Abstract
The isoprostanes, which differ from prostaglandins by thecis orientation of their side chains, are believed to exert their biological effects on either a prostanoid TP receptor or a “unique” isoprostane receptor. Preliminary experiments suggested that canine colonic epithelium possessed no prostanoid TP receptor activity, in contrast to the muscularis mucosae, which responds well to the selective prostanoid TP receptor agonist U46619. To define the receptors involved, the in vitro responses of the epithelium and muscularis mucosae from the canine proximal colon to both 8-iso-PGE2 and 8-iso-PGF2α were compared. The epithelium responded to 8-iso-PGE2 but not to 8-iso-PGF2α. Under basal conditions, 8-iso-PGE2 produced concentration-dependent increases in short circuit current (pEC50 = 6.4 ± 0.1) that were not antagonized by the selective prostanoid TP receptor antagonist SQ29548 (10−6 M). Cross-desensitization experiments suggested that the stimulant effects involved a prostanoid EP receptor. Desensitization of the epithelium to PGE2 resulted in unexpected decreases in short circuit current in response to 8-iso-PGE2(10−6 M). This effect was mimicked by the selective prostanoid TP receptor agonist U46619 (10−5 M), and antagonized by three structurally different prostanoid TP receptor antagonists: L670596 (10−6 M), SQ29548 (10−6M) and GR32191 (10−6 M). 8-Iso-PGE2, 8-iso-PGF2α and U46619 caused concentration-dependent increases in the force of contraction of the muscularis mucosae strips. These responses were antagonized by selective prostanoid TP receptor antagonists, arguing for the involvement of prostanoid TP receptors. Thus, the effects of isoprostanes on the canine colon involve both prostanoid TP and EP receptors.
Footnotes
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Send reprint requests to: Dr. P. K. Rangachari, McMaster University, HSC-3N5C, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada. E-mail:chari{at}fhs.mcmaster.ca
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↵1 This work was supported by an operating grant to P.K..R from the Medical Research Council of Canada. The work formed part of the fourth-year undergraduate thesis in the Honors Biology and Pharmacology Coop Program for J.E., who received a studentship from the Crohn’s and Colitis Foundation of Canada.
- Abbreviations:
- AA
- arachidonic acid
- PG
- prostaglandin
- DK
- 13,14-dihydro-15-keto-PGD2
- Isc
- short-circuit current
- Tmax
- tissue maximum
- PSS
- psychological salt solution
- TP
- prostanoid TP
- EP
- prostanoid EP
- Received November 1, 1996.
- Accepted May 21, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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