Remission of diabetes in patients with long-standing type 2 diabetes following placement of adjustable gastric band: a retrospective case control study.

Rates of remission in obese patients with long-standing type 2 diabetes (>2 years), following an adjustable gastric band are unclear. We conducted a retrospective case-control study of patients (n = 89) matched for age and body mass index with non-surgical controls. Cases had a longer duration of diabetes (99 ± 53 and 80 ± 59 months, p < 0.05) and a lower HbA1c than controls (7.9 ± 1.6 vs. 8.5 ± 1.9%, p < 0.05). At follow-up (median 105 weeks) cases had lost 16.8 ± 13.5 kg and controls 1.7 ± 8.9 kg (p < 0.001) and HbA1c decreased by 0.6-0.8% (p < 0.001 for time) with no difference between cases and controls. Diabetes resolution, defined by HbA1c less than 6.5% and taking no medications, occurred in 14 (16%) cases and 2 controls. This is in contrast to published outcomes of resolution of type 2 diabetes after bariatric surgery. We conclude that there is a clear need for randomized studies of the effect of gastric banding in patients with long-standing type 2 diabetes.

Galanin receptor antagonist m35 but not m40 or c7 ameliorates cerulein-induced acute pancreatitis in mice.

BACKGROUND/AIMS: We compared the galanin antagonists C7, M35, M40 and galantide, for their ability to ameliorate acute pancreatitis (AP). METHODS: Galanin antagonists were co-administered with 7 hourly cerulein injections used to induce AP. Plasma amylase and lipase activities were measured as indices of AP, and pancreata were harvested at 12 h for histological examination and estimation of myeloperoxidase (MPO) activity. RESULTS: Treatment with galantide, M35 and C7 ameliorated the AP-induced plasma hyperenzymemia by 40-75%. Administration of M40 did not significantly alter plasma hyperenzymemia. Galantide, M35 and M40 significantly reduced the pancreatic MPO activity by 65-80%, whereas C7 increased MPO activity. Galantide and M35 but not C7 or M40 treatment significantly reduced the AP-induced necrosis score by 30-50% compared to the AP alone group. C7 alone increased plasma lipase activity and the pancreatic necrosis score compared with saline treatment alone, whereas the other antagonists were without effect. CONCLUSION: Galantide and M35 ameliorated the severity of AP, but M40 and C7 had mixed effects. Complex galanin pathways may be involved in cerulein-induced AP. M35 and galantide are potential therapeutic peptides for the treatment of AP and further evaluation should be considered. and IAP.

Associates of change in liver fat content in the morbidly obese after laparoscopic gastric banding surgery.

AIM: Hepatic steatosis affects up to 30% of the population. After weight loss, monitoring of the change in hepatic steatosis is not routinely performed. This study aimed to define the closest associates of change in liver fat content in a population of obese females following laparoscopic gastric banding surgery. METHODS: Before and 3 months after surgery, proton magnetic resonance spectroscopy and magnetic resonance imaging were used to estimate the amount of lipid contained within the liver and abdominal subcutaneous and visceral compartments of 29 obese [mean body mass index (BMI) 39 +/- 5 kg/m(2)], non-diabetic women aged between 20 and 62 years. Liver enzymes, fasting plasma glucose and insulin were also measured as well as body weight, BMI and waist circumference. Insulin sensitivity was estimated using homeostasis model assessment insulin resistance index. RESULTS: Significant reductions occurred in body weight (p < 0.001), abdominal fat volumes (p < 0.001) and liver fat (p = 0.037) 3 months after surgery. Change in liver fat content more closely associated with change in serum gamma-glutamyl transferase (GGT; r = 0.71, p < 0.001) than with changes in weight (r = 0.10, p = 0.612) and waist circumference (r = 0.15, p = 0.468). CONCLUSIONS: Our findings suggest that obese non-diabetic female patients who have undergone significant weight loss over 3 months can be better assessed for the regression of excess liver fat content by monitoring changes in serum GGT levels rather than changes in simple anthropometry.

