Effect of YNS-15P, a New Alpha-2 Adrenoceptor Antagonist, on Stress-Stimulated Colonic Propulsion in Rats

We studied effects of a novel alpha -2 adrenoceptor antagonist, YNS-15P (N-[(2R,11bS)-9-methoxy-1,3,4,6,7,11b-hexahydro-2H-benzoquinolizin-2-yl]-N-methylmethanesulfonamide hydrochloride), on colonic propulsion stimulated by wrap-restraint stress (WRS) or bethanechol, on normal colonic propulsion and on diarrhea induced by castor oil in rats. Alpha -2 adrenoceptor antagonists, rauwolscine and RX821002, decreased the increase in the number and weight of fecal pellets induced by WRS. YNS-15P also inhibited WRS-stimulated fecal excretion in a dose-dependent manner. A 5-hydroxytryptamine3 receptor antagonist, granisetron, trimebutine and diazepam, but not a 5-hydroxytryptamine4 receptor antagonist, GR113808, significantly inhibited WRS-stimulated fecal excretion. YNS-15P inhibited WRS-stimulated colonic transit in a dose-dependent manner. However, YNS-15P had no significant effect on normal fecal excretion and colonic transit or on bethanechol-stimulated fecal excretion. YNS-15P also failed to inhibit castor-oil-induced diarrhea. These results indicate that YNS-15P selectively inhibits WRS-stimulated colonic propulsion, and that alpha -2 adrenoceptors may be involved in stress-induced colonic motor dysfunction in fed rats.