Lennart Jivegård

Enteric nervous system

It is becoming increasingly evident that the nerves of mucosal surfaces may play an important role both during physiological and pathophysiological circumstances. This has, of course, been known for a long time with regard to the skin with its triple reponse. However, research performed during the last decade has shown that this is also true for mucosal membranes. In bronchial asthma, for example, nerves may play an important role in its pathophysiology, explaining the bronchial constriction, hypersecretion, and tissue edema associated with this disease (1). The mucosal lining of the gastrointestinal tract, including the biliary tract, is provided with an extensive nervous supply, the enteric nervous system (ENS). Although known for more than a century, its function has only recently been studied in any detail. This review will deal with our present knowledge of the physiology and pathophysiology of the ENS in the intestines and the gallbladder. The review is divided into two parts, the first being devoted to the intestines and a following one to the gallbladder.It is becoming increasingly evident that the nerves of mucosal surfaces may play an important role both during physiological and pathophysiological circumstances. This has, of course, been known for a long time with regard to the skin with its triple reponse. However, research performed during the last decade has shown that this is also true for mucosal membranes. In bronchial asthma, for example, nerves may play an important role in its pathophysiology, explaining the bronchial constriction, hypersecretion, and tissue edema associated with this disease (1). The mucosal lining of the gastrointestinal tract, including the biliary tract, is provided with an extensive nervous supply, the enteric nervous system (ENS). Although known for more than a century, its function has only recently been studied in any detail. This review will deal with our present knowledge of the physiology and pathophysiology of the ENS in the intestines and the gallbladder. The review is divided into two parts, the first being devoted to the intestines and a following one to the gallbladder.

Fluid secretion by gallbladder mucosa in experimental cholecystitis is influenced by intramural nerves

The normal fluid absorption across the gallbladder mucosa is, in experimental cholecystitis, changed to an active net fluid secretion. This fluid secretion, studied in anesthetized cats, is not abolished by extrinsic gallbladder denervation and is unaffected by atropine but is strongly reduced by intraarterial tetrodotoxin or intraluminal administration of lidocaine hydrochloride. Intravenous somatostatin or hexamethonium administration also reduce this secretion. Indomethacin, known to abolish this fluid secretion, did not further reduce it when administered after nerve blocking agents in the present study. These data demonstrate that the prostaglandin-induced gallbladder fluid secretion in experimental cholecystitis is influenced by intramural nerves. It is suggested that gallbladder inflammation is associated with prostaglandin-induced activation of intrinsic nerves which may stimulate the epithelial cells to fluid secretion. In the obstructed gallbladder, this secretion causes gallbladder distension by increasing the intraluminal pressure. This mechanism may have a key role in the pathophysiology of acute cholecystitis.The normal fluid absorption across the gallbladder mucosa is, in experimental cholecystitis, changed to an active net fluid secretion. This fluid secretion, studied in anesthetized cats, is not abolished by extrinsic gallbladder denervation and is unaffected by atropine but is strongly reduced by intraarterial tetrodotoxin or intraluminal administration of lidocaine hydrochloride. Intravenous somatostatin or hexamethonium administration also reduce this secretion. Indomethacin, known to abolish this fluid secretion, did not further reduce it when administered after nerve blocking agents in the present study. These data demonstrate that the prostaglandin-induced gallbladder fluid secretion in experimental cholecystitis is influenced by intramural nerves. It is suggested that gallbladder inflammation is associated with prostaglandin-induced activation of intrinsic nerves which may stimulate the epithelial cells to fluid secretion. In the obstructed gallbladder, this secretion causes gallbladder distension by increasing the intraluminal pressure. This mechanism may have a key role in the pathophysiology of acute cholecystitis.

The Effects of Morphine and Enkephaline on Gallbladder Function in Experimental Cholecystitis: Inhibition of Inflammatory Gallbladder Secretion

Administration of morphine or its derivatives is the traditional way to treat biliary pain. Despite the common use of morphine and its analogues in patients with cholecystitis and biliary pain, their effects on the function of the inflamed gallbladder are not known. In the present study it is demonstrated that morphine usually contracts the normal gallbladder but does not influence the fluid transport across the mucosa. In experimental cholecystitis morphine and enkephaline do not further contract the gallbladder but, by specific opioid receptors, reduce the inflammatory fluid secretion by the mucosa. In case of obstruction of the gallbladder, fluid secretion by the mucosa will distend its wall and induce biliary pain. It is suggested that the pain-relieving effect of morphine in cholecystitis and attacks of biliary pain is mediated not only by a central analgesic effect but also by an influence on the function of the inflamed gallbladder.

VIP-antiserum inhibits fluid secretion by the inflamed gallbladder mucosa

The inflammatory fluid secretion by the gallbladder mucosa in experimental cholecystitis is induced by an increased prostaglandin formation and is mediated by intramural nerves. In the present study the effect of VIP-antiserum on the inflammatory fluid secretion in the gallbladder was tested in a validated experimental model in cats. The animals were studied in acute experiments 6 weeks after a procedure when the cystic duct was tied and gallstones were implanted in the gallbladder. During basal conditions there was a continuous secretion of fluid into the lumen of the inflamed gallbladder averaging 0.43 +/- 0.18 ml/h. Injection of VIP antiserum, obtained from immunized rabbits and diluted with saline 1:10 in a bolus of 4 ml into the coeliac artery reversed this secretion into an absorption of 1.72 +/- 0.44 ml h-1 (P < 0.001). VIP-antiserum did not affect the fluid adsorption in control animals with an intact gallbladder and injection of control serum from rabbits not immunized to VIP did not affect fluid secretion in the inflamed gallbladders. The results support the idea that the inflammatory fluid secretion in the gallbladder mucosa is mediated by VIP-ergic nerve fibres.