Relationship of sphincter of Oddi spike bursts to gastrointestinal myoelectric activity in conscious opossums.

The oppossum sphincter of Oddi (SO) exhibits peristaltic spike bursts with accompanying contraction waves that originate proximally in the sphincter of Oddi and propagate toward the duodenum. In this study we recorded myoelectrical activity of the opossum SO and upper gastrointestinal tract in six conscious animals using chronically implanted electrodes. Biopolar electrodes were implanted in the gastric antrum, duodenum, SO segment, jejunum, and ileum. During fasting the frequency of SO spike bursts, scored as number per minute, showed a cyclic pattern consisting of four phases (A to D). Phase A had a low spike burst frequency of approximately 2/min that lasted approximately 20 min. In phase B, the spike burst frequency increased progressively during a 40-45 min interval culminating in a short interval of phase C activity characterized by a maximal spike burst frequency of approximately 5/min. During phase D, the spike bursts decreased over 15 min to merge with the low frequency of phase A and the cycle repeated. Cycle length of the interdigestive SO cycle, 87+/-11 SD min, was virtually identical with that of the interdigestive migrating myoelectric complex (MMC) of the upper gastrointestinal tract. The onset of phase C activity in the SO began 1-2 min before phase III of the MMC activity in the duodenum. Feeding abolished the cyclic pattern of spike burst activity in the SO as well as in the upper gastrointestinal tract. After feeding the SO spike bursts occurred at a frequency of 5-6/min for at least 3 h. We conclude that: (a) During fasting, the oppossum SO exhibits cyclic changes in its spike burst frequency; (b) Maximal spike burst frequency of the SO occurs virtually concurrent with passage of phase III MMC activity through the duodenum and; (c) Feeding abolishes the interdigestive cyclic spike burst pattern of the SO as well as that of the gastrointestinal tract.

Motor function of the opossum sphincter of Oddi.

We studied the opossum sphincter of Oddi (SO) because in this species the SO is approximately 3 cm in length and its extraduodenal location permits recording of motor activity with negligible interference from duodenal motor activity. The SO segment of 120 animals was evaluated by one or more of the following: (a) intraluminal manometry; (b) electromyography; (c) common bile duct (CBD) flow monitored by a drop counter; (d) cineradiography of intraductal contrast medium; and (e) histologic examination. SO pull-throughs using an infused catheter of 0.6-mm o.d. invariably showed a high pressure zone (HPZ) of 18 +/- 3 SE mm Hg in the terminal 4-5 mm of the SO segment. This HPZ had a narrow lumen, 0.5-0.7 mm in diam, and prominent circular muscle. The HPZ in the terminal SO had both active and passive components. HPZ with minimal amplitude and a paucity of underlying smooth muscle were present inconstantly at the junction of the SO segment with the CBD and pancreatic duct, respectively. The dominant feature of the SO segment was rhythmic peristaltic contractions that originated in the proximal SO and propagated toward the duodenum. These contractions occurred spontaneously at a rate of 2-8/min, ranged up to 200 mm Hg in magnitude, had a duration of approximately 5 s and were not abolished by tetrodotoxin. Concurrent myoelectric and manometric recordings showed that each phasic contraction was immediately preceded by an electrical spike burst. Simultaneous recordings of cineradiography, CBD inflow of contrast medium, SO manometry, and SO electromyography indicated that rhythmic peristaltic contractions stripped contrast medium from the SO into the duodenum. During SO systole, CBD emptying was transiently interrupted, whereas SO filling occurred during the diastolic interval between SO peristaltic contractions. SO distention increased the frequency of SO peristalsis. We conclude that (a) the dominant feature of the opossum SO is rhythmic peristaltic contractions that originate in the proximal SO and propagate toward the duodenum; (b) these forceful SO peristaltic contractions are myogenic in origin and serve as a peristaltic pump that actively empties the SO segment; (c) CBD outflow occurs passively during SO diastole, but is interrupted transiently during each SO peristaltic contraction; and (d) a short HPZ with active as well as passive components exists in the distal SO segment and acts as a variable resistor to SO outflow.

