: A F
authors.initials: AF
authors.lastname: Roffel
authors.forename: L J
authors.initials: LJ
authors.lastname: Zeilstra
authors.forename: A
authors.initials: A
authors.lastname: Vissink
authors.forename: A W
authors.initials: AW
authors.lastname: Konings
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000528:radiation effects; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D010306:Parotid Gland / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D010862:Pilocarpine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000502:physiology*; D012463:Saliva / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D016210:Methacholine Chloride; D011433:Propranolol