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Vol. 282, Issue 3, 1198-1205, 1997
Intestinal Disease Research Program, Department of Medicine and
Honors Biology and Pharmacology Program, McMaster University, Hamilton,
Ontario, Canada
The isoprostanes, which differ from prostaglandins by the
cis 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-PGF2
were compared. The epithelium
responded to 8-iso-PGE2 but not to
8-iso-PGF2. 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
(106 M). This effect was mimicked by the
selective prostanoid TP receptor agonist U46619
(105 M), and antagonized by three structurally
different prostanoid TP receptor antagonists: L670596
(106 M), SQ29548 (106
M) and GR32191 (106 M).
8-Iso-PGE2,
8-iso-PGF2 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.
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