Physiology of the sphincter of Oddi--the present and the future?--Part 1.

The mechanisms controlling the sphincter of Oddi (SO) have received considerable attention over the past two decades. Progress towards their elucidation has been slow, perhaps because of the sphincter's relative inaccessibility and the different responses of the human "resistor" as compared to the "pumper" observed in several animal models. The list of agents affecting the sphincter grows alarmingly. In this review, divided into two parts, substances have been classified as neurotransmitters, hormones, local factors and pharmacological agents. The first part considers the roles of neurotransmitters. These include (a) vasoactive intestinal polypeptide (VIP) and nitric oxide (NO). Both cause relaxation. A recent model of their complex interrelationships in smooth muscle is described. (b) Substance P (SP) and enkephalins. These produce contractions. The former can act directly. An indirect effect via cholinergic neurones may be the result of SP release from vagal afferents. (c) Catecholamines, which cause contraction or relaxation via activation of alpha- or beta-adrenoreceptors, respectively. In the second part attention is focussed on cholecystokinin (CCK) which normally relaxes the SO via neuronal mechanisms. A CCK-sensitive pathway from sensory duodenal neurones to SO ganglia has been described. Reactive oxygen species are among the local factors discussed. Their description as being "the good, the bad and the ugly" seems merited. Pharmacological agents include NO donors, octreotide and botulinum toxin (BTX). Octreotide induces tachyoddia and may impair biliary flow. BTX has exciting potential in the diagnosis of SO abnormalities and as a therapeutic alternative to sphincterotomy. In both parts of the review current concepts of different aspects of smooth muscle control are presented. In several instances data regarding the SO is lacking. We discuss (a) the role of interstitial cell of Cajal in the control of slow waves, (b) different pathways contributing to tonic and phasic contractions, (c) the 4 levels of neural control, (d) interrelationships of immune and nervous systems, and (e) links between emotional states and gut functions.

The physiology of the biliary tree. Motility of the gallbladder--part 1.

An incomplete picture has emerged of the complex means by which gallbladder motility is controlled under normal and pathophysiological conditions. In the first part of this review an overall account is presented. The mechanisms of cholecystokinin release, its stimulation by dietary factors and peptides elaborated by both pancreas and small intestine are discussed. The inhibition of cholecystokinin release by bile acids and proteases is also described. In the second part attention is focussed on other peptides affecting motility. These include (a) octreotide, effective for treatment of acromegaly, (b) peptide YY, contributing to a "colonic brake', (c) motilin. associated with interdigestive contractions, analogues of which possibly correct gallbladder hypomotility, and (d) substance P and calcitonin gene-related peptide, which facilitate ganglionic transmission after release from extrinsic sensory neurones and alter gallbladder responses to vagal stimulation. The sympathetic nervous system and diabetes mellitus also influence vagal responses. The former, acting presynaptically, may provide a "brake" to prevent vagal overactivity. The latter could cause hypomotility via autonomic neuropathy, although hyperglycaemia, itself, may play a role. The role of nitric oxide, released from neurones also producing vasoactive intestinal peptide is recognized. Both lengthen muscle, the former producing responses without requiring plasma membrane receptors. Gallbladder motility also changes during pregnancy and stone formation. Progesterone and cholesterol can limit G protein actions, thus impairing contractions. Inflammation is associated with abnormal motility. The production of reactive oxygen metabolites, acting directly or releasing prokinetic prostaglandins, may be responsible. It has been proposed that the gastrointestinal tract may be normally in a state of controlled inflammation, primed to react to harmful challenges.

Swallowing-induced cardio-respiratory responses in man.

Swallowing transiently increases heart rate. One of the authors developed pronounced bradycardia while breath holding, particularly after an expiration. The objective, therefore, was to study his cardiac responses during swallowing as pronounced bradycardia developed. When, after a maximum inspiration (supine), the heart rate slowly fell below 50 beats min' well-defined P waves (lead II) disappeared. By swallowing 6 times on command after the P waves disappeared his heart rate increased immediately (68 +/- 1 beats min(-1); n=6). P waves with similar morphology to those pre-swallowing were recorded 0.7 +/- 0.1 s (n=6) after the first swallow. He continued breath holding after swallowing. P waves again disappeared, although at faster heart rates (57 +/- I beats min(-1); n=6). Furthermore, well-defined P waves were observed after the second disappearance at heart rates within the range 30-40 beats min(-1). Small amplitude P waves continued to be recorded from lead I with P wave disappearance in lead II, suggesting a pacemaker shift, although not to the av node. Autonomic nerves can shift the dominant pacemaker within the sa node. The present report indicates that increased vagal tone may be rapidly reversed by swallowing.

Breast consciousness in American society and it's effect on the American woman's adaptation to mastectomy.

The American Cancer Society estimates that more than a hundred thousand American women develop breast cancer every year. Mastectomy is the treatment of choice. While this surgery performs a gratifying service by saving a woman's life, her appreciation is muted by the price she must pay--the loss of a breast and permanent disfigurement. Within the value system of American culture, that price is a considerable one. This paper will attempt to interpret that cost.

Effect of actively transported hexoses on afferent nerve discharge from rat small intestine.

