Prostaglandin cytoprotection of gastric mucosa

The hypothesis that active transport of sodium is inhibited by a damaging agent and is stimulated by a protective agent, the latter appearing to act via increased accumulation of intracellular cyclic AMP, is supported.

Abstract

The mechanisms by which prostaglandins protect the gastric mucosa against the erosive action of t&erogenic drugs, such as indomethacin, is unknown.The hypothesis was tested that topical damaging agents inhibit the active transport of sodium in the gastric mucosa and that a cytoprotective prostaglandin will reverse this effect.Paired mucosal segments from the corpus of the dog stomach were mounted between bathing chambers to allow measurement of unidirectional fluxes of 22Na, the electrical potential difference (PD) across the mucosa which is generated by the active transport of sodium, and the short-circuit current.The electrical resistance (R) was calculated from Ohm's law.The flux of 22Na from serosa to mucosa (J!!,) is an index of the passive transport of the ion and is a measure of membrane permeability.The difference between the two unidirectional fluxes (Jfzt) represents the rate of active transport of the ion.If a topical damaging drug acted exclusively by increasing membrane permeability one would anticipate the following responses to the agent: increased JZ,,, little effect on Ji& decreased PD and decreased R. Adding indomethacin to the mucosal bathing solution in a concentration of 2.2 x low4 M caused no change in JN.,,,, decreases in both Jia and PD, and an increase in R.These findings suggest a primary effect on active transport of sodium.Effects of indomethacin on Ji& PD, and R were reversed by 16,16 dimethyl prostaglandin Ee (8 x 100' M) and by agents known to increase intracellular cyclic AMP content (theophylline and dibutyryl cyclic AMP).Incubation of mucosae with the prostaglandin increased measured cyclic AMP content 60% at a time before the full electrophysiological response.These data support the hypothesis that active transport of sodium is inhibited by a damaging agent and is stimulated by a protective agent, the latter appearing to act via increased accumulation of intracellular cyclic AMP.Prostaglandins protect the gastrointestinal mucosa against numerous experimental ulcerogens.14Prominent among such damaging agents are nonsteroidal antiinflammatory compounds, such as indomethacin, which also inhibit biosynthesis of endogenous prostaglandins in the mucosa.343 One explanation for prostaglandin cytoprotection might be the potent gastric antisecretory effect of prostaglandins; however, prostaglandins also protect the jejunoileal mucosa against indomethacin ulceration> 4 and the distal small intestine is not exposed to gastric secretions.The present study was undertaken to explore the possibility that prostaglandins protect the gastric mucosa by stimulation of the active transport of sodium.'Methods Twenty-one mongrel dogs of either sex weighing from 12 to 18 kg were used in these studies.Animals were fasted but