Gareth J. Sanger

Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers.

1 Gas chromatography‐mass spectrometry demonstrated the presence of arachidonic acid (AA), 6‐keto‐prostaglandin F1α and thromboxane B2 (TxB2) in all extracts of homogenized muscle or mucosa from human stomach, terminal ileum or sigmoid colon. Prostaglandin D2 (PGD2), PGE2 or PGF2α were usually found more often in the mucosal extracts. The 12‐hydroxy‐derivative of AA (12‐HETE) was detected in all extracts of the colon but in only some of the other tissues 2 Most prostanoids tested contracted the longitudinal muscle, the order of potency being U‐46619 (an epoxymethano analogue of PGH2)>PGE2>PGF2α>PGD2; PGI2 usually caused relaxation, whereas its breakdown products or TxB2 had weak and variable effects 3 U‐46619 or, less potently, PGF2α contracted the circular muscle, whereas PGI2 and usually PGE2 caused relaxation. PGD2, 6‐keto‐PGF1α, 6, 15‐diketo‐PGF1α or TxB2 usually had little or no effect 4 PGI2 antagonized contractions to some excitatory prostanoids, without greatly affecting contractions to acetylcholine 5 For both muscle layers there was a gradient in sensitivity to prostanoids along the gastrointestinal tract. The sensitivities were stomach>distal ileum>sigmoid colon 6 The results are discussed in relation to gastrointestinal physiology and pathophysiology.

ANTAGONISM OF PROSTANOID‐INDUCED CONTRACTIONS OF RAT GASTRIC FUNDUS MUSCLE BY SC‐19220, SODIUM MECLOFENAMATE, INDOMETHACIN OR TRIMETHOQUINOL

1 The effects of SC‐19220, sodium meclofenamate, indomethacin or trimethoquinol were studied on contractions of the rat stomach longitudinal muscle to prostaglandin D2 (PGD2), PGE2, PGF2α, PGH2, epoxymethano PGH2 analogues, PGI2, 6‐keto‐PGF1α, 6,15‐diketo‐PGF1α and thromboxane B2. All the drugs reduced contractions to all the prostanoids, but the degree of reduction differed widely. Selectivity of blockade was assessed by comparison with acetylcholine (ACh). 2 With SC‐19220 5 μg/ml the effect on thromboxane B2, PGD2 or PGH2 and its epoxymethano analogues was not significantly different from the small effect on ACh, but the other prostanoids were blocked to greater extents. 3 The effect of the cyclo‐oxygenase inhibitor sodium meclofenamate, 1 or 2 μg/ml, on 6,15‐diketo‐PGF1α or thromboxane B2 was similar to the small antagonism of ACh, whereas the other prostanoids were blocked to greater extents. Indomethacin, 1 μg/ml, also reduced contractions to the prostanoids, but antagonism of the PGH2 epoxymethano analogues was considerably less than with meclofenamate. 4 The β‐adrenoceptor stimulant trimethoquinol, 50 ng/ml, was the most potent prostanoid antagonist tested; all the prostanoids except PGE2 were antagonized more than ACh.

Antagonism by fenamates of prostaglandin action in guinea-pig and human alimentary muscle.

1 Low concentrations of meclofenamate, flufenamate or mefenamate had little effect on contractions in response to acetylcholine in any tissue studied. 2 Sodium meclofenamate potently antagonized contractions of guinea‐pig ileum longitudinal muscle to prostaglandin E2 (PGE2), PGF2α or PGD2. 3 In guinea‐pig colonic longitudinal muscle, contractions to PGE2 were reduced by sodium meclofenamate, but contractions of the longitudinal or circular muscle to PGF2α or PGD2 were less effectively inhibited. 4 In human gastrointestinal longitudinal muscle, sodium meclofenamate or flufenamate potently inhibited contractions to PGF2α, but not to PGE2. 5 Sodium mefenamate or mefenamic acid, even in high concentrations, had little effect on contractions to PGF2α, but tended to inhibit PGE2‐induced contractions of human gastrointestinal longitudinal muscle. 6 The therapeutic advantages of prostaglandin synthesis inhibitors which also antagonize responses to certain prostaglandins are discussed.

