The contribution of prostaglandins in the muscle of human isolated small intestine to neurogenic responses.

1. In stris cut parallel to the longitudinal or circular muscle, indomethacin (2--10 microgram/ml) usually lowered the tone, thus probably accounting for the reduction of nerve-mediated relaxations to electrical field stimulation. 2. In longitudinal muscle strips, indomethacin enhanced contractions which occurred during electrical stimulation, probably because tone fell, but antagonized after-contractions. By contrast, in the circular muscle indomethacin reduced initial contractions but enhanced after-contractions. 3. Prostaglandin E2 counteracted all of the effects of indomethacin in the longitudinal muscle and most of those in the circular muscle; prostaglandin F2alpha restored circular muscle tone. 4. The results suggest that prostaglandins affect the muscle directly and contribute to the regulation of tone. They may also mediate non-cholinergic contraction in longitudinal muscle and suppress contractility in the circular muscle.

Estimation and characterization of prostaglandins in the human gastrointestinal tract.

1 Prostaglandin-like material was extracted from muscle and mucosa of surgically removed human stomach, ileum and colon and assayed against prostaglandin E(2) on strips of rat gastric fundus. Superfused human isolated gastric mucosa released prostaglandin-like material and release was increased by stretching or clamping the tissue.2 The relative amounts of extracted biological activity were broadly as follows: gastric antral mucosa > colon muscle > gastric body mucosa approximately ileal mucosa > colon mucosa approximately gastric muscle approximately ileal muscle.3 Prostaglandin E and F were tentatively identified by chromatography and sensitivity to inactivation by alkali.4 Prostaglandin E apparently contributed most to the biological activity, possibly because the assay tissue is more sensitive to prostaglandin E than to F. Chromatography of gastric body mucosal extracts located material running with prostaglandin E(2) and a little with E(1). Colonic muscle and mucosal extracts contained material with R(F) values of prostaglandins E(1), E(2), E(3) and F(1a), whereas F(2a) and F(3a)-like substances were found only in the mucosa. The proportions of prostaglandin F varied between specimens.5 The amount of extracted prostaglandin-like activity was increased by adding cofactors and arachidonic acid, and lessened by homogenization with acid-ethanol.6 The type and amount of activity generated from arachidonic acid by partly purified colonic mucosal prostaglandin synthetase depended on the substrate concentration.7 The possible relationships of prostaglandins to mucus secretion and other physiological and pathological gut functions are discussed.

Relaxations mediated by adrenergic and non-adrenergic nerves in human isolated taenia coli.

In human taenia coli electrical field stimulation after cholinergic blockade excited mainly non-adrenergic inhibitory nerves. Adrenergic relaxations during stimulation were demonstrated only with short electrical pulses at high frequencies or with ganglion stimulants. Reduction by tetrodotoxin of relaxations to indirectly acting sympathomimetics supports the histochemical finding that colonic adrenergic nerves are mainly preganglionic, and possibly synapse with non-adrenergic inhibitory nerves. When the latter undergo direct maximal stimulation, responses to adrenergic nerve excitation are masked.

The effects of prostaglandins E1, E2, F1alpha and F2alpha on guinea-pig ileal and colonic peristalis.

Prostaglandins (PGE1, E2, F1alpha and F2alpha) have been tested on the peristaltic reflex in isolated segments of guinea-pig ileum and colon using simultaneous recordings of fluid propulsion and longitudinal and circular muscle activity. Propulsion and circular muscle peristaltic activity were increased by serosally applied PGF compounds in the ileum and PGE or PGF compounds in the colon following initial contraction of the longitudinal muscle. This is consistent with a role for prostaglandins in peristalsis. Mucosally applied PGF compounds has no significant effect.

Inhibition of peristalsis in guinea-pig isolated ileum and colon by drugs that block prostaglandin synthesis.

