The beta 3-adrenoceptor agonist CL316243 prevents indomethacin-induced jejunal ulceration in the rat by reversing early villous shortening.
Jejunal villi undergo early histological shortening and vascular injury in indomethacin-induced ulcerative enteropathy in the rat. The protective effects of the beta 3-adrenoceptor agonist CL316243 on this rat model and the mechanism of action were examined using histological techniques. Groups of rats received oral indomethacin (15 mg/kg) and oral CL316243 (0, 0.01-10 mg/kg) 0.5 h beforehand. Jejunal ulceration was assessed 48 h after indomethacin. Other groups received CL316243 either 6 h before or 3 or 6 h after indomethacin. Plasma indomethacin and jejunal prostaglandin E2 levels were determined in groups of rats with and without prior CL316243. CL316243 was a potent dose-dependent inhibitor of jejunal ulceration (> 98 percent inhibition at doses > or = 0.1 mg/kg; ED50 = 0.025 mg/kg) but was not protective when given 6 h after indomethacin. CL316243, 1 mg/kg, reversed early villous shortening and vascular injury. CL316243 did not affect either indomethacin bioavailability or the inhibition of prostaglandin E2. To conclude, the beta 3-adrenoceptor agonist CL316243 is a potent inhibitor of indomethacin-induced jejunal ulceration and the mechanism of protection involves reversal of both villous shortening and vascular injury, which are usefully assessed by histomorphological techniques.
Anthony
A
A
University Department of Histopathology, Royal Free Hospital School of Medicine, London, U.K.
Bahl
A K
AK
Oakley
I G
IG
Spraggs
C F
CF
Dhillon
A P
AP
Trevethick
M A
MA
Piasecki
C
C
Pounder
R E
RE
Wakefield
A J
AJ
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity; D004149:Dioxoles / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D007213:Indomethacin / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007579:Jejunal Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014456:Ulcer / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control
D000318:Adrenergic beta-Agonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004149:Dioxoles; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D007213:Indomethacin