Synergistic effects of cAMP- and calcium-mediated amylase secretion in isolated pancreatic acini from cystic fibrosis mice

We evaluated pancreatic enzyme secretory response to secretagogues (cAMP- a nd Ca2+-mediating) involved in exocytosis and in chloride channel activatio n in an exon 10 knockout cystic fibrosis (CF) mouse model. Experiments were performed in isolated pancreatic acini from liquid-fed Cftr(-/-) mice (5 s imilar to 6 wk of age) and age-matched Cftr(+/+) controls fed a solid or li quid diet. BrcAMP and forskolin alone induced higher amylase secretion (% i nitial amylase content) in the Cftr(+/+) acini than carbachol (p < 0.05). C arbachol and BrcAMP or BrcAMP and forskolin, given in combination, produced additive effects on enzyme secretion in the Cftr(+/+) acini. Ca2+- and cAM P-mediated amylase secretion in isolated pancreatic acini from the Cftr(-/- ) mice Was no different to that observed in the age- and diet-matched Cftr( +/+) animals. However, Cftr(-/-) pancreatic acini showed a significantly gr eater amylase response to the combination of BrcAMP and carbachol than the sum of the individual responses in separate experiments (p < 0.05). The amy lase response was not different in acini from solid-fed or liquid-fed Cftr( +/+) controls. In summary, this study suggests that cystic fibrosis transme mbrane conductance regulator is not essential for enzyme secretion as evide nced by no reduction in cAMP-mcdiated amylase secretion in Cftr(-/-) mice. The results in Cftr(+/+) acini suggest pancreatic enzyme secretion is media ted via multiple intracellular pathways acting in parallel and probably con verge at a distal step in the secretory process. However, Cftr(-/-) pancrea tic acini exhibited a synergistic secretory response following stimulation by BrcAMP plus carbachol, The enhanced secretory response may partially con tribute to the development of pancreatic dysfunction in CF patients by faci litating occlusion of digestive enzymes in the secretory canaliculus of the pancreatic acini.