Regional differences in the responses to prostanoids of circular muscle from guinea‐pig isolated intestine

The effects of prostaglandins (PGs) D2, E2, F2α, an epoxymethano analogue of PGH2 (U‐46619), prostacyclin (PGI2), 6‐keto‐PGFlα and thromboxane (Tx) B2 were tested on spirally‐cut strips of guinea‐pig isolated ileum or colon. In the ileum no prostanoid exerted a marked effect on the resting tissue, but PGD2, PGE2 or PGI2 1 μg ml−1 inhibited submaximal contraction to KC1. U‐46619 1 μg ml−1 either inhibited or increased contractions to KC1, but PGF2α, 6‐keto‐PGF1α or TxB2 1 μg ml−1 had no significant effect. PGE2 relaxed colonic strips whereas the other prostanoids caused contraction, except for TxB2 which had no effect. The PG antagonist SC‐19220 blocked colonic contractions to the prostanoids, and a residual inhibitory effect of PGD2, U‐46619 or PGI2 was demonstrated by the reduction of submaximal contractions to acetylcholine. Our results suggest that prostanoid receptors mediating inhibitory responses of circular muscle predominate in the ileum, whereas in the colon both excitatory and inhibitory prostanoid receptors occur.

The effects of various peptides on human isolated gut muscle

Abstract— The effects of eleven peptides of gastrointestinal origin have been studied on the contraction, relaxation and spontaneous activity of circular and longitudinal muscle strips from different regions of the human gastrointestinal tract. The effects varied with the peptides and sometimes with the region and muscle layer. There was either contraction, no effect, or relaxation and/or inhibition of an acetylcholine‐induced contraction. Responses to some peptides are consistent with the possibility that they may contribute directly to the control of motility: galanin, neurotensin and substance P might be involved in contraction, and vasoactive intestinal peptide, peptide histidine isoleucine and peptide histidine methionine might be inhibitory transmitters.

Secoverine hydrochloride is a muscarinic antagonist in human isolated gastrointestinal muscle and myometrium.

Secoverine is a new antimuscarinic agent thought to be selective for smooth muscle. We have found it to be a potent anticholinergic antagonist of acetylcholine in strips of human gastrointestinal and uterine muscle. The pA2 values in gut longitudinal and circular muscle and myometrium were 9·1, 9·3 and 8·6 respectively.

A prostaglandin analogue which potently relaxes human uterus but not gut muscle

Abstract A prostaglandin analogue, (±)-5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin was tested on strips of human isolated myometrium and gastro-intestinal muscle. The analogue usually caused marked dose-dependent myometrial relaxation and inhibition of spontaneous activity, with a threshold concentration sometimes of 10 pg/ml and a maximum effect at 10 ng/ml. In contrast 1–10 000 ng/ml had no effect on longitudinal muscle strips of human stomach or colon.

PINANE THROMBOXANE A2 ANALOGUES ARE NON-SELECTIVE PROSTANOID ANTAGONISTS IN RAT AND HUMAN STOMACH MUSCLE

1 Pinane thromboxane A2 (PTxA2) and its epi‐OH isomer were studied on rat and human stomach longitudinal muscle. 2 PTxA2 (0.5 μg/ml) usually caused a slight contraction of rat gastric fundus. Contractions to PGE2, PGF2α, PGI2 and expoxymethano analogues of PGH2 (U‐46619 and U‐44069) were substantially inhibited, whereas those to PGD2 and acetylcholine were only slightly reduced. 3 In human stomach, PTxA2 0.5 μg/ml rarely stimulated the muscle. Contractions to PGE2, PGF2α and U‐46619 were antagonized, with little effect on those to acetylcholine. 4 epi‐PTxA2 (0.5 μg/ml) did not affect rat gastric tone. It was moderately potent against PGI2 on rat gastric fundus, but was less effective than PTxA2 against U‐44069.

Identification and Distribution of Arachidonic Acid Metabolites in the Human Gastrointestinal Tract, and the Ways in Which Some of these Affect the Longitudinal Muscle

Prostaglandins (PGs) may have various roles in gastrointestinal function. They have also been implicated as contributors to various gastrointestinal diseases, including gastritis, gastric ulcer formation, ulcerative colitis, irritable bowel syndrome, idiopathic intestinal pseudo-obstruction, food intolerance, and radiation-induced and other forms of diarrhoea (1–8). In contrast, PGs administered as drugs may be useful in the treatment of peptic ulceration, prevention of aspirin- or indomethacin-induced gastric mucosal damage (9) and reversal of post-operative ileus (10). Knowledge of the types of compounds formed from the C20-unsaturated fatty acids eicosatrienoic, eicosatetraenoic (arachidonic) and eicosapentaenoic acids, and their actions on the human gut, is therefore important. Most studies to date have concerned PGE and PGFα compounds, but we have now extended this to include other metabolites of arachidonic acid.

Techniques for Studying Gastrointestinal Motility in Vitro

Many different techniques are used for studying gastrointestinal motility in vitro. Muscle strips and whole segments of stomach or intestine can be studied by adding drugs to the surrounding bathing solution and/or through the vasculature, by electrical stimulation of nerve activity, and during muscle stretch. Responses are usually consistent and reproducible, since the environment of the isolated system is precisely controlled.