Selective iNOS inhibition enhances spontaneous gallbladder motility in the Australian possum.

Gallbladder inflammation is a common and painful disease. Inducible nitric oxide synthase (iNOS) plays a major role in inflammatory diseases, and iNOS inhibitors are being developed as therapeutic agents. Reports are inconsistent regarding iNOS expression in normal gallbladder. The aim of this study was to determine the effect of iNOS inhibition on spontaneous gallbladder motility. mRNA extracted from normal possum gallbladders was analysed by PCR. Gallbladder contractility was evaluated using a highly selective iNOS inhibitor AR-C102222AA (AR-C) in in vitro muscle strips (0.1-10 000 microm) and in vivo (0.1-30 micromol kg(-1)) experiments. Gene expression analysis revealed the presence of iNOS mRNA in normal gallbladder (n = 3). In vitro, AR-C (0.1-1000 micromol L(-1)) produced a concentration-dependent increase in spontaneous gallbladder contractile activity and basal tension (P < 0.05; n = 6). The maximum effect was a 1.8-fold increase in activity and 2.1-fold increase in basal tension. Pretreatment of muscle strips with tetrodotoxin (1 micromol L(-1)) did not block the AR-C-induced response (n = 5). In vivo, AR-C (30 micromol kg(-1), i.v.) increased gallbladder contraction frequency (P < 0.05; n = 8). These data suggest that iNOS is continually expressed in the normal gallbladder, which presumably releases low levels of nitric oxide and in turn may modulate spontaneous gallbladder motility. AR-C may be a beneficial treatment for patients suffering from acute cholecystitis.

Sphincter of Oddi function in the Australian brush-tailed possum is inhibited by intragastric ethanol.

The role of sphincter of Oddi (SO) function in alcoholic acute pancreatitis (AP) is unclear. We aimed to compare the effect of i.v. and intragastric (IG) ethanol on SO function (i.e. trans-sphincteric flow; TSF) and investigate possible neural mechanisms. The involvement of gastric mucosal damage was also investigated by pretreatment with pantoprazole. In anaesthetized Australian possums, blood pressure (BP), TSF and blood ethanol concentrations were measured after i.v. or IG ethanol. Possums were subjected to acute vagotomy, atropine, L-nitro arginine methyl ester (L-NAME) or pantoprazole pretreatment prior to IG ethanol. BP was not significantly altered by ethanol. Ethanol decreased TSF in a dose and route-dependent manner. The lowest dose of IG ethanol reduced TSF but this response was not duplicated by i.v. ethanol producing the same blood ethanol concentrations. Acute vagotomy, atropine or L-NAME pretreatment blocked the ethanol-induced decrease in TSF and simultaneously suppressed the blood ethanol concentration. Pantoprazole pretreatment reduced the TSF response and blood ethanol concentrations implicating mechanisms induced by gastric mucosal damage. We conclude that ethanol (and/or its metabolites) reduces TSF via humoral and neural mechanisms involving vagal pathways, muscarinic receptors and nitric oxide. Reduced TSF could contribute to the onset of AP.

Exogenous purines induce differential responses in the proximal and distal regions of the possum sphincter of Oddi.

1. The aim of this study was to compare the effect of exogenous ATP and adenosine on spontaneous motility of the proximal and distal regions of the possum sphincter of Oddi (SO). 2. ATP or adenosine (1 microm-1 mm) was applied to distal-SO or proximal-SO muscle rings in organ baths in the absence or presence of tetrodotoxin (TTX) or P1/P2 antagonists. 3. Both ATP and adenosine altered spontaneous activity, predominantly in proximal-SO rings. 4. Exogenous ATP induced a bi-phasic response consisting of a brief TTX-sensitive excitatory component, and a longer-lasting TTX-insensitive inhibitory component. 5. The excitatory ATP response likely involves P2X receptors, whereas the late inhibitory response likely involves P2Y receptors. 6. Exogenous adenosine decreased spontaneous SO activity, via a TTX-insensitive mechanism. 7. Exogenous purines modulate SO motility, acting primarily in the proximal region of the SO, via neural and non-neural mechanisms and multiple purine receptor subtypes.

