Prostanoids stimulate K secretion and Cl secretion in guinea pig distal colon via distinct pathways.
Short-circuit current (I(sc)) and transepithelial conductance (Gt) were measured in guinea pig distal colonic mucosa isolated from submucosa and underlying muscle layers. Indomethacin (2 microM) and NS-398 (2 microM) were added to suppress endogenous production of prostanoids. Serosal addition of PGE2 (10 nM) stimulated negative I(sc) consistent with K secretion, and concentrations >30 nM stimulated positive I(sc) consistent with Cl secretion. PGE2 also stimulated Gt at low and high concentrations. Dose responses to prostanoids specific for EP prostanoid receptors were consistent with stimulating K secretion through EP2 receptors, based on a rank order potency (from EC50 values) of PGE2 (1.9 nM) > 11-deoxy-PGE1 (8.3 nM) > 19(R)-hydroxy-PGE2 (13.9 nM) > butaprost (67 nM) > 17-phenyl-trinor-PGE2 (307 nM) >> sulprostone (>10 microM). 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) > PGD2 (30 nM) > PGE2 (203 nM). Agonists specific for FP, IP, and TP prostanoid receptors were ineffective in stimulating I(sc) and Gt at concentrations <1 microM. These results indicate that PGE2 stimulated 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 (<100 nM) or pathophysiological concentrations of PGE2 (>100 nM) that could occur during inflammatory conditions.
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Department of Physiology and Biophysics, Wright State University, Dayton, Ohio 45435, USA. dan.halm@wright.edu
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D000818:Animals; D002034:Bumetanide / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000033:anatomy & histology / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000737:chemistry / Q000494:pharmacology*; D004232:Diuretics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000378:metabolism*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000378:metabolism; D014966:Xanthenes / Q000494:pharmacology; D044004:Xanthones
D002712:Chlorides; D016861:Cyclooxygenase Inhibitors; D004232:Diuretics; D011448:Prostaglandin Antagonists; D011982:Receptors, Prostaglandin; D014966:Xanthenes; D044004:Xanthones; D002034:Bumetanide; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D015232:Dinoprostone; D011188:Potassium; D007213:Indomethacin