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1 Department of Internal Medicine, VA Connecticut Healthcare, West Haven, CT, USA; Department of ell Biology, Yale University School of Medicine, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: fred.gorelick{at}yale.edu.
A characteristic of acute pancreatitis is the premature activation and retention of enzymes within the pancreatic acinar cell. Because ligands linked to cAMP production may prevent some forms of pancreatitis, we evaluated the effects of increased intracellular cAMP in the rat pancreatic acinar cell. Specifically, this study examined the effects of the cholinergic agonist, carbachol, and agents that increase cAMP (secretin and 8-Br-cAMP) on zymogen activation (trypsin and chymotrypsin), enzyme secretion, and cellular injury in isolated pancreatic acini. Although cAMP agonists affected the responses to physiological concentrations of carbachol [1 µM], their most prominent effects were observed with supraphysiologic concentrations [1mM]. When secretin was added to 1 mM carbachol, there was a slight increase in zymogen activation, but no change in the secretion of amylase or chymotrypsin. Further, co-addition of secretin increased parameters of cell injury (trypan blue exclusion, LDH release, and morphologic markers) compared to carbachol [1 mM] alone. Although directly increasing cellular cAMP by 8-Br-cAMP caused much greater zymogen activation than carbachol [1 mM] alone or with secretin, 8-Br-cAMP co-treatment reduced all parameters of injury to the level of unstimulated acini. Further, 8-Br-cAMP dramatically enhanced the secretion of amylase and chymotrypsin from the acinar cell. This study demonstrates that increasing acinar cell cAMP can overcome the inhibition of enzyme secretion caused by high concentrations of carbachol and eliminate acinar cell injury.
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