Surgical versus endoscopic treatment of bile duct stones.

BACKGROUND: 10% to 18% of patients undergoing cholecystectomy for gallstones have common bile duct (CBD) stones. Treatment options for these stones include pre- or post-operative endoscopic retrograde cholangiopancreatography (ERCP) or open or laparoscopic surgery. OBJECTIVES: To systematically review the management of CBD stones by four approaches: (1) ERCP versus open surgical bile duct clearance. (2) Pre-operative ERCP versus laparoscopic bile duct clearance. (3) Post-operative ERCP versus laparoscopic bile duct clearance. (4) ERCP versus laparoscopic bile duct clearance in patients with previous cholecystectomy. SEARCH STRATEGY: We systematically searched key relevant electronic databases, bibliographies of relevant papers, and abstracts of relevant subspecialty meetings until November 2005. SELECTION CRITERIA: The quality of included trials was assessed by adequacy of allocation sequence generation, allocation concealment, blinding, and follow-up. DATA COLLECTION AND ANALYSIS: Published and unpublished data relevant to 12 predefined outcome measures were used to conduct fixed- and random-effects models meta-analyses, with exploration of heterogeneity and use of sensitivity and subgroup analysis where required. MAIN RESULTS: Thirteen trials randomised 1351 patients. Eight trials (n = 760) compared ERCP with open surgical clearance, three (n = 425) compared pre-operative ERCP with laparoscopic clearance, and two (n = 166) compared post-operative ERCP with laparoscopic clearance. There were no trials of ERCP versus laparoscopic clearance in patients without an intact gallbladder. Methodology was considered adequate in at least two of three assessable fields in ten trials. A significantly increased number of total procedures (including for complications) per patient was seen in the ERCP arms in all three comparisons with weighted mean differences of 0.62 (95% CI 0.15 to 1.09), 0.96 (95% CI 0.96 to 0.96), and 1.09 (95% CI 0.93 to 1.24), respectively. ERCP was less successful than open surgery in CBD stone clearance (Peto OR 2.89, 95% CI 1.81 to 4.61) with a tendency towards higher mortality (risk difference 1%, 95% CI -1% to 4%). Laparoscopic CBD stone clearance was as efficient as pre- (Peto OR 1.00, CI 0.53 to 1.80) and post-operative ERCP (OR 2.27, 95% CI 0.37 to 13.9) and with no significant difference in morbidity and mortality. Laparoscopic trials universally reported shorter hospital stays in surgical arms. Insufficient data were reported for cost analysis. AUTHORS' CONCLUSIONS: In the era of open cholecystectomy, open bile duct surgery was superior to ERCP in achieving CBD stone clearance. In the laparoscopic era, data are close to excluding a significant difference between laparoscopic and ERCP clearance of CBD stones. The use of ERCP necessitates increased number of procedures per patient.

Pancreatobiliary afferent recordings in the anaesthetised Australian possum.

