An inhibitory innervation at the gastroduodenal junction.

Transverse muscle strips, 2-mm wide, were cut serially from the gastroduodenal junction in opossums, cats, dogs, and man. Electrical field stimulation with trains of rectangular current pulses of 0.5 ms in all opossums, all cats, some dogs, and the one human specimen induced relaxation in strips from the thickened circular muscle proximal to the mucosal junction. In some opossums weak relaxations also occurred in the first few strips below the mucosal junction. All other strips contracted or showed no response. This relaxation in opossums was abolished by tetrodotoxin but was not affected by antagonists to adrenergic and cholinergic transmission, nor by tripelennamine, methysergide, pentagastrin, secretin, cerulein, or cholecystokinin. Optimal frequency for stimulus-relaxation was 12 Hz. Chronaxie was 0.85 ms. The junctional strips also showed greater resistances to stretch than those remote from the junction. With apparent species variations, the junctional muscle possesses a nonadrenergic inhibitory innervation which is either absent or unexpressed in adjacent muscle of stomach and duodenum. This suggests the existence of a distinctive inhibitory neural control mechanism for pyloric muscle.

Drugs and gastric damage.

The effects of aspirin, salicylate formulations and substitutes, smoking (nicotine), indomethacin, corticosteroids, phenylbutazone, ethanol, caffeine and reserpine on the gastric mucosa are discussed. The damaging effects of the drugs are considered in terms of the gastric mucosal barrier, gastric erosions, microbleeding and haematemesis and melaena and finally whether they cause peptic ulcer. There is suggestive evidence that unbuffered aspirin is a cause of haematemesis and melaena and of gastric ulcer but the incidence rates for hospital admission are low, being 10 to 15 per 100,000 heavy users per year. Aspirin in solution as acetylsalicylate buffered to maintain a neutral pH protects against gastric damage. Newer aspirin substitutes (mefenamic acid, fenoprofen, naproxen, tolmetin and ibuprofen) appear to cause less faecal blood loss than aspirin but their long-term effects have not been fully evaluated. Smoking is definitely associated with peptic ucler but the mechanism is unknown. Corticosteroids are probably not ulcerogenic despite clinical bias that they are. Indomethacin and phenylbutazone may be ulcerogenic but there is insufficient evidence to make firm judgements. Ethanol, caffeine and reserpine, on available evidence, are probably not ulcerogenic.

Laboratory aids in the diagnosis of pancreatitis.

The diagnosis of both acute and chronic pancreatitis continues to be a challenge despite the development of new techniques and the refinement of old methods. The problem is best approached by the application of a combination of tests which can provide a reasonable degree of sensitivity and specificity applicable to the different forms of pancreatitis. In acute pancreatitis an elevation of serum amylase and amylase/creatinine clearance ratio is diagnostically useful. In chronic pancreatitis, several tests are needed to enhance the diagnostic yield, and such tests can include the secretin-pancreozymin test, ERCP, fecal fat measurement, Lundh test meal, and the administration of the synthetic peptide BZ-Ty-PABA.

Gastric damage by drugs and the role of the mucosal barrier.

There are six drugs usually implicated in peptic ulceration and these are adrenal corticosteroids, aspirin, phenylbutazone, indomethacin, ethanol and caffeine. The types of data upon which these conclusions rest follows three lines of evidence. First, the production of ulcers in experimental animals; all the drugs mentioned above can produce experimental ulcers. Second, the cause and effect relationship in man, i.e. epidemiological evidence; the epidemiological evidence is very weak except for aspirin. Third, a mechanism suspected of participating in the pathogenesis; the pathogenesis of drug ulceration is not fully understood but aspirin may be the only one with a body of data to support its ulcerogenic effect. The pathogenesis of peptic ulcer is usually considered in terms of the equation, acid-pepsin versus mucosal resistance. Caffeine is a moderately strong stimulus of acid secretion but corticosteroids, phenylbutazone, ethanol and indomethacin are very weak stimulants or have no effect. Aspirin decreases acid secretion...

Effect of first part of duodenum on gastric emptying in dogs: response to acid, fat, glucose, and neural blockade.