Vasoactive intestinal peptide in the normal and inflamed feline gallbladder

Intravenous infusion of vasoactive intestinal peptide (VIP) causes gallbladder mucosal fluid secretion by an action on epithelial cell receptors in the cat. Gallbladder fluid secretion is observed also in experimental cholecystitis and this secretion is abolished when the intramural gallbladder nerves are blocked. In the present study, immunoreactive VIP was detected in the gallbladder contents (29 +/- 5 (S.E.M.) pM) in the obstructed lumen of the gallbladder in cats with experimental cholecystitis and gallbladder mucosal fluid secretion, but not in the normal feline gallbladder. During luminal perfusion of the gallbladder in vivo, the calculated secretion of VIP into the gallbladder lumen in animals with experimental cholecystitis was significantly higher (0.31 +/- 0.08 (S.E.M.), pmol/h) than in controls (0.11 +/- 0.02 (S.E.M.), pmol/h) while plasma levels of VIP were similar. Recovery of exogenously administered VIP was similar in normal and inflamed gallbladders. The present results support the hypothesis that intramural VIP-releasing nerve fibers may be activated in cholecystitis.

Effects of Intraluminal Prostaglandin E2 In Vivo on Secretory Behavior and Ultrastructural Changes in Mouse Gallbladder Epithelium

It has been suggested that glycoproteins play an important role as a nucleating agent in the pathogenesis of gallstone formation. Arachidonic acid, by an indomethacin-sensitive mechanism, is known to enhance gallbladder mucus release, suggesting that prostaglandins may regulate gallbladder epithelial release of mucus. In this study, the glycoprotein granules of the principal cells of the mouse gallbladder epithelium were morphometrically analyzed using electron microscopy. It was shown that 5 micrograms of prostaglandin E2, injected into the gallbladder lumen of the anesthetized mouse, reduced the relative volume of glycoprotein granules from 3.0% to 0.7% of the cytoplasmic volume within 20 min, whereas injection of the same amount of the solvent for prostaglandin E2 had no such effect.

Inflammation Reduces Mucosal Secretion of Hydrogen Ions and Impairs Concentrating Function and Luminal Acidification in Feline Gallbladder

BACKGROUND The gallbladder mucosa normally absorbs fluid and secretes H+ ions. The fluid secretion in inflamed gallbladders is induced by prostaglandins and mediated by intramural vasoactive intestinal peptide (VIP)-ergic nerves. METHODS The influence of inflammation on gallblader contents due to secretion of H+ into the lumen. In animals with inflamed gallbladder this acid secretion was reduced; there was secretion of HCO3- and no evident acidification of the gallbladder contents. Injection of VIP antiserum or indomethacin restored H+ secretion and inhibited HCO3- and fluid secretion by the inflamed gallbladder mucosa. An impaired acidification of the gallbladder contents due to mucosal inflammation may reduce the solubility of calcium salts in gallbladder bile and increase the risk of their precipitation in the lumen. CONCLUSION Mucosal inflammation reduces H+ secretion and impairs acidification of the gallbladder contents.

Adrenergic Influence on Gallbladder Function in Experimental Cholecystitis

In experimental cholecystitis a net secretion of fluid to the gallbladder lumen is seen in animals with morphological signs of acute inflammation. This fluid secretion, which increases the intraluminal pressure in the obstructed gallbladder, is suggested to be influenced by non-cholinergic intramural gallbladder nerves activated by prostaglandins. In the present study in vivo we show that this fluid secretion, measured by a perfusion technique, is markedly inhibited by electrical activation of the splanchnic nerves that contain adrenergic fibres to the gallbladder and by intravenous administration of an alpha 2-adrenergic agonist, demonstrating that this fluid secretion can be modulated by activation of alpha 2-adrenergic receptors. In patients with an obstructed gallbladder outlet, inhibition of this secretion may reduce gallbladder distension and thus relieve biliary pain. The results suggest that pharmacological activation of adrenergic mechanisms could be useful in the treatment of cholecystitis and biliary pain.

Loperamide inhibits gallbladder inflammatory fluid secretion in experimental cholecystitis.

SummaryFluid secretion by the gallbladder mucosa is suggested to have a key pathophysiological role in acute cholecystitis, since it causes distension of the obstructed gallbladder. The present study investigates the actions of loperamide on the gallbladder function in experimental cholecystitis. Gallbladder fluid transport and motility were studied in vivo with a continuous perfusion technique. A net fluid secretion by the gallbladder mucosa was seen in cats in which cholecystitis was induced whereas there was a net fluid absorption from the gallbladder lumen in the control animals. The net fluid secretion in experimental cholecystitis was inhibited by loperamide (1 mg/kg), an effect that was blocked by naloxone (1 mg/kg), suggesting an involvement of specific opiate receptors. Loperamide (1 mg/kg) relaxed the normal gallbladder but had no significant effects on its fluid absorption. Since loperamide reduces mucosal fluid secretion in experimental cholecystitis without contracting the gallbladder wall, it is suggested that this peripherally acting opiate agonist could be useful in the treatment of patients with acute cholecystitis.