The sensory innervation to the pancreatobiliary system is poorly characterized. Afferent signals from the gastrointestinal tract and biliary tree are transmitted to the central nervous system via the vagus and spinal nerves. We aimed to record afferent discharge in order to characterize the vagal and splanchnic afferent signals from the possum upper gastrointestinal tract, biliary tree and pancreas. In 21 anaesthetised possums nerve fibres were teased from the vagus or splanchnic nerve for multi-unit recording. Mechanical stimuli consisted of balloon distension of the gallbladder and duodenum (2-7 ml) and fluid distension (0-20 mm Hg) of the bile or pancreatic ducts. Approximately 60% of fibres from all nerves displayed spontaneous discharge. Spinal afferent responses to mechanical stimuli were infrequent (n=13). Increased discharge occurred in response to duodenal (12/99 fibres) or gallbladder (7/96 fibres) distension, but not to bile duct (0/73 fibres) or pancreatic duct (0/51 fibres) distension. Vagal afferent responses to distension of the duodenum or stomach (5-30 ml) were more common (n=8). Increased discharge was recorded in response to duodenal (49/134 fibres), or gastric (22/70 fibres) distension. Responses to gallbladder distension were less frequent (6/99 fibres) and as with the spinal afferent no response to bile duct (0/66) or pancreatic duct (0/70) distension were recorded. We conclude that mechanosensitive afferents in the pancreatobiliary system are relatively rare, particularly within the ducts, and/or that they are adapted to monitor stimuli other than luminal distension.

Innervation of the sphincter of Oddi: physiology and considerations of pharmacological intervention in biliary dyskinesia.

The sphincter of Oddi is a small sphincter which is strategically placed at the junction of the bile duct and pancreatic duct with the duodenum. It regulates the flow of bile and pancreatic juice into the duodenum and prevents reflux of duodenal contents into the ducts. The structure of the sphincter of Oddi differs from species to species and consequently its physiological action varies in different species. Anatomical and immunohistochemical investigations have demonstrated that the sphincter of Oddi is richly innervated by cholinergic, adrenergic and peptidergic neurons. In addition, neural connections exist between the sphincter, gallbladder and proximal gastrointestinal tract. These nerves in addition to hormones are important in the control of sphincter of Oddi motility and function. The normal human sphincter of Oddi is characterized by prominent phasic contractions which are superimposed on a modest basal pressure. These contractions are present throughout the interdigestive period. The contractions and basal pressure are inhibited by ingestion of a meal or infusion of cholecystokinin octapeptide, thus enhancing the flow of bile and pancreatic juice into the duodenum. Sphincter of Oddi dysfunction has been described in patients who present with recurrent biliary type pain and no evidence of a structural cause for the pain. Motility disorders characterized as an elevated basal pressure, rapid contraction frequency, paradoxical response to cholecystokinin octapeptide or excess of retrograde contractions have been identified. A number of pharmacologically active substances have been used in an attempt to treat these patients. Such pharmaceuticals include nitrites, Ca2+ channel blockers and smooth muscle relaxants. Their effect is transient and side effects relating to cardiovascular actions preclude their longterm use. Division of the sphincter either endoscopically or by open operation has been demonstrated by prospective clinical trials to be the most efficacious treatment for patients with a stenosed sphincter manometrically demonstrated by a high basal pressure. Improved understanding of the controlling mechanisms of sphincter of Oddi motility and the pathophysiology of sphincter of Oddi dysfunction should assist in the development of effective pharmacotherapy for these disorders.

The sphincter of Oddi: understanding its control and function.

The most common functional disorders of the biliary tract and pancreas are associated with disordered motility of the sphincter of Oddi (SO). The SO is a neuromuscular structure located at the junction of the bile and pancreatic ducts with the duodenum. The primary functions of the SO are to regulate the delivery of bile and pancreatic juice into the duodenum, and to prevent the reflux of duodenal contents into the biliary and pancreatic systems. Disordered motility of the SO leads to the common and painful clinical conditions of SO dysfunction and acute pancreatitis. In order to understand normal SO motility, studies have been performed addressing SO function, control of spontaneous SO activity, responses to bioactive agents, SO innervation, and reflexes with other gastrointestinal organs. These studies have led to the current understanding of how the SO functions and may permit the development of targeted therapy for SO dysfunction and acute pancreatitis. This review summarizes the current knowledge regarding the control and regulation of SO motility, highlighting laboratory based and clinical research performed over the last 5 years.

A2A and A3 receptors mediate the adenosine-induced relaxation in spontaneously active possum duodenum in vitro.