Five dogs were prepared, each with a gastric and duodenal fistula (5 cm distal to the pylorus), to study the inhibitory role of the first 5 cm of the duodenum on gastric emptying. The basic design of the experiments was to instill the test meal (300 ml at 37 degrees C, containing phenol red 40 mg 1(-1)) into the stomach and collect it at 1- or 2-min intervals for 10 or 20 min from the duodenal fistula. As the test meal emptied from the stomach it bathed the first 5 cm of duodenum and thus stimulated the appropriate receptor. A Foley catheter with an inflated balloon prevented passage into the second part of the duodenum. Test meals of hypertonic glucose (15%, 865 milliosmoles kg-1) or 20 and 80 mM of sodium oleate emptied at the same rate as water when allowed to bathe the first 5 cm of duodenum, whereas test meals of 100 mM of HCl were slowed. In further studies using neural blocking agents, the emptying of water meals was slowed with subcutaneous atropine sulfate (0.03 and 0.15 mg kg-1), intravenous hexamethonium chloride (10 mg kg-1), and norepinephrine bitartrate (0.04 mg kg-1). The emptying of 100 to 120 mM HCl meals was slowed by subcutaneous atropine sulfate (0.03 and 0.15 mg kg-1), intravenous norepinephrine bitartrate (0.04 mg kg-1), and the intravenous alpha-receptor blocking agents phenoxybenzamine HCl (2 mg kg-1) and phentolamine (2 mg kg-1), was unaffected by intravenous hexamethonium chloide (10 mg kg-1), and was unchanged (1.0 mg kg-1) or slightly slowed (2.0 mg kg-1) by the beta-receptor blocker propranolol. In contrast, acid test meals were emptied at the same rate as water when treated with intravenous guanethidine monosulfate (2 mg kg-1) or intramuscular reserpine (1 mg kg-1), indicating that the acid inhibition was mediated by an adrenergic mechanism. The emptying of water meals was unchanged by these two drugs. The authors suggest that the first 5 cm of duodenum contain receptors for inhibition of emptying of acid but not for fat or hypertonic glucose. Furthermore, the neural blocking studies indicate that the inhibitory effect of acid in the first part of the duodenum is an adrenergic mechanism which appears to be neither alpha nor beta-receptor-mediated.

Effect of a fixed pyloric opening on gastric emptying in the cat and dog.

The effect of preventing pyloric closure on the rate of gastric emptying without alteration of the gastroduodenal junction was studied in six dogs and four cats with gastric fistulas. Each had a Teflon cannula with an internal diameter of 1.0 or 1.25 cm (dog) and 0.6 cm (cat) sewn into the pyloric channel. At the completion of the initial series of tests, the cannulas were removed and the studies repeated. Test meals were 240 and 480 ml of water, acid (120 mM HC1), and hyperosmotic glucose (555 mM) in the dogs and 50 ml of water, acid (100 mM HC1) and fat (20 mM Na oleate) in the cats. Phenol red was used as a nonabsorbable marker. The residual volumes were collected at 15-40 min in the dogs and 15-20 min in the cats. In both species, the rate of emptying of all the meals was unaffected by the pyloric cannula. In the dog, added secretions were greater with the pyloric cannula in place, suggesting reflux of duodenal contents. This study indicates that while the pylorus is unimportant in the gastric emptying of liquids in the dog and cat, it may have a role in prevention of duodenal reflux.

Gastric and duodenal ulcer and their associated diseases.

Assessments of likely associations between ulcer and other diseases are hindered by the frequent lack of controls, by controls which are inadequate, and by inadequate descriptions of techniques used. The inherent biases in some of the techniques have also probably been insufficiently appreciated. Ulcer is common in the community and much of the evidence adduced to suggest ulcer/other-disease associations may well be describing oridinary ulcer frequency which has been underestimated. With such problems in mind, few of the proposed associations bear examination. Ulcer is probably unusually frequent in patients undergoing treatment for chronic renal failure. It is possibly more frequent in association with hyperparathyroidism and in cirrhotics, in cardiovascular disease (except hypertension), and in chronic respiratory disease. Evidence for other associations is not compelling.

Effect of tryptophan and its metabolites on gastric emptying of liquid meals in dogs.

