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 injur y in indomethacin-induced ulcerative enteropathy in the rat, The prote ctive effects of the beta(3)-adrenoceptor agonist CL316243 on this rat model and the mechanism of action were examined using histological te chniques, Groups of rats received oral indomethacin (15 mg/kg) and ora l CL316243 (0, 0.01-10 mg/kg) 0.5 h beforehand, Jejunal ulceration was assessed 48 h after indomethacin. Other groups received CL316243 eith er 6 h before or 3 or 6 h after indomethacin, Plasma indomethacin and jejunal prostaglandin E(2) levels were determined in groups of rats wi th and without prior CL316243, CL316243 was a potent dose-dependent in hibitor of jejunal ulceration (>98 per cent inhibition at doses greate r than or equal to 0.1 mg/kg; ED(50) = 0.025 mg/kg) but was not protec tive when given 6 h after indomethacin. CL316243, 1 mg/kg, reversed ea rly villous shortening and vascular injury, CL316243 did not affect ei ther indomethacin bioavailability or the inhibition of prostaglandin E (2). To conclude, the beta(3)-adrenoceptor agonist CL316243 is a poten t inhibitor of indomethacin-induced jejunal ulceration and the mechani sm of protection involves reversal of both villous shortening and vasc ular injury, which are usefully assessed by histomorphological techniq ues.