Yvan M. Van Maercke

Evidence for nitric oxide as mediator of non-adrenergic non-cholinergic relaxations induced by ATP and GABA in the canine gut.

1 The effects of haemoglobin, and the nitric oxide (NO) biosynthesis‐inhibitors NG‐monomethyl‐l‐arginine (l‐NMMA), its enantiomer d‐NMMA, and NG‐nitro‐l‐arginine (l‐NNA) were investigated on non‐adrenergic non‐cholinergic (NANC)‐mediated relaxation of circular muscle strips of the canine terminal ileum and ileocolonic junction induced by electrical stimulation, adenosine 5′‐triphosphate (ATP), γ‐aminobutyric acid (GABA) and NO. 2 Tetrodotoxin, l‐NMMA and l‐NNA, but not d‐NMMA, inhibited the relaxations induced by electrical stimulation, ATP and GABA, but not those in response to NO. 3 The inhibitory effect of l‐NMMA and l‐NNA was prevented by l‐arginine, but not by d‐arginine. l‐Arginine did not potentiate any of the NANC relaxations. 4 Haemoglobin reduced the relaxation induced by electrical stimulation, ATP and GABA, and abolished those in response to NO. 5 Our results demonstrate that the ATP‐ and GABA‐induced relaxations resulting from stimulaton of intramural NANC neurones, in addition to those induced by electrical impulses, are mediated by NO or a NO releasing substance and thus provide further evidence in support of the proposal that NO is the final inhibitory NANC neurotransmitter in the canine terminal ileum and ileocolonic junction.

The role of nitric oxide in inhibitory non-adrenergic non-cholinergic neurotransmission in the canine lower oesophageal sphincter.

1 The role of nitric oxide (NO) in non‐adrenergic non‐cholinergic (NANC) neurotransmission was studied on circular muscle strips of the canine lower oesophageal sphincter (LOS). Electrical field stimulation evoked frequency‐dependent relaxations, which were resistant to adrenergic and cholinergic blockade and abolished by tetrodotoxin. 2 Exogenous administration of NO induced concentration‐dependent and tetrodotoxin‐resistant relaxations which mimicked those in response to electrical stimulation. 3 NG‐nitro‐l‐arginine (l‐NNA), a stereospecific inhibitor of NO‐biosynthesis, inhibited the relaxations induced by electrical stimulation but not those by exogenous NO or vasoactive intestinal polypeptide (VIP). 4 The effect of l‐NNA was prevented by l‐arginine, the precursor of the NO biosynthesis but not by its enantiomer d‐arginine. 5 Haemoglobin abolished the NO‐induced responses and reduced those evoked by electrical stimulation. 6 Cumulative administration of VIP induced concentration‐dependent relaxations, which were slow in onset and sustained. A complete relaxation to VIP was not achieved and the relaxations were not affected by l‐NNA. 7 In conclusion, our results provide evidence that NANC relaxations are mediated by NO, suggesting NO or a NO releasing substance as the final inhibitory NANC neurotransmitter in the canine LOS.

Bioassay of nitric oxide released upon stimulation of non‐adrenergic non‐cholinergic nerves in the canine ileocolonic junction

1 The release and the nature of the inhibitory non‐adrenergic non‐cholinergic (NANC) neurotransmitter was studied in the canine ileocolonic junction. A circular muscle strip of the canine ileocolonic junction served as donor tissue in a superfusion bioassay in which rings of rabbit aorta with the endothelium removed served as detector tissue. 2 The ileocolonic junction released a labile factor with vasodilator activity upon stimulation of non‐adrenergic non‐cholinergic (NANC) nerves in response to electrical impulses and the nicotinic receptor agonist 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP). This release was respectively frequency‐ and concentration‐dependent. 3 The release was reduced by the blocker of neuronal conductance, tetrodotoxin, and by the inhibitor of the nitric oxide (NO) biosynthesis NG‐nitro‐l‐arginine. The biological activity was enhanced by superoxide dismutase and eliminated by haemoglobin. Hexamethonium abolished only the release in response to DMPP. 4 Injection of adenosine 5′‐triphosphate (ATP) or vasoactive intestinal polypeptide (VIP) onto the cascade induced relaxations of the rabbit aorta but they were different from those induced by NO or the transferable factor. 5 Based on organ bath experiments in which the reactivity of different parts of the circular smooth muscle layer of the ileocolonic junction was investigated, a muscle strip of superficial circular muscle with submucosa was chosen as the detector strip in the bioassay cascade. 6 The ileocolonic junction dose‐dependently relaxed in response to nitroglycerin and NO. NO was much more potent in the rabbit aorta than in the canine ileocolonic junction. Equivalent amounts of the transferable factor, endothelium‐derived relaxing factor and NO, as assessed by the relaxation of the rabbit aorta, failed to affect the ileocolonic junction. 7 In conclusion, our results demonstrate the release of a transferable vasorelaxant factor in response to NANC nerve stimulation which behaves pharmacologically like NO but not like ATP or VIP. Therefore, we suggest that NO or a NO releasing substance is the inhibitory NANC neurotransmitter in the canine ileocolonic junction.

Value of transrectal ultrasonography in Crohn's disease.