The effects of tryptophan and its metabolites were studied to determine whether the known inhibiting effect of tryptophan on emptying was due to local or systemic effects or due to tryptophan metabolites. In five dogs with chronic gastric fistulas, instillation of 300 ml of DL-kynurenine (5mM), 5-hydroxytryptophan (mM), or 5-hydroxytryptamine (20 mM) into the gut did not slow gastric emptying. Furthermore, iv infusion of L-tryptophan (5, 20, 50 mM), DL-kynurenine (2, 5, 10 mM), 5-hydroxytryptamine (2mM, 10 mM), and 3-indolepyruvic acid (2, 5, 10 mM) also did not slow gastric emptying. These studies indicate that tryptophan slows gastric emptying by exciting a receptor in the gut and not by a direct effect on the stomach or brain or via its major metabolites.

Aspirin revisited.

ASA is a safe drug to relieve pain, lessen fever, diminish the inflammatory reaction and treat arthritis. This drug can be given to people in a very safe soluble and buffered form which minimizes its major potential side effect: G.I. bleeding. The G.I. bleeding seen with ASA is due to its local effect on the gastric mucosa. The evidence that exists shows that ASA's effect upon the platelet does not contribute to the gastric bleeding. It is unclear to what extent those diseases mediated by thrombosis can be prevented by ASA and other platelet-suppressive drugs. Thrombosis is not equivalent to hemostasis, but is a distortion of the hemostatic process. Clinical trials are now underway but they will probably be inconclusive. Presently, the literature is contradictory and, therefore, the decision to use ASA as an anti-thrombotic durg remains with the individual physician.

Effect of tryptophan on transport properties of newborn rabbit jejunum.

The effect of tryptophan on sodium and chloride fluxes was determined simultaneously on paired flat-sheet preparations of newborn rabbit jejunum under short-circuit conditions. In the absence of amino acids, the newborn rabbit jejunum actively absorbed sodium, and possibly bicarbonate, whereas chloride appeared to be distributed passively across the jejunum. Tryptophan (2 mM) caused an increment in short-circuit current (Isc) that was due to an increase in net active sodium flux and had no significant effect on tissue conductance. At a 10 mM concentration, tryptophan initially increased Isc, although not to as large a degree as phenylalanine or alanine, and then caused a progressive decline that reached a plateau around 60 min. The reduction in Isc was attributed primarily to abolition of sodium absorption and stimulation of chloride secretion. Tryptophan reduced the unidirectional fluxes of sodium, increased those of chloride, and decreased total tissue conductance. These results suggest that 10 mM tryptophan initially causes a predicted increase in sodium absorption, followed by an inhibition of sodium absorption and stimulation of chloride secretion. The mechanism of action of tryptophan resulting in changes in ion fluxes is unknown.

Effects of some gastrointestinal hormones on two muscle layers of duodenum.

The duodenums of opossums and cats were cut into strips 2 mm wide and 2-2.5 cm long. Strips cut in the oral-caudal axis were called longitudinal strips; those cut at 90 degrees to that axis were called circular strips. Cholecystokinin (CCK) and cerulein stimulated phasic contractions of circular muscle of opossum duodenum, but had no effect on the longitudinal muscle. The effect of CCK was not blocked by tetrodotoxin (10(-7)M), indicating a direct muscle stimulation. CCK had no effect of both muscle layers of the cat duodenum. Vasoactive intestinal peptide raised tension in longitudinal muscle, but reduced tension in circular muscle of opossum duodenum. Glucagon slightly reduced tension in both longitudinal and circular muscle of opossum duodenum. It also inhibited contractions of circular muscle caused by acetylcholine. Pentagastrin and secretin had no effect on either muscle layer in either species. These findings suggest that the circular and longitudinal muscle layers of the duodenum respond differently to at least some gastrointestinal hormones. Also, there is species variation in response to gastrointestinal hormones.

Achlorhydria and benign gastric ulcer.

A 76 year-old man with a benign gastric ulcer and pernicious anemia is reported. The etiology of the ulcer is unexplained.

Parallel pathways for ion transport across rat gastric mucosa: effect of ethanol.

Transmural fluxes of 22Na or 36Cl across the isolated rat gastric mucosa were measured simultaneously with [3H]mannitol in an attempt to separate transmural ionic movement into cellular and noncellular components. The relationships between mannitol flux and the fluxes of Na and Cl are characteristic of simple diffusion, suggesting that mannitol traverses the isolated epithelium largely via noncellular pathways. The total tissue conductance can be described as the sum of two components, one of which is highly correlated with the transmural mannitol flux and presumably represents the conductance of a noncellular leak path. The cellular components of the mucosa-to-serosa Na flux and of both Cl fluxes are highly correlated with the short-circuit current. Exposure of the mucosal surface of the epithelium to 4% ethanol reduces the short-circuit current and increases the electrical conductance. Ethanol inhibits the active transport of Na and Cl and increases the apparent permeability of noncellular pathways for transmural ionic diffusion.

