Abstract
The isoprostanes are prostaglandin (PG)-like compounds formed in vivo by free-radical-catalyzed peroxidation of polyunsaturated fatty acids and are synthesized independent of cyclooxygenase. It has been debated whether the biological effects of the isoprostanes are exerted on prostanoid receptors [thromboxane A2 (TP) receptors and prostanoid E (EP) receptors] or on a “unique” isoprostane receptor. We sought to define the receptors involved in the actions of isoprostanes on the porcine small intestine. Stripped intestinal sheets were mounted in Ussing chambers, and bioelectrical parameters were recorded. Serosal application of 8-iso-PGE2(pEC50 = 5.71), PGE2(pEC50 = 6.45 and pEC50 = 5.04), and PGF2α (pEC50 = 5.07) elicited concentration-dependent increases in the short-circuit current (I SC). No responses were seen with 8-iso-PGF2α. The TP receptor agonist U46619 induced transient increase in I SC, and the tissue responded to a further challenge to PGE2. Pretreatment withU46619 did not alter responses to a subsequent addition of either PGE2 or 8-iso-PGE2. The TP receptor antagonist SQ29,548 significantly reduced responses to the TP agonist, U46619, but did not antagonize responses to 8-iso-PGE2. Homologous and heterologous desensitization between 8-iso-PGE2, PGE2, and PGF2αsuggested the involvement of prostanoid EP and prostanoid F (FP) receptors in the response elicited to 8-iso-PGE2. The effects of 8-iso-PGE2 were not inhibited by tetrodotoxin. Pretreatment of the tissues with bumetanide significantly reduced the increase in I SC. The results indicate that 8-iso-PGE2 induces a Cl− secretion, and the effects involve prostanoid EP and FP receptors but not TP receptors in the porcine small intestine.
Footnotes
- Received July 18, 2000.
- Accepted October 16, 2000.
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Send reprint requests to: Dr. Martin Unmack, Department of Anatomy and Physiology, The Royal Veterinary and Agricultural University, Gronnergardsvej 7, DK-1870 Frederiksberg C, Denmark. E-mail: mau{at}kvl.dk
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This work was supported by grants to M. A. Unmack from The Hannibal Sander's Foundation (Margrethe Brinch's Grant), The Else and Mogens Wedell-Wedellsborg's Foundation, The King Christian IX and Queen Louise Anniversary Foundation, The Dagmar Marshall's Foundation, The Ingeborg Roikjer's Foundation, The Landed Proprietor Viktor A. Goldschmidt's Foundation (Dept. B), The Merchant Mr. Sven Hansen and Mrs. Ina Hansen's Foundation, The Director Mr. Jacob Madsen's and Mrs. Olga Madsen's Foundation, The King Christian Xth's Foundation, The Novo Nordisk Foundation, and The Carlsberg Foundation (The Royal Veterinary and Agricultural University, Denmark). P. K. Rangachari was supported by The Medical Research Council of Canada. E. Skadhauge was supported by The Simon Fougner Hartmann Family's Foundation.
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A preliminary report of this work was presented in abstract form at the Physiological Society's meetings in January and June 1998, and at the Internet World Congress on Biomedical Sciences (INABIS '98) in December 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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