1 Methods of analysing peristaltic activity have been evaluated by the use of recordings of longitudinal and circular muscle activity and of propulsion in whole segments of guinea-pig ileum and colon. 2 Some prostaglandin synthesis inhibitors, and antagonists of prostaglandin action were tested for their suitability for studying the role of prostaglandins in peristalsis. Aspirin was suitable; at 10-200 mug/ml it had little effect on responses of longitudinal muscle strips of the guinea-pig ileum to acetylcholine (ACh), histamine, nicotine or prostaglandin E2. Indomethacin (1-4 mug/ml) reduced responses to nicotine and prostaglandin E2. The prostaglandin antagonists polyphloretin phosphate and SC-19220 reduced contractions of ileal longitudinal muscle caused by nerve excitation with either nicotine or transmural stimulation. 3 Aspirin (20-100 mug/ml) or indomethacin (1-4 mug/ml) applied serosally greatly inhibited all aspects of peristalsis in guinea-pig ileum and colon. Inhibition of peristalsis of the ileum by aspirin was antagonized by prostaglandin E2 and that by indomethacin was removed by prostaglandin F2alpha or ACh. Inhibition of colonic peristalsis by aspirin was antagonized by prostaglandin E2 but rarely by ACh, and that by indomethacin by prostaglandin E1 or E2. Mucosal application of aspirin had little effect on either ileum or colon but indomethacin caused some inhibition. 4 These results support the supposition that prostaglandins contribute to peristaltic activity.

The intrinsic innervation of the human alimentary tract and its relation to function.

The intrinsic innervation of the human gut has been studied in strips of circular and longitudinal muscle removed at operation. Electrical stimulation of the nerves at a wide range of frequencies (0-1 to 128 Hz) can evoke a variety of responses due to activation of four types of nerves. There is evidence for cholinergic, adrenergic, non-adrenergic inhibitory, and non-cholinergic excitatory fibres, which may be stimulated at different frequencies. The various regions of the alimentary tract, and even the muscle layers within a region, may respond differently to nerve stimulation. This is most marked at 4 Hz and the observed differences correlate with the function of each part and its dependence on extrinsic innervation. The stomach is relatively insensitive to electrical stimulation, and this is consistent with its reliance on vagal innervation. The dominant excitatory responses in the longitudinal muscle of the oesophagus and ileum correlate with their high motility and propulsive function, whereas the dominant inhibitory responses in the colon correlate with its lower motility and storage function.

The effects of prostaglandins on guinea-pig isolated intestine and their possible contribution to muscle activity and tone.

1 Prostaglandins F(1alpha) and F(2alpha) caused contraction of the longitudinal muscle of both guinea-pig isolated ileum and colon, apparently by acting directly on the muscle and on cholinergic nerves. They had little effect on ileal circular muscle.2 Prostaglandins E(1) and E(2) caused contraction of the longitudinal muscle of guinea-pig isolated colon, apparently by acting directly on the muscle and on excitatory nerves which are non-cholinergic. Prostaglandin E(1) seems more effective than E(2) in stimulating these nerves.3 It seems likely that prostaglandin release in vitro maintains the tone of the longitudinal muscle of guinea-pig colon, whereas release of a prostaglandin E compound inhibits circular muscle tone.

Modulation by prostaglandins of contractions in guinea-pig ileum.

A high concentration of indomethacin (40mu-g/ml) substantially reduced contractions of guinea-pig isolated ileum in Krebs solution to nerve stimulation with electrical pulses or nicotine. Responses to acetylcholine and histamine were also inhibited, but to a smaller extent. Low concentrations of prostaglandin E-2 (2 or 4ng/ml) mainly restored all the excitatory responses. Using a modified bathing solution (lacking in phosphate and with some other changes) indomethacin 0.36mu-g/ml selectively inhibited nerve-mediated contractions. The results explain differences in various reports, and support the possibility that prostaglandins modulate the response to cholinergic nerve activity.