Anorectal lesions are common and can develop silently in patients with Crohns disease. Transrectal ultrasound examinations were performed to study 40 healthy individuals and 40 patients with Crohns disease. A rigid linear endorectal probe was used to examine the rectal wall, the perirectal tissues, and the anal sphincter. In healthy individuals, the rectal wall showed five layers with a total diameter of maximum 4 mm. The anal sphincter was clearly visualized as an echo-poor and sharply delineated structure. No pathological lesions were detected perirectally. In Crohns disease, an enlargement of the rectal wall was seen in 16 patients and heterogeneity of the anal sphincter in 19 patients. This technique detected lesions missed with the routine proctological examinations: four pararectal abscesses, two pararectal fistulas, two para-anal abscesses, and one para-anal fistula. In all examined subjects, the anal sphincter increased in breadth during squeezing and in length during straining. It is concluded that transrectal ultrasonography sharply delineates the rectal wall and the anal sphincter at rest and under dynamic conditions and detects unknown abscesses and fistulas in the pararectal and para-anal tissues in patients with Crohns disease.

Prejunctional modulation of the nitrergic innervation of the canine ileocolonic junction via potassium channels

1 The effects of different K+ channel blockers were studied on nitric oxide (NO)‐mediated non‐adrenergic non‐cholinergic (NANC) relaxations in the canine ileocolonic junction. 2 The non‐selective blockers of K+ channels, 4‐aminopyridine (4‐AP) and tetraethylammonium (TEA) and the blocker of large conductance Ca2+‐activated K+ channels, charybdotoxin, potently enhanced the NANC relaxations induced by low frequency stimulation. The blocker of small conductance Ca2+‐activated K+ channels, apamin, had no effect on electrically‐induced NANC relaxations. 3 NANC nerve‐mediated relaxations induced by adenosine 5′‐triphosphate (ATP), acetylcholine (ACh) and γ‐aminobutyric acid (GABA) were significantly enhanced by 4‐AP and charybdotoxin but not by apamin. TEA significantly enhanced the NANC relaxations in response to GABA and ATP while that in response to ACh was abolished. 4 None of the K+ channel blockers had an effect on the dose‐response curve to NO, on the noradrenaline‐induced contraction or on the relaxation to nitroglycerine (GTN). 5 From these results we conclude that inhibition of prejunctional K+ channels increases the nitrergic relaxations induced by electrical and chemical receptor stimulation of NANC nerves and thus suggests a regulatory role for these prejunctional K+ channels in the release of NO from NANC nerves in the canine ileocolonic junction.

Drug-induced gallbladder disease. Incidence, aetiology and management

SummaryA great variety of drugs is reported to induce gallbladder disease by various pathogenetic mechanisms.Early epidemiological studies indicated a doubled risk of gallbladder disease in women taking oral contraceptives. More recent studies, however, have failed to confirm those findings; these conflicting results might be explained by the different methods used to define gallbladder disease. It was shown that the lithogenic index of the bile is increased during intake of oral contraceptives. Estrogens cause hypersécrétion of cholesterol in bile, due to increase in lipoprotein uptake by the hepatocyte. Progesterone inhibits acyl coenzyme A-cholesterol acyl transferase (ACAT) activity, causing delayed conversion of cholesterol to cholesterol esters.Of the lipid lowering drugs, only clofibrate has been shown to increase the risk for gallstone formation. The other fibric acid derivatives have similar properties, but clinical experience is not as extensive. They seem to be inhibitors of the ACAT enzyme system, thereby rendering bile more lithogenic.Conflicting epidemiological data exist regarding the induction of acute cholecystitis by thiazide diuretics.Ceftriaxone, a third-generation cephalosporin, is reported to induce biliary sludge in 25 to 45% of patients, an effect which is reversible after discontinuing the drug. The sludge is occasionally a clinical problem. It was clearly demonstrated that this sludge is caused by precipitation of the calcium salt of ceftriaxone excreted in the bile.Long term use of octreotide is complicated by gallstone formation in approximately 50% of patients after 1 year of therapy, due to gallbladder stasis.Hepatic artery infusion chemotherapy by implanted pump is shown to be associated with a very high risk of chemically induced cholecystitis. Prophylactic cholecystectomy at the time of pump implantation is therefore advocated.Some drugs, such as erythromcyin or ampicillin, are reported to cause hypersensitivityinduced cholecystitis.Furthermore, there are reports on the influence of cyclosporin, dapsone, anticoagulant treatment, and narcotic and anticholinergic medication in causing gallbladder disease.

Clinical significance of focal echogenic liver lesions

During a 4-year period, 53 focal echogenic liver lesions were demonstrated by sonography in 41 patients, in whom there was no evidence of metastatic origin. Most of the lesions were hemangiomas.One of the purposes of this study was to determine the characteristic ultrasound features for liver hemangioma. Small (less than 2 cm), homogeneous, echogenic, well-circumscribed, subcapsular lesions almost prove their hemangiomatous nature. Lesions with a diameter of more than 2 cm are usually more lobulated and heterogeneous. They are located more centrally in the liver and nearly all show a close anatomical relation with 1 of the hepatic veins. Very large lesions (greater than 5 cm) with a heterogeneous and irregular aspect suggest focal nodular hyperplasia, which must be proven by a Tc-isotopic liver scan.

A rare cause of colitis--Brucella melitensis. Report of a case.

Documentation of gastrointestinal lesions inBrucellainfections is sparse. A case ofBrucella melitensistype 3 infection accompanied by erosive lesions of the colon, observed by endoscopy and histopathologic examination, is reported. Such gastrointestinal lesions have not been described since 1934. Before 1934 only postmortem observations are recorded.

Polypoid hamartoma of the jejunum

The authors report an unusual case of jejunal mesenchymal hamartoma which presented as a bleeding pedunculated polyp in a 67-year-old woman. The lesion was detected by enteroclysis and resected after localization by intraoperative endoscopy.