CYCLIC ADENOSINE-MONOPHOSPHATE IS THE 2ND MESSENGER OF PROSTAGLANDIN E(2)- AND VASOACTIVE INTESTINAL POLYPEPTIDE-STIMULATED ACTIVE BICARBONATE SECRETION BY GUINEA-PIG DUODENUM

In a guinea-pig model we determined the intracellular events mediating the response of duodenal epithelial cells to vasoactive intestinal po lypeptide (VIP) and prostaglandin (PG) E(2) Intravenous administration of VIP (10(-9) to 10(-7) mol/kg) and PGE(2) (10(-9) to 10(-6) mol/kg) dose-dependently increased duodenal epithelial bicarbonate secretion against an HCO; concentration gradient, measured by a luminal perfusio n technique, in anaesthetized guinea-pigs up to 4.5-fold. This secreti on could be mimicked by intraduodenal dibutyryl cyclic adenosine monop hosphate (dBcAMP; 10(-9) to 10(-7) mol/kg). Secretin (10(-9) mol/kg) a nd PGF(2 alpha) (10(-9) to 10(-7) mol/kg), both given intravenously, w ere without effect or considerably less efficient. For VIP and PGE(2), specific receptors coupled to adenylate cyclase could be demonstrated in homogenates of isolated duodenal epithelial cells. VIP and PGE(2) stimulated adenylate cyclase activity up to sixfold, whereas PGF(2 alp ha) and secretin were considerably less potent and efficient. VIP and PGE(2) increased intracellular cyclic AMP levels up to fivefold and ni nefold, respectively. This was followed by an increase in cytosolic pr otein kinase A activity. Bicarbonate secretion was maximal at 30 min. Examination of the subcellular distribution of protein kinase A showed a predominant cytosolic location. These data support the notion that PGE(2) and VIP cause bicarbonate secretion by the serial activation of adenylate cyclase and protein kinase A in duodenal epithelial cells.