1. The aim of this study was to define the P1 purinergic receptors that regulate spontaneous or adenosine-induced duodenal motor activity. 2. Spontaneous contractile activity was recorded isometrically from possum longitudinal duodenal muscle strips. Adenosine (0.5 micro M-1 mM) was administered noncumulatively and repeated after pretreatment with a P1 antagonist or tetrodotoxin (TTX, 1 micro M), (n=4-7). Antagonists used were: A(1), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 10 nM); A(2A), 8-(3-chlorostyryl)caffeine (CSC, 10 micro M); A(2B), 3-isobutyl-8-pyrrolidinoxanthine (IPDX, 10 micro M); A(3), 9-chloro-2-(2-furanyl)-5-[(phenylacetyl) amino][1,2,4]-triazolo(1,5-c)quinazoline (MRS1220, 10 micro M). Changes in activity are expressed as percentage of baseline. Statistical analysis utilised nonparametric tests. 3. Adenosine (n=34) induced a long-lasting, concentration-dependent decrease in activity by 55.6+/-3.2% area under curve (AUC), 47.3+/-4.0% contraction amplitude, 31.6+/-3.6% basal tension and 10.4+/-1.7% contraction frequency (all P<0.001). The adenosine-induced decrease in contraction amplitude was blocked by CSC (P<0.01) or inhibited by MRS1220 (P<0.03) pretreatment, but not modified by TTX, DPCPX or IPDX pretreatment. 4. Adenosine antagonists modified spontaneous contractile activity. Pretreatment with DPCPX or CSC increased basal tension, whereas IPDX or MRS1220 pretreatment decreased contractile activity. 5. In conclusion, exogenous adenosine reduced duodenal longitudinal motor activity via A(2A) and A(3) receptors. Our findings suggest that endogenous purines may modulate spontaneous duodenal motor activity.

Early results of laparoscopic swedish adjustable gastric banding for morbid obesity

AIMS: Gastric bypass and vertical banded gastroplasty (VBG) are currently the most commonly performed bariatric procedures but neither are ideal. The results of the first 56 patients who had laparoscopic Swedish adjustable gastric banding (SAGB) are presented. METHODS: All patients referred for bariatric surgery were considered for SAGB. Each was given the alternative of gastric bypass. Patients with a body mass index of less than 35, large hiatus hernia, under 18 years of age, gastric pathology and significant psychiatric illness were excluded. Preoperative gastroscopy, ultrasonographic examination of the gallbladder and specialist anaesthetic assessment were arranged. All but five patients had attempted laparoscopic procedures. Patients were discharged when they were mobile and could tolerate 1500 ml fluid per day. Patients were given a liquidized diet for 6 weeks. Assessments were made at 6 weeks and 3, 6, 9 and 12 months. RESULTS: Some 56 consecutive patients were followed for up to 12 months. The conversion rate fell from 52 per cent for the first 25 patients to 20 per cent for the last 20. Conversion rates were higher in men and in superobese patients. The duration of a laparoscopic operation fell significantly with experience but was still significantly longer than that of an open procedure (P < 0.004). The length of hospital stay was significantly shorter for laparoscopic procedures (P < 0.001). There was no death and little morbidity. Two bands had to be removed (easily) by open surgery, one for infection and one for a recurrence of gastric herniation. The mean excess weight loss was 60 per cent at 12 months. Greater than 50 per cent of excess body-weight was lost by 48 per cent of patients at 6 months and 69 per cent at 12 months. Band adjustments in most patients achieved further weight loss to compensate for late pouch dilatation. Most failures were in patients who failed to attend. CONCLUSION: SAGB appears to have many advantages over gastric bypass and VBG; it avoids stapling the stomach, should not cause any malabsorption, can be performed laparoscopically, is adjustable, is more readily reversed (if necessary) and, therefore, has the potential for lower associated morbidity and mortality rates. In terms of excess weight loss, the early results are certainly as good, if not better, than those of gastric bypass and VBG.

Inhibition of sphincter of Oddi motility in Australian possum by cholic acid.

