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To further clarify the relationship between physical-chemical characteristics of bile acids and biliary lipid secretion, we investigated the effect of ursocholic acid, the 7 beta-hydroxyepimer of cholic acid, on bile lipid secretion and composition. The study included acute duodenal infusion (1 g/h for 5 h) of ursocholic acid contrasted with a less hydrophilic bile acid, ursodeoxycholic acid, in 3 T-tube patients and short-term oral administration (2 wk) of ursocholic acid (10-15 mg/kg X day) to 10 gallstone patients. Following acute infusion, ursocholic acid, similarly to ursodeoxycholic acid, accounted for greater than 80% of the biliary bile acids. However, ursocholic acid induced (per micromole of secreted bile acid) a significantly lower (p less than 0.01) secretion of cholesterol (0.013 mumol) and phospholipids (0.054 mumol) than that induced by ursodeoxycholic acid (0.034 mumol of cholesterol and 0.138 mumol of phospholipids). Biliary alkaline phosphatase activity during ursocholic acid administration was significantly lower (p less than 0.01) than during ursodeoxycholic acid administration. After short-term oral administration, ursocholic acid, undetectable before treatment, constituted 20.50% +/- 8.60% of the biliary bile acids. The percentage of deoxycholic acid increased from 32.35% +/- 18.79% to 47.53% +/- 16.19% (p less than 0.05). Mean saturation index decreased from a pretreatment value of 1.23 +/- 0.22 to 0.99 +/- 0.17 (p less than 0.05), but only in 4 of 10 subjects did bile become undersaturated. It is concluded that ursocholic acid, due to its higher hydrophilicity, stimulates a lower cholesterol and phospholipid output than ursodeoxycholic acid. Consequently, despite the low enrichment of the biliary bile acids with ursocholic acid, oral administration of ursocholic acid induces a reduction of bile cholesterol saturation.

The profile of the spasmolytic 4,4-diphenyl-N-isopropyl-cyclohexylamine-hydrochloride (pramiverine, Sistalgin) is outlined on the basis of fundamental research. Evidence is provided that a combination with metamizole is useful in the case of Sistalgin comp. Description of the clinical and clinico-experimental examinations confirmed the margin of indications for Sistalgin and Sistalgin comp. Reference is made to the applications with a view to facilitate endoscopic and radiological procedures. The tabulated list of 2368 patients demonstrates the positive ratio between therapeutic effect and undesirable cholinolytic concomitant effect of Sistalgin comp.

Effects of cisapride on the motility of the digestive tract in vivo in dogs and the guinea-pig intestine in vitro were studied. Cisapride (0.05-2.0 mg/kg, i.v.) produced an increase in amplitude of spontaneous contractions and basal tone in the stomach, duodenum, jejunum and proximal and distal colon in dogs. In some animals, however, it induced an inhibition with decrease in amplitude and tone. It also induced an increase in amplitude of contractions in the gallbladder and the sphincter of Oddi in dogs. The tone of the gallbladder was elevated by the same dose of cisapride, but the tone of the sphincter of Oddi was decreased. The drug produced a reverse response in some animals. These excitatory responses to cisapride were abolished by atropine (0.2 mg/kg, i.v.). Motility of the guinea-pig isolated ileum and colon was enhanced with an increase in their amplitude of contractions and basal tone at low concentrations of cisapride (10(-9)-10(-6)M) but it was inhibited at higher concentrations (10(-5)-10(-4)M). Atropine abolished the excitatory response of the ileum to cisapride in all cases. It abolished the excitation of the colon in some preparations but reduced only in some degree in the other. The inhibitory effect of cisapride on isolated preparations was unaffected by tetrodotoxin. From these results, it is concluded that cisapride enhances motility of the gastrointestinal tract and biliary tract by acting on myenteric cholinergic neurons and inhibits it by acting on the smooth muscle itself.

The effect of Rowachol (200 mg tid), an essential oil preparation, on biliary lipid secretion and serum lipids was measured in six healthy male volunteers before and after four weeks of treatment. Biliary cholesterol and phospholipid secretion increased significantly from 113 +/- 36 (SD) mumol/h to 155 +/- 52 mumol/h (p less than 0.05) and from 409 +/- 145 mumol/h to 587 +/- 185 mumol/h (p less than 0.05), respectively. Bile acid secretion increased from 1519 +/- 662 mumol/h to 2287 +/- 1175 mumol/h (p greater than 0.05 and greater than 0.10). This marked increase in biliary lipid secretion was not followed by a change in molar composition of biliary lipids and lithogenicity of bile. Serum cholesterol and triglycerides declined from 4.9 mmol/l to 4.1 mmol/l (p less than 0.05) and from 1.2 mmol/l to 0.9 mmol/l (p less than 0.05) respectively. The ratio of high-density-lipoprotein cholesterol to total cholesterol increased from 0.22 to 0.31 (p less than 0.05). Although it has been shown previously that Rowachol could dissolve cholesterol gall stones the present results indicate that Rowachol alone has only weak litholytic properties, at least in normal volunteers, but might have several advantages when combined with chenodeoxycholic or ursodeoxycholic acid.

