Prophylactic and therapeutic benefits of COX-2 inhibitor on motility dysfunction in bowel obstruction: roles of PGE₂ and EP receptors.
We reported previously that mechanical stretch in rat colonic obstruction induces cyclooxygenase (COX)-2 expression in smooth muscle cells. The aims of the present study were to investigate whether in vivo treatment with COX-2 inhibitor has prophylactic and therapeutic effects on motility dysfunction in colon obstruction, and if so what are the underlying mechanisms. Partial colon obstruction was induced with a silicon band in the distal colon of 6-8-wk-old Sprague-Dawley rats; obstruction was maintained for 3 days or 7 days. Daily administration of COX-2 inhibitor NS-398 (5 mg/kg) or vehicle was started before or after the induction of obstruction to study its prophylactic and therapeutic effects, respectively. The smooth muscle contractility was significantly suppressed, and colonic transit rate was slower in colonic obstruction. Prophylactic treatment with NS-398 significantly prevented the impairments of colonic transit and smooth muscle contractility and attenuated fecal collection in the occluded colons. When NS-398 was administered therapeutically 3 days after the initiation of obstruction, the muscle contractility and colonic transit still improved on day 7. Obstruction led to marked increase of COX-2 expression and prostaglandin E(2) (PGE(2)) synthesis. Exogenous PGE(2) decreased colonic smooth muscle contractility. All four PGE(2) E-prostanoid receptor types (EP1 to EP4) were detected in rat colonic muscularis externa. Treatments with EP1 and EP3 antagonists suppressed muscle contractility in control tissue but did not improve contractility in obstruction tissue. On the contrary, the EP2 and EP4 antagonists did not affect control tissue but significantly restored muscle contractility in obstruction. We concluded that our study shows that COX-2 inhibitor has prophylactic and therapeutic benefits for motility dysfunction in bowel obstruction. PGE(2) and its receptors EP2 and EP4 are involved in the motility dysfunction in obstruction, whereas EP1 and EP3 mediate PGE(2) regulation of colonic smooth muscle contractile function in normal state.
Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-0655, USA.
You-Min
YM
Lin
Sushil K
SK
Sarna
Xuan-Zheng
XZ
Shi
D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007415:Intestinal Obstruction / Q000188:drug therapy* / Q000517:prevention & control; D009578:Nitrobenzenes / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; D015232:Dinoprostone