The effect of intravenous administration of cholic acid on sphincter of Oddi (SO) and gallbladder motility was studied. Bolus doses of cholic acid, 20 to 60 mg/kg, produced inhibition of SO wave frequency, a fall in gallbladder pressure and enhanced bile flow. However, hydrocortisone, 10 and 20 mg/kg, produced comparable elevation in bile flow with no effect on SO and gallbladder motility. The effect of cholic acid on SO motility was not influenced by prior treatment with atropine. Phentolamine or propranolol administration did not influence SO wave frequency SO wave frequency, but subsequent injection of cholic acid resulted in a decrease in SO wave frequency. Gallbladder pressure was not influenced by atropine, phentolamine, or propranolol, and these agents did not influence the cholic acid-induced fall in gallbladder pressure. These findings suggest that bile acids influence the motility of the biliary tract.

Action of cholecystokinin-octapeptide on sphincter of Oddi basal pressure and phasic wave activity in humans.

The human sphincter of Oddi (SO) exhibits phasic wave activity over a 4 to 6 mm segment. Approximately 60% of these waves occur in an antegrade direction, 14% are retrograde, and 26% occur simultaneously. Because cholecystokinin-octapeptide (CCK-OP) stimulates the flow of bile into the duodenum, its effect on SO phasic wave contractions and contraction sequences was evaluated at ERCP manometry. An infused triple-lumen catheter of 1.7 mm outer diameter with side orifices spaced 2 mm apart was stationed in the SO segment so that all three orifices recorded phasic pressure waves. We studied 31 patients with normal ductal anatomy and normal SO pressures. In 21 of these patients CCK-OP (20 ng/kg) was given intravenously after a 2- to 3-minute baseline recording was obtained. Pressure recordings were continued for up to 10 minutes following CCK-OP administration. CCK-OP caused a significant inhibition in the frequency and amplitude of SO phasic waves as well as a significant decrease in basal SO pressure. Before CCK-OP most phasic contractions were antegrade, and after CCK-OP the sequence pattern remained unchanged. We conclude that CCK-OP reduces or transiently abolishes SO phasic contractions but that it does not change their temporal sequence. In addition, CCK-OP produces a decrease in basal SO pressure. These findings suggest that the action of CCK-OP in humans is to inhibit SO phasic activity and reduce SO basal pressure to allow increased flow of bile.

Galanin modulates sphincter of Oddi function in the Australian brush-tailed possum.

The neuropeptide galantin (GAL) is found in neurons in the biliary tract of several species. We mapped the distribution of GAL-like immunoreactive nerve (GAL-LI) fibers in the sphincter of Oddi of the Australian brush-tailed possum by immunohistochemistry. The pharmacological effects of GAL in vitro and in vivo were studied by measuring sphincter of Oddi muscle strip contractility and transsphincteric flow, respectively. Muscle layers, and ganglionated and perivascular plexuses, contained GAL-LI nerve fibers. Exogenous GAL caused a concentration-dependent (10(9)-10(-6)M) increase in the spontaneous longitudinal but not circular muscle contractions. At 10(-6) M GAL, contractile activity was elevated two- to fourfold. This response was tetrodotoxin insensitive but competitively inhibited by galantide (10(-8)-10(-7) M). In vivo, intra-arterial bolus injections of GAL (1001000 ng/kg), decreased transsphincteric flow, with a maximum reduction to 80.2 +/- 6.8% of control. In conclusion, GAL appears to selectively stimulate longitudinally oriented sphincter of Oddi smooth muscle via a direct mechanism, which results in a modest reduction in transsphincteric flow.

Endothelin-1 induces contraction of human and Australian possum gallbladder in vitro.

