Twelve healthy subjects were given aspirin (975 mg four times a day) for four days. On days three and four, each dose of aspirin was preceded by a synthetic protaglandin E1 analog (misoprostol, Searle) either 25 micrograms, 50 micrograms, or placebo in a double-blind balanced full crossover design. Bleeding, gastric secretion of acid and chloride, and accumulation of gastric luminal DNA and calcium as indices of cell shedding and mucus secretion were measured by three daily morning gastric washouts, corrected for gastric emptying. Both bleeding and gastric secretion were greater on day 4 with aspirin and placebo than on day 0. With 50 micrograms misoprostol, and to a lesser extent with 25 micrograms, bleeding and gastric secretion were reduced on day 4 compared to day 4 with placebo or aspirin only days. The reduction in gastric bleeding with the 50-microgram dosage of misoprostol was directly related to the reduction in acid secretion. The ratios of changes in acid and chloride outputs did not indicate any increase in bicarbonate secretion. No changes in the recoveries of calcium or DNA were seen.
Isolated canine parietal cells were used to study the ability of misoprostol to inhibit acid secretion in the presence of a number of acid secretagogues. Misoprostol inhibited histamine-stimulated acid secretion in a dose-dependent and noncompetitive manner. A concentration of 2-3 X 10(-9) M misoprostol inhibited maximal histamine-stimulated acid secretion by one half. Misoprostol had little to no effect on acid secretion stimulated by carbachol and dibutyryl cAMP, had no effect on the acid secretion directly stimulated by pentagastrin, and only modestly inhibited acid secretion stimulated by forskolin. Misoprostol noncompetitively inhibited cAMP formation in response to histamine, with an IC50 value similar to that for the inhibition of histamine-stimulated acid secretion. These results indicate that: (1) misoprostol specifically inhibits histamine-stimulated acid secretion in parietal cells, and (2) the antisecretory action of misoprostol is closely related to the reduction of histamine-stimulated cAMP formation with the site of major action most likely in the coupling process between histamine H2 receptor sites and histamine-sensitive adenylate cyclase.
In enriched canine parietal cell preparations, misoprostol, an analog of prostaglandin E1 methyl ester, was rapidly deesterified to misoprostol free acid. Under this circumstance, misoprostol and misoprostol free acid exhibited equal antisecretory potency against histamine-stimulated acid secretion and bound equally well to prostaglandin E receptors. When the deesterification of misoprostol was inhibited by paraoxon, an esterase inhibitor, the antisecretory and receptor binding activity of misoprostol was markedly reduced, with potency much less than misoprostol free acid. These results indicate that misoprostol free acid is the active biological form of misoprostol that binds to prostaglandin E receptors and mediates the antisecretory action of misoprostol.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.