The availability of selective beta-receptor agonists such as terbutaline is a stimulus to research dealing with various beta-receptor functions. The aim of such work is to demonstrate the physiological importance of the hormonal or nervous activation of receptors and to establish a scientific basis for therapeutic trials with beta-receptor active drugs. A brief account is given of the therapeutic possibilities as related to certain beta-receptor functions in the biliary tract, the urinary tract, the lung and the uterus. It is concluded that many beta-receptor functions can be described as therapeutically interesting. The practical importance of beta-agonist therapy is at present confined to relatively few organs, in particular the lung and the uterus.

A review of the techniques and presentation of a new method.--Cholangiomanometric techniques and methods described in the literature are reviewed, with particular reference to their associated anaesthesiological and pharmacological problems. Original physiological concepts are relied on in a proposal for the adoption of a new intraoperative method with pharmacological tests and specifically direct to functional evaluation of Oddi's sphincter as a means of determining indications for surgery.

Bilary re-excretion of sulfobromophthalein sodium (BSP) (1.2 mumol/rat) after retrograde intrabilary injection is markedly inhibited by dehydrocholate sodium (Decholin) given intravenously as a constant infusion (3.1 mumol/min/kg body weight) or as a bolus injection (24.8 mumol/rat) to rats. Most interestingly Decholin demonstrates the same inhibitory effects on the biliary re-excretion of BSP when it is administered by retrograde intrabiliary injection (24.8 mumol/rat) together with the dye. In contrast to the inhibition of biliary re-excretion of BSP its biliary reabsorption from the biliary tract seems to be rather increased: about 80-85% of 1.2 mumol BSP are reabsorbed in all sets of experiments with Decholin in comparison to about 65% to the control group. Combined with histological data it is suggested that reabosorption of BSP after retrograde intrabiliary injection occurs at the ductular site whereas re-excretion takes place at the cannalicular membrane of the hepatocyte.

The effect of i.v. administration of bilirubin on biliary phospholipid secretion was studied in sham operated and two-thirds hepatectomized Wistar rats. Following bilirubin infusion at 260 nmol/100 g body wt/min, a maximal biliary bilirubin excretion was reached in the sham operated rats. No modifications of bile flow or bile acid secretion appeared, but biliary phospholipid secretion was significantly inhibited. At 12 and 24 h after hepatectomy, the maximal bilirubin excretion was markedly lowered but biliary phospholipid secretion still remained significantly inhibited. The infusion of taurocholate at 200 nmol/100 g body wt/min counteracted the impairment of phospholipid secretion, both in sham operated and hepatectomized animals. Bile acid secretions more than two-fold that of the controls were needed to reach half maximal biliary phospholipid secretion in bilirubin-infused animals, with or without the addition of taurocholate.

Previous studies in this laboratory demonstrated incorporation of manganese (Mn) and bilirubin (BR) in rat liver bile canalicular membrane (BCM) following a cholestatic regimen composed sequentially of Mn plus BR. The present study investigates biliary tree permeability using segmented retrograde intrabiliary injection (SRII) with [3H]mannitol and [3H]inulin as marker substances. Male Sprague-Dawley rats were given the following iv: (a) Mn (high and low dose), (b) BR, (c) sulfobromophthalein (BSP), (d) Mn-BSP-BR, (e) MnBR. Results obtained with mannitol showed a approximately 63% decrease (p less than 0.05) in marker recovery following administration of MnBR combination. While BSP alone had no effect on mannitol recovery, BSP abolished the MnBR response when administered in the Mn-BSP-BR sequence. With inulin, Mn (high dose), MnBR, and Mn-BSP-BR all produced a approximately 45% decrease (p less than 0.05) in recovery, while BSP or BR alone caused a approximately 25% decrease (p less than 0.05). Mn (low dose) was without effect. These results and others obtained when the time pattern of the MnBR treatment was modified suggest: (1) MnBR treatment increases biliary tree permeability by altering both BCM and the junctional complex; (2) BCM alteration is probably the more critical event, since BSP, which protects against MnBR cholestasis, protected against the MnBR-induced change in mannitol recovery, but exerted no effect on inulin recovery.