Failure of intravenous aspirin to increase gastrointestinal blood loss.

Studies of the effect of intravenous sodium acetylsalicylate (aspirin) on gastrointestinal blood loss with (51)Cr-labelled red cells were made on 15 healthy male volunteers. After a control period of five days 1 g. of sodium acetylsalicylate was infused over a period of 100 minutes twice daily for three days. Faecal blood loss was not increased.In a further six subjects 3 g. of sodium acetylsalicylate was infused over a period of 120 minutes. No salicylate or acetylsalicylate was detected in saliva or gastric washings from these six subjects. Hence gastrointestinal blood loss induced by aspirin may be explained by a local effect on mucosa and not by any systemic effect.

Alcohol, aspirin, and gastrointestinal bleeding.

In 20 healthy male subjects faecal blood loss was measured by means of a chromium-51-labelled red blood cell technique. Mean daily faecal blood loss associated with unbuffered aspirin ingestion was significantly increased by alcohol in the 13 subjects studied. In seven others alcohol alone did not cause gastrointestinal bleeding. These findings suggest that alcohol may accentuate gastrointestinal blood loss associated with unbuffered aspirin ingestion.

Effects of essential and nonessential amino acids on gastric emptying in the dog.

Five dogs with gastric fistulas were studied to assess the effect on gastric emptying of two potent cholecystokinin (CCK) releasers (tryptophan and phenylalanine) and six other essential amino acids; the nonessential amino acids alanine, beta-alanine, arginine, asparagine, aspartic acid, citrulline, cysteine, cystine, glutamic acid, glutamine, D-glutamine, histidine, hydroxyproline, ornithine, proline, serine, tyrosine, and D-tryptophan; four peptide and amino acid preparations; and solutions of glucose, glycine, and mannitol. Of the essential amino acids, only tryptophan significantly slowed emptying and it was above 4 mM that there was a difference between control and test meal. The delay in response to tryptophan was dose-related and approached maximum at 40 mM; D-tryptophan had no effect at these concentrations. In concentrations up to 80 mM, none of the nonessential amino acids slowed emptying significantly. The four peptide and amino acid preparations in concentrations ranging from 80 to 700 milliosmoles had dose responses identical to those of D-glucose, glycine, and mannitol at similar osmolalities. It is concluded that L-tryptophan is a uniquely potent delayer of gastric emptying in the dog which is dose-dependent and stereospecific. Phenylalanine, a potent CCK releaser, did not slow emptying, which suggests that CCK release may not be the only mechanism by which tryptophan acts. The peptide and amino acid preparations (casein hydrolysate, Bacto-peptone, Amigen, FreAmine) seem to delay emptying by stimulation of osmoreceptors which is distinct from the mechanism of action of tryptophan.

A comparison of intrinsic nerve supplies of two muscular layers of duodenum.

The duodenums of opossums and cats were cut into strips 2 mm wide and 2-2.5 cm long. Strips cut in the direction of the oral-caudal axis were called longitudinal strips, and those cut at 90 degrees to that axis were called circular strips. Each muscle strip was stimulated with trains of electrical rectangular pulses (10 Hz, 50-70 V, 0.5 ms). In the longitudinal strips, electrical field stimulation caused contraction, and this contraction was abolished by atropine, 10(-7) M. In the circular strips, electrical field stimulation caused relaxation. This relaxation was abolished by tetrodotoxin, 10(-7) M, but it was not affected by antagonists to adrenergic and cholinergic transmission, nor by some gastrointestinal hormones. Reserpinization of the opossums or alteration of the frequencies of electrical field stimulation from 0.1-50 Hz did not affect or alter the relaxation of the circular strips or the contraction of the longitudinal strips. These findings suggest that the longitudinal muscle is dominated by an excitatory cholinergic innervation, and the circular muscle is dominated by a nonadrenergic, noncholinergic inhibitory innervation.