Efflux of cAMP in the exocrine pancreas: Role of secretin and atrial natriuretic factor (ANF)

Abstract

We previously reported that ANF dose‐dependently reduces secretin secretory response and intracellular signaling in the exocrine pancreas through NPR‐C receptors coupled to the PLC/PKC pathway. In this study we evaluated if cAMP efflux contributed to ANF response in isolated pancreatic acini. Results showed that ANF favored the efflux of cAMP formed by secretin. The export of cAMP was also observed with secretin alone but not with isoproterenol or amthamine. Evoked‐cAMP efflux was blocked by probenecid, suggesting that multidrug resistant proteins (MRPs) were involved. RT‐PCR analysis revealed that MRP‐4 but not MRP‐5 (transport cyclic nucleotides) was expressed in the pancreas. Time course studies in the presence of phosphodiesterase (PDE) activity showed that tissue cAMP increased peaking at 3 min onset secretin stimulation and declining thereafter. With ANF, secretin‐induced cAMP augmented reaching a peak at 1 min after which it rapidly decreased. Extracellular cAMP accumulation occurred earlier and persisted throughout the experiment whereas with secretin alone it was delayed. Similar findings were observed in studies with PDE inhibition, except that cAMP content was higher and its appearance delayed in tissues and the media. Present findings suggest that cAMP export is likely mediated by MRP‐4 and further it may contribute to ANF‐induced desensitization of secretin response in the exocrine pancreas.(CONICET PIP5929/ UBACYT B079)