1. The afferent discharge of mesenteric nerves has been recorded while perfusing salines of different composition through the lumen of rat ileum. The p.d. across the ileum and hexose absorption have also been measured. 2. The ileal mesenteric nerves were sensitive to actively transported hexoses. The discharge recorded increased dramatically on perfusion with 10 or 50 mM-glucose, quietening within 3 min of returning to glucose-free saline. A similar response was obtained with galactose. 3. No change in afferent discharge could be detected on perfusion of mannitol or the slowly transferred hexose, mannose. It is concluded that the response to glucose and galactose is not dependent on the stimulation of non-specific luminal osmoreceptors. 4. Phlorhizin prevented glucose from increasing the afferent nerve discharge. Subsequent perfusion with saline removed the phlorhizin and an afferent nerve response to glucose was restored. It is concluded that this response requires glucose transfer beyond the phlorhizin-sensitive glucose entry mechanism at the luminal side of the mucosal epithelial cell. 5. Very small amounts of glucose or galactose were absorbed under the conditions employed. The time course for the change in p.d. correlated well with that described for the alteration in afferent nerve discharge. 6. Electron micrographs show that ileal nerves consist of bundles of small non-myelinated fibres of approximately 1 micron diameter. 7. The significance of the findings is discussed remembering that carbohydrate absorption is considered to be completed normally in the jejunum.

The effect of bradykinin on the electrical activity of rat jejunum.

Bradykinin increased the potential difference across both the jejunum and colon of the rat. This effect was significantly reduced by indomethacin, suggesting that it was mediated by prostaglandins. The possibility that bradykinin may contribute to the diarrhoea of the carcinoid syndrome by inducing a net secretory state in the intestine is discussed.

The role of acetylcholine in the regulation of ion transport by rat colon mucosa.

1. Acetylcholine increases the potential difference across rat proximal colon both in vivo and in vitro.2. There is a sigmoid relationship between the change in potential difference and the logarithm of the dose of acetylcholine. The dose-response curve is shifted to the left by neostigmine and to the right by atropine, suggesting that the action of acetylcholine is mediated by a muscarinic type of receptor.3. The dose-response curve for acetylcholine in vivo is not altered by the ganglion-blocking agents hexamethonium and pentolinium, suggesting a direct effect of this transmitter on the colon.4. Acetylcholine causes an increase in potential difference, a small decrease in resistance and hence a rise in the current generated by both normal and stripped everted sacs of rat colon.5. In the absence of sodium, the calculated current change produced by acetylcholine is reduced, and the removal of chloride has a similar inhibitory effect. The absence of bicarbonate does not significantly affect the response.6. Acetylcholine virtually abolished net sodium movement and induced net chloride secretion and these changes accounted for the increased short-circuit current.7. Acetylcholine had no effect on oxygen consumption by rings of colon.8. Tracts staining for acetylcholinesterase were observed running from the submucous plexus towards the mucosal epithelium.9. This study shows that acetylcholine can influence ion movement by rat colonic mucosa and suggests that the autonomic nervous system might be involved in the regulation of transport mechanisms in this tissue.

Extracellular polysaccharide from the black yeast NRRL Y-6272: improved methods for preparing a high-viscosity, pigment-free product.

When the extracellular polysaccharide from the black yeast NRRL Y-6272, composed of two parts N-acetyl-D-glucosamine and one part N-acetyl-D-glucosaminuronic acid, is isolated at maximum culture viscosity, adhering black pigment gives the polysaccharide preparations a gray-to-black appearance. Precipitation of the polysaccharide from cell-free culture supernatants with either ethanol of hexadecyltrimethylammonium bromide failed to remove the pigment. Various other methods were therefore tried for obtaining a high-viscosity polysaccharide product free of pigment. By systematically varying ingredients of defined and semidefined media, an improved medium was found that not only gave polysaccharide preparations of increased viscosity, but also increased yield. A key ingredient in this medium is L-asparagine. Also, adding autoclaved bovine serum albumin or egg albumin to this medium at the time of inoculation allowed a pigment-free polysaccharide to be isolated by standard procedures. None of several other proteins of synthetic polyamides tested were as effective as bovine serum albumin or egg albumin. In an alternate approach, pink mutants obtained by irradiation of the parent black strain with ultraviolet light, apparently produce the same extracellular polysaccharide free of any pigment but in lower yields or inferior in quality.

The effect of fasting on hexose transfer in rat intestine.

1. A technique has been developed whereby accurately defined segments of rat intestine can be isolated in vivo, and this technique was used to study the influence of fasting on hexose transport.2. In the distal ileum the transport of glucose and galactose was stimulated by fasting. The effect was specific as neither amino acid transport nor the permeability of the luminal membrane of the absorbing epithelium was altered by fasting. The increased hexose transport was accompanied by a reduced accumulation of hexose in the gut wall. In the proximal jejunum hexose transport was not stimulated by fasting.3. The results of in vitro experiments show the relative importance of hexose metabolism in providing energy for transport in different regions of the small intestine in both fed and fasted animals. In conditions where hexose metabolism was reduced, e.g. by fluoride, the proximal jejunum behaved more like the distal ileum and a stimulation of hexose transport in response to fasting was demonstrable in vivo.4. Motility studies showed that phenol red introduced into the stomach reached the ileum sooner, achieved a higher concentration and remained there for a longer period of time in the fasted animal.5. The changes in carbohydrate metabolism, hexose transport capacity and gastrointestinal motility are discussed in relation to adaptations of the rat to fasting.

Metabolism and transfer of choline in hamster small intestine.

1. The transfer and metabolism of choline was studied with sacs of everted intestine of hamster.2. Approximately half the choline transferred from the mucosal fluid may be metabolized. High voltage electrophoresis, paper chromatography and ion exchange chromatography have been used to identify this meta bolite as betaine.3. The concentration of choline and betaine together accumulating in the gut wall and serosal fluid are greater than that of choline present initially in the mucosal fluid indicating some kind of specific mechanism for choline transport.4. A detailed analysis of choline transfer suggests that the movement of choline cannot be accounted for by simple diffusion. The concentration of choline accumulating in the gut wall and serosal fluid, the inhibitory effects of hemicholinium-3 and alpha-methylglucoside on choline transfer, and the insensitivity of betaine transfer to hemicholinium-3 suggest a specific active transport process for choline independent of active betaine transport.