Early to late sparing of radiation damage to the parotid gland by adrenergic and muscarinic receptor agonists

Damage to salivary glands after radiotherapeutic treatment of head and neck tumours can severely impair the quality of life of the patients. In the cu rrent study we have investigated the early-to-late pathogenesis of the paro tid gland after radiation. Also the ability to ameliorate the damage using pretreatment with adrenergic or muscarinic receptor agonists is studied. Ra ts were locally irradiated with or without i.p. pretreatment with phenyleph rine (alpha -adrenoceptor agonist, 5 mg kg(-1)), isoproterenol (beta -adren oceptor agonist, 5 mg kg-1), pilocarpine (4 mg kg(-1)), methacholine (3.75 mg kg(-1)) (muscarinic receptor agonists) or methacholine plus phenylephrin e. Parotid salivary flow rate, amylase secretion, the number of cells and g land histology were monitored sequentially up to 240 days postirradiation. The effects were described in 4 distinct phases. The first phase (0-10 days ) was characterised by a rapid decline in flow rate without changes in amyl ase secretion or acinar call number. The second phase (10-60 days) consists of a decrease in amylase secretion and is paralleled by acinar cell loss, Flow rate, amylase secretion and acinar cell numbers do not change in the t hird phase (60-120 days). The fourth phase (120-240 days) is determined by a further deterioration of gland function but an increase in acinar cell nu mber, albeit with poor tissue morphology. All drug pretreatments used could reduce radiation effects in phase I and H. The protective effects were los t during phase IV, with the exception of methacholine plus phenylephrine pr etreatment. The latter combination of drugs ameliorated radiation-damage th roughout the entire follow-up time. The data show that combined pre-irradia tion stimulation of muscarinic acetylcholine receptors with methacholine pl us alpha -adrenoceptors with phenylephrine can reduce both early and late d amage, possibly involving the PLC/PIP2 second messenger pathways. This open s perspectives for the development of clinical applicable methods for long- term sparing of parotid glands subjected to radiotherapy of head and neck c ancer patients. (C) 2001 Cancer Research Campaign http://www.bjcancer.com.