cl-316243 and Ulcer

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.

Topics: Adrenergic beta-Agonists; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dioxoles; Dose-Response Relationship, Drug; Drug Administration Schedule; Indomethacin; Intestinal Mucosa; Jejunal Diseases; Male; Rats; Rats, Sprague-Dawley; Ulcer