BACKGROUND: Endothelin-1 (ET-1) stimulates guinea pig gallbladder (GB) muscle strip contractility; however, the role and source of ET-1 in the GB remains to be elucidated. AIMS: To determine the effect of ET-1 on human and possum GB muscle strip contractility and evaluate whether ET-1 is present in GB tissue. METHODS: GB muscle strips were mounted in organ baths to measure isometric tension. ET-1 was added cumulatively with and without pretreatment with the neural blocker tetrodotoxin (TTX) or the ET receptor antagonists BQ-123, BQ-788, and tezosentan. Immunohistochemical localization of ET was performed on freshly fixed and cultured GBs. RESULTS: ET-1 induced concentration-dependent increases in tone in human and possum GB strips (p<0.05). This response was unaffected by BQ-123, BQ-788, and TTX but antagonized by BQ-123+BQ-788 in the human tissue only. Tezosentan (10(-4) mol/l) blocked the ET-1-induced response in human and possum GB strips (p<0.001). Although ET immunoreactivity was absent in freshly fixed possum GB, immunoreactivity was observed in the GB epithelium of freshly fixed human tissue and in both possum and human tissue following 24 h of organ culture. CONCLUSION: ET-1 acts directly on human and possum GB smooth muscle producing contractions, possibly via ET-B receptors. ET may be present under pathophysiological conditions altering GB function.

Characterization of the intrinsic and extrinsic innervation of the gall bladder epithelium in the Australian Brush-tailed possum (Trichosurus vulpecula).

Intrinsic neurones of the gall bladder modulate its function. Nitric oxide synthase (NOS) and vasoactive intestinal polypeptide (VIP) are present in gall bladder neurones and nitric oxide and VIP modulate its epithelial functions. As an extensive extrinsic innervation of the gall bladder is also present, the source of the epithelial innervation is unclear. In this study the source of the gall bladder epithelial innervation is defined. Immunoreactivity for VIP, NOS, substance P (SP), calcitonin gene related peptide (CGRP) and tyrosine hydroxylase (TH) in organotypic cultured and freshly fixed gall bladder were compared. Retrograde tracing in vitro from the epithelium was used to identify putative intrinsic secretomotor neurones, which were then characterized by immunohistochemistry. Abundant spinal afferent and sympathetic innervation of the gall bladder epithelium was demonstrated by CGRP/SP and TH immunohistochemistry, respectively. The intrinsic secretomotor innervation of the epithelium is derived exclusively from neurones of the subepithelial plexus. A majority of these neurones were immunoreactive for NOS. Some of the NOS-immunoreactive neurones of the subepithelial plexus also contained VIP and/or SP. Gall bladder subepithelial plexus neurones, containing NOS and/or VIP/SP, innervate the epithelium, as do extrinsic neurones.

Endothelin-1 stimulates sphincter of Oddi motility and decreases trans-sphincteric flow: a possible mechanism contributes to cholestasis in disease states.

Endothelin-1 (ET-1) is a potent stimulator of gallbladder contractility. Its role in modulation of sphincter of Oddi (SO) motility and trans-sphincteric flow (TSF) has not been evaluated. To characterize the effects of ET-1 on SO motility and TSF, 10 anaesthetized Australian possums (in vivo, n = 6) were given graded doses of ET-1 (5-200 pmol kg-1) via closed intra-arterial injection. Blood pressure, TSF and SO motility (basal pressure, phasic amplitude, contraction frequency) were analysed. For in vitro studies, eight SO rings were subjected to 10-12-10-7 mol L-1 cumulative concentrations of ET-1 in organ bath and SO motility was measured. Data are expressed as mean +/- SEM. Statistical analysis used anova. ET-1 induced a dose-related increase in blood pressure with a maximal increase of 37.5 +/- 2.5 mmHg at 200 pmol kg-1, (P < 0.001). ET-1 also increases SO basal pressure (P < 0.001) and contraction frequency (P < 0.0001). However, the contraction amplitude was not significantly affected. ET-1 decreased TSF in a dose-related manner (P < 0.001) with cessation of TSF at the highest dose (P < 0.001). In vitro studies showed a significant increase in mean SO motility index, and frequency of contractions at higher ET-1 concentrations (10-9-10-7 mol L-1). ET-1 is a potent stimulator of SO motility resulting in a reduction in TSF.