Modulation of gastrointestinal afferent sensitivity by a novel substitutedbenzamide (ecabapide)

The effects of ecabapide, a novel substituted benzamide compound (3-[2-(3,3 -dimethoxyphenyl)ethylcarbamoylmethyl]methylbenzamide) that has gastrointes tinal prokinetic action, were examined on the discharge of extrinsic affere nt nerves supplying the stomach and jejunum in anaesthetized rats. Ecabapid e (60 and 180 mu g kg(-1), iv) had no effect on the baseline discharge of v agal gastric distension-sensitive afferents or the stimulus-response profil e to gastric distension. Ecabapide also had no effect on either spontaneous jejunal mesenteric afferent nerve discharge or responses to intestinal dis tension. Ecabapide (180 mu g kg(-1)) significantly inhibited the maximum di scharge of jejunal afferents induced by cholecystokinin (CCK8; 50 pmol, iv) , whereas it failed to inhibit the excitatory action of 2-methyl-5-hydroxyt ryptamine (2Me-5-HT; 10 mu g, iv), a selective 5-HT3 receptor agonist. A mo del of acute focal intestinal ischaemia was used to evaluate the actions of ecabapide on the discharge of activated jejunal afferents. Ischaemia produ ced a substantial increase in afferent discharge which was reproducible whe n the duration of ischaemia was limited to less than 10 min and repeated ev ery 15 min. Ecabapide at doses of 60 and 180 mu g kg(-1) significantly redu ced ischaemia-induced increases in afferent discharge. In addition to its t herapeutic efficacy as a gastrointestinal prokinetic agent, these findings show also that ecabapide may also have an inhibitory action on the discharg e of intestinal afferents activated by ischaemia. (C) 2000 Elsevier Science B.V. All rights reserved.