Abstract

Cevimeline and pilocarpine are clinically used muscarinic agonists to rescue dry mouth. In this study, we explored fluid secretion from mouse submandibular glands to determine the mechanism of cevimeline, pilocarpine and an experimentally used agent carbachol. Cevimeline evoked almost the same amount of secretion from 30 μM to 1 mM. Pilocarpine also induced secretion at a concentration as low as 1 μM and was the most powerful secretagogue at 10 μM. Secretion was induced by carbachol at 0.1 μM, with maximum secretion at 1.0 μM. Cevimeline induced monophasic secretion at all concentrations tested, whereas higher concentrations of pilocarpine and carbachol induced secretion with variable kinetics, i.e., an initial transient high flow rate, followed by decreased secretion after 2-3 minutes. In the presence of an epithelial Na⁺ channel blocker amiloride, neither carbachol nor pilocarpine affected the Na⁺ level of secreted saliva; however, it significantly increased the Na⁺ content of cevimeline-induced saliva. The intracellular Ca²⁺ response of acinar cells was almost identical among all three agents, although recovery after drug removal was slower for cevimeline and pilocarpine. A profound decrease in intracellular pH was observed during pilocarpine and carbachol treatment, whereas intracellular acidification induced by cevimeline was only seen in the presence of a Na⁺/H⁺-exchange inhibitor. When external HCO₃^- was removed, cevimeline-induced saliva significantly decreased. These findings suggest that cevimeline specifically activates Na⁺/H⁺ exchange and may promote Na⁺ reabsorption by stabilizing epithelial sodium channel activity.