Mechanisms of Antisecretory Action of Intragastric FPL-52694: A Mast Cell Stabilizer in Anesthetized Rats

Abstract

Mechanisms of antisecretory action of intragastric FPL-52694, a mast cell stabilizer, were investigated in anesthetized rats. In Schild’s rat preparation, intravenous FPL-52694 (10 mg/kg) significantly suppressed acid secretion in response to only tetragastrin (20 μg/kg, i.v.) (42.1 ± 19.4%), while intragastric application of FPL-52694 (100 mg/kg) for 30 min produced a marked, unequivocal inhibition (over 70%) in acid secretory responses to histamine (1 mg/kg, i.v.) and carbachol (2.5 μg/kg, i.v.) as well as tetragastrin. The inhibitory effect of intragastric FPL-52694 was confirmed in the lumen-perfused rats, where acid secretion (24–25 μmol/10 min) induced by intravenous infusion of histamine (8 mg/kg/h) was abolished for 1 h after exposure of the stomach for 30 min to this agent. Inhibition of histamine-stimulated acid secretion by intragastric FPL-52694 was much greater and lasted longer (2 h) as compared with xylocaine (4% solution), but significantly mitigated by pretreatment of the rats with subcutaneous administration of indomethacin (3 mg/kg). Furthermore, application of FPL-52694 but not of xylocaine to the stomach caused a reduction of transmucosal potential difference, an increase of luminal appearance of HCO₃^- (1–2 μmol/10 min), and an enhancement of H⁺ back-diffusion, although no damage was appreciated in the mucosa. These results suggest that antisecretory action of intragastric FPL-52694 may involve local mechanisms such as neutralization of acid with HCO₃^-, a loss of acid due to H⁺ back-diffusion, and inhibition of acid production mediated by endogenous prostaglandins, but is not related to the local anesthetic activity.

Cytoprotective Action of Mast Cell Stabilizers against Ethanol-Induced Gastric Les ons in Rats

“…Intraperitoneally administered FPL-52694 and DSCG, however, had no effect on acid secretion even at the dose of 30 mg/kg. In a previous study (18), we have shown that the inhibitory effect of intra gastric administration of FPL-52694 on acid secretion was partially antagonized by indo methacin at a dose of 5 mg/kg. Gastric PD and HC03 output: The normal stomach generated PD of -35 to -40 mV (moucosa negative) and secreted HCO3_ in an amount of 1.5-2 itEq/hr under acid inhibition with omeprazole (30 mg/kg).…”