EFFECTS OF CUBAN ANALOG (SWR-104SA), A NE W HISTAMINE H-2-RECEPTOR ANTAGONIST, ON GASTRIC-ACID SECRETION AND EXPERIMENTAL ULCER FORMATION

The antagonism of histamine H-2-receptor by SWR-104SA -N-[3[3-(1-piper idinylmethyl)phenoxy]propyl]-spiro ne-2,9'-pentacyclo-[4.3.0.0.O-2,O-5 .O-3,O-8.(4,7)] nonane]-4'-carboxamide monooxalate) was estimated usin g the isolated guinea-pig atrium and gastric acid secretion in rats. T he concentration-response curves for the positive chronotropic effect of histamine on the atrium were displaced to the right in parallel wit hout change in the maximum response by SWR-104SA and roxatidine acetat e hydrochloride (roxatidine). The pA(2) values of SWA-104SA and roxati dine acetate hydrochloride were 7.27 and 7.38, respectively. The slope s of the regression line of log (DR-1) against log SWR-104SA and roxat idine concentration were 1.00 and 0.92, respectively. There was no sig nificant difference between the two compounds with respect to the hist amine H-2-receptor antagonism and/or binding manner in vitro. In the r at gastric fistula model stimulated by histamine, however, antisecreto ry potency of SWR-104SA was 3 times less than that of roxatidine. SWR- 104SA given p.o. prevented the formation of gastric lesion induced by HCl-ethanol and indomethacin dose-dependently, roxatidine also prevent ed its formation by HCl-ethanol, but failed to prevent that by indomet hacine. These antiulcer activities of SWR-104SA were shown at the less er doses of antisecretory activity. On the other hand, roxatidine did not prevent the ulcer formation at the same dose level of antisecretor y activity. These results indicate that the antiulcer effect of SWR-10 4SA is not caused by the antisecretory action alone.In addition, the m ucosal protective activity of SWR-104SA for HCl-ethanol induced gastri c lesion was independent of endogenous prostaglandins. Moreover SWR-10 4SA had inhibitory effects on indomethacin-induced gastric hypermotili ty in rats. These actions may partly explain the gastric protection of this compound and additional mechanisms such as mucosal blood flow co uld be involved in the antiulcer efficacy. Consequently, it appears th at SWR-104SA is a new antiulcer drug that exerts a potent cytoprotecti ve effect in addition to its gastric antisecretory activity.