The antagonism of
histamine H2-receptor by
SWR-104SA (1'-bromo-N-[3-[3-(1-piperidinylmethyl) phenoxy] propyl]-spiro [1,3-
dioxolane-2,9'-pentacyclo-[4.3.0.0.(2,5)0.(3,8) 0.(4,7)]
nonane]-4'-carboxamide monooxalate) was estimated using the isolated guinea-pig atrium and gastric acid secretion in rats. The concentration-response curves for the positive chronotropic effect of
histamine on the atrium were displaced to the right in parallel without change in the maximum response by
SWR-104SA and
roxatidine acetate hydrochloride (
roxatidine). The pA2 values of SWA-104SA and
roxatidine acetate hydrochloride were 7.27 and 7.38, respectively. The slopes of the regression line of log (DR-1) against log
SWR-104SA and
roxatidine concentration were 1.00 and 0.92, respectively. There was no significant difference between the two compounds with respect to the
histamine H2-receptor antagonism and/or binding manner in vitro. In the rat
gastric fistula model stimulated by
histamine, however, antisecretory 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 prevented its formation by HCl-
ethanol, but failed to prevent that by indomethacine. These antiulcer activities of
SWR-104SA were shown at the lesser doses of antisecretory activity. On the other hand,
roxatidine did not prevent the
ulcer formation at the same dose level of antisecretory activity. These results indicate that the antiulcer effect of
SWR-104SA is not caused by the antisecretory action alone. In addition, the mucosal protective activity of
SWR-104SA for HCl-
ethanol induced gastric lesion was independent of endogenous
prostaglandins. Moreover
SWR-104SA had inhibitory effects on
indomethacin-induced gastric hypermotility in rats. These actions may partly explain the gastric protection of this compound and additional mechanisms such as mucosal blood flow could be involved in the antiulcer efficacy. Consequently, it appears that
SWR-104SA is a new antiulcer
drug that exerts a potent cytoprotective effect in addition to its gastric antisecretory activity.