Prostanoids Stimulate K Secretion and Cl Secretion in Guinea Pig Distal Colon via Distinct Pathways

Short-circuit current (I sc) and transepithelial conductance (G t) were measured in guinea pig distal colonic mucosa isolated from submucosa and underlying muscle layers. Indomethacin (2 μM) and NS-398 (2 μM) were added to suppress endogenous production of prostanoids. Serosal addition of PGE2 (10 nM) stimulated negative I scconsistent with K secretion, and concentrations \u3e30 nM stimulated positive I sc consistent with Cl secretion. PGE2 also stimulated G t at low and high concentrations. Dose responses to prostanoids specific for EP prostanoid receptors were consistent with stimulating K secretion through EP2receptors, based on a rank order potency (from EC50 values) of PGE2 (1.9 nM) \u3e 11-deoxy-PGE1 (8.3 nM) \u3e 19(R)-hydroxy-PGE2 (13.9 nM) \u3e butaprost (67 nM) \u3e 17-phenyl-trinor-PGE2 (307 nM) ≫ sulprostone (\u3e10 μM). An isoprostane, 8-iso-PGE2, stimulated K secretion with an EC50 of 33 nM. Cl secretory response was stimulated by PGD2 and BW-245C, a DP prostanoid receptor-specific agonist: BW-245C (15 nM) \u3e PGD2 (30 nM) \u3e PGE2 (203 nM). Agonists specific for FP, IP, and TP prostanoid receptors were ineffective in stimulating I sc and G t at concentrations \u3c1 \u3eμM. These results indicate that PGE2stimulated electrogenic K secretion through activation of EP2 receptors and electrogenic KCl secretion through activation of DP receptors. Thus stimulation of Cl secretion in vivo would occur either via physiological concentrations of PGD2(\u3c100 \u3enM) or pathophysiological concentrations of PGE2(\u3e100 nM) that could occur during inflammatory conditions