Stimulation of salivary secretion in vivo by CFTR potentiators in Cftr(+/+) and Cftr(-/-) mice

Background: Physiologically, salivary secretion is controlled by cholinergic and adrenergic pathways but the role of ionic channels in this process is not yet clearly understood. In cystic fibrosis (CF), most exocrine glands failed to response to beta-adrenergic agonists. Methods: To determine the implication of CFTR in this process, we measured in vivo the salivary secretion of Cftr(+/+) and Cftr(-/-) mice in the presence of 2 water-soluble benzo[c]quinolizinium derivatives;, MPB-07 a potentiator of CFTR Cl- channel and MPB-05 an inactive analogue. We also used genistein and its vehicle ethanol to confirm the implication of CFTR in salivary secretion. Results: We showed that subcutaneous injection of MPB-07 in the mice cheek enhanced in a dose dependent manner the isoprenaline-induced salivary secretion in Cftr(+/+) but not in Cftr(-/-) mice. By contrast, MPB-05 did not activate the salivary secretion in Cftr(+/+) mice. The CFTR activator genistein (50 mu M) significantly potentiated the secretory response of Cftr(+/+) mice whereas its vehicle, ethanol, had no effect. Conclusions: These results show for the first time in vivo pharmacological stimulation of salivary secretion by a water-soluble CFTR potentiator, MPB-07 and by the isoflavone, ethanol-soluble genistein and suggest that this chloride channel plays an important role in salivary gland physiology. (c) 2007 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.