PGE2 triggers recovery of transmucosal resistance via EP receptor cross talk in porcine ischemia-injured ileum

16,16-Dimethyl-PGE(2) (PGE(2)) may interact with one of four prostaglandin type E (EP) receptors, which signal via cAMP (via EP2 or EP4 receptors) or intracellular Ca2+ (via EP1 receptors). Furthermore, EP3 receptors have several splice variants, which may signal via cAMP or intracellular Ca2+. We sought to determine the PGE(2) receptor interactions that mediate recovery of transmucosal resistance (R) in ischemia-injured porcine ileum. Porcine ileum was subjected to 45 min of ischemia, after which the mucosa was mounted in Ussing chambers. Tissues were pretreated with indomethacin (5 muM). Treatment with the EP1, EP2, EP3, and EP4 agonist PGE2 (1 muM) elevated R twofold and significantly increased tissue cAMP content, whereas the EP2 and EP4 agonist deoxy-PGE(1) (1 muM) or the EP1 and EP3 agonist sulprostone (1 muM) had no effect. However, a combination of deoxy-PGE(1) and sulprostone stimulated synergistic elevations in R and tissue cAMP content. Furthermore, treatment of tissues with deoxy-PGE(1) and the Ca2+ ionophore A-23187 stimulated synergistic increases in R and cAMP, indicating that PGE(2) triggers recovery of R via EP receptor cross talk mechanisms involving cAMP and intracellular Ca2+.