Modulation of gastrointestinal afferent sensitivity by a novel substituted benzamide (ecabapide)

The effects of ecabapide, a novel substituted benzamide compound (3-[2-(3,4-dimethoxyphenyl)ethylcarbamoylmethyl]amino-N-methylb enzamide) that has gastrointestinal prokinetic action, were examined on the discharge of extrinsic afferent nerves supplying the stomach and jejunum in anaesthetized rats. Ecabapide (60 and 180 microg kg(-1), i.v.) had no effect on the baseline discharge of vagal gastric distension-sensitive afferents or the stimulus-response profile to gastric distension. Ecabapide also had no effect on either spontaneous jejunal mesenteric afferent nerve discharge or responses to intestinal distension. Ecabapide (180 microg kg(-1)) significantly inhibited the maximum discharge of jejunal afferents induced by cholecystokinin (CCK8; 50 pmol, i.v.), whereas it failed to inhibit the excitatory action of 2-methyl-5-hydroxytryptamine (2Me-5-HT; 10 microg, i.v.), a selective 5-HT3 receptor agonist. A model of acute focal intestinal ischaemia was used to evaluate the actions of ecabapide on the discharge of activated jejunal afferents. Ischaemia produced a substantial increase in afferent discharge which was reproducible when the duration of ischaemia was limited to less than 10 min and repeated every 15 min. Ecabapide at doses of 60 and 180 microg kg(-1) significantly reduced ischaemia-induced increases in afferent discharge. In addition to its therapeutic efficacy as a gastrointestinal prokinetic agent, these findings show also that ecabapide may also have an inhibitory action on the discharge of intestinal afferents activated by ischaemia.