Long-lasting salivation induced by a novel muscarinic receptor agonist SNI-2011 in rats and dogs
Introduction
Xerostomia is a clinically important symptom experienced by many patients with Sjögren's syndrome or as a side effect of head/neck irradiation. The patients have extremely low rates of saliva flow from salivary glands and so experience difficulties in eating, speaking and swallowing, and in tolerating dentures (Sreebny and Valdini, 1987; Mandel, 1987; Peters, 1989). They frequently suffer from oral and pharyngeal candidiasis and severe tooth decay (Peters, 1989). Several clinical investigations have shown that pilocarpine has promise as a salivary stimulant in normal volunteers (Mandel et al., 1968), patients with xerostomia secondary to radiation therapy (Greenspan and Daniels, 1987; Schuller et al., 1989), and patients with salivary gland dysfunction and/or Sjögren's syndrome (Fox et al., 1986). However, pilocarpine has a short duration of action and at higher doses induces numerous unpleasant side effects, including excessive sweating, nausea, vomiting, diarrhea and arrhythmia (Weaver et al., 1992). These side effects make it difficult to use pilocarpine in the treatment of xerostomia because it must be repeatedly administered at short time intervals to optimize the salivary response and to minimize adverse effects.
A novel muscarinic receptor agonist SNI-2011, (±)-cis-2-methylspilo [1,3-oxathiolane-5,3′-qunuclidine] hydrochloride, hemihydrate (Fig. 1), is a rigid analogue of acetylcholine. It has been reported that SNI-2011 elicits saliva secretion from the salivary glands of rats (Iwabuchi and Masuhara, 1994). This compound could be useful in the treatment of xerostomia in patients suffering from the side effects of head/neck irradiation therapy or in association with Sjögren's syndrome. Therefore, the aim of the present study was to characterize the sialogogic effect of SNI-2011 in comparison with that of pilocarpine hydrochloride.
Section snippets
Drugs and reagents
SNI-2011, (±)-cis-2-methylspilo [1,3-oxathiolane-5,3′-quinuclidine] hydrochloride, hemihydrate (Snow Brand Milk Products, Tokyo), and pilocarpine hydrochloride (Wako Pure Chemical, Osaka) were dissolved in saline. Deuterated (d4-)SNI-2011 (Snow Brand Milk Products, Tokyo) was used as an internal standard for SNI-2011 for gas chromatography–mass spectrometry (GC-MS) analysis. Clonidine hydrochloride (Wako Pure Chemical, Osaka) was used as an internal standard for pilocarpine for high performance
Results
In rats, hypertension was observed during the first 10 min after the i.d. administration of 2.0 mg/kg pilocarpine, but not after 60 mg/kg SNI-2011 (Fig. 2). Diarrhea was also observed in the rats receiving 2.0 mg/kg pilocarpine. The administration of pilocarpine (0.66–2.0 mg/kg i.d.) induced marked saliva secretion, but salivation lasted only for a short time. In contrast, SNI-2011 (20–60 mg/kg i.d.) resulted in a dose-dependent prolongation of the period of salivation rather than an elevation
Discussion
Saliva secretion is mainly mediated by the muscarinic receptors in the salivary gland (Laniyonu et al., 1990; Dai et al., 1991; Iwabuchi and Masuhara, 1992). It has been reported that the sialogogic effects of SNI-2011 and pilocarpine are caused by direct stimulation of muscarine receptors in salivary glands (Iwabuchi and Masuhara, 1994). Oral or intravenous administration of pilocarpine has been used frequently to evoke the secretion of saliva in humans (Dawes, 1966; Mandel and Katz, 1971;
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