Ceruletide, a decapeptide, is a potent cholecystokinetic agent with a direct spasmogenic effect on the gallbladder muscle and bile ducts in humans and animals. It was recently approved by the Food and Drug Administration for use as an adjunct in x-ray examination of the gallbladder and small bowel. The drug causes a coordinated propulsive activity from the duodenum to the ileum and segmenting activity in the colon. Because of this stimulatory effect, ceruletide is useful not only diagnostically as an aid in x-ray examination of the small bowel, but also therapeutically for treatment of postoperative ileus, intestinal atonia, and chronic fecal statis. Because of its pancreatic stimulatory action, it is useful in evaluation of exocrine pancreatic function. In therapeutic doses the adverse effects noted are mild, transient extensions of the drug's pharmacologic actions and are manifest as nausea, vomiting, abdominal pain, and rarely hypotension and tachycardia. On the basis of current evidence, ceruletide is a safe and effective cholecystokinetic agent and small bowel and exocrine pancreatic stimulant.

The effects of morphine on the terminal bile duct (terminal cavity and ampulla) and gallbladder were investigated in vitro. Morphine, above 10(-7) M, inhibited spontaneous contraction of the terminal cavity and ampulla. The contraction evoked by transmural stimulation, which was inhibited by atropine and tetrodotoxin, was dose dependently suppressed by morphine above 10(-10) M in the amp]ulla, and above 10(-8) M in the terminal cavity. Morphine did not affect the acetylcholine (ACh)-induced contraction, but reduced the contraction evoked by 5-hydroxytryptamine (5-HT) which was suppressed by atropine. In the gallbladder, morphine did not affect the spontaneous contraction, or the contraction evoked by transmural stimulation, ACh, or 5-HT. The 5-HT-induced contraction was not affected by atropine. The results show that morphine reduces acetylcholine release from cholinergic neurons in the terminal bile duct, but not in the gallbladder. The contraction induced in gallbladder by 5-HT was not mediated by cholinergic neurons.

A variety of different methods have been used for the measurement of pressures during operations on the biliary tract. However, there are few data on the experimental evaluation of the methods, and there has been no controlled comparative evaluation of the most commonly used techniques. In these experiments, we have compared the manometric technique of Caroli, the syringe barrel method of Daniel and White et alii, and the constant infusion apparatus of Cushieri. The experiments were performed in pigs because of the similarity of their biliary tract to that of man. Resting and opening pressures were recorded, and flow into the duodenum via the ampulla was measured simultaneously. The manometric and syringe barrel techniques gave highly reproducible measurements of resting and opening pressure, and valid measurements of opening pressure. The constant infusion apparatus gave reproducible measurements of resting pressure, but did not measure opening pressure. The manometric technique was shown to measure changes in the resistance of the choledochoduodenal junction in response to morphine and atropine.

Potentiation of haloalkane hepatonecrosis by various ketones is a well-documented observation. The present study investigates the hepatobiliary effects of such treatments. Male Sprague-Dawley rats were pretreated with acetone (A), 2-butanone (MEK), 2-hexanone (MBK), 15 mmol/kg (po), or chlordecone (CD) and its nonketonic analog, mirex (M), 50 mg/kg (po). Following the pretreatment at various time intervals ranging from 10 to 96 hr, groups of animals received a challenging dosage of CHCl3 (0.5 ml/kg, po). In a collateral experiment, groups of animals were pretreated with vehicle and 18 hr later received either 0.50, 0.75, or 1.00 ml/kg CHCl3 (po). In each case hepatobiliary function was evaluated 24 hr later using bile flow rate and plasma bilirubin concentration. The results showed (1) that the ketones alone had no effect; mirex alone increased bile flow; (2) CHCl3 alone had no effect on bile flow but slightly increased plasma bilirubin; (3) all pretreatments potentiated the effect of CHCl3 on plasma bilirubin; (4) combinations of A, MBK, or CD plus CHCl3 were cholestatic within a restricted time frame. A study of biliary tree permeability by the segmented retrograde intrabiliary injection technique, using mannitol and inulin as marker compounds, suggested that cholestasis may result from potentiation of CHCl3-induced alterations in canalicular membrane permeability.

This paper reviews the principal effects of phenobarbital on biliary function. Phenobarbital administration is followed by an increase in bile flow. This is mainly due to an increase in the bile salt-independent fraction of canalicular bile flow possibly through an increase in canilicular Na+-K+ ATPase activity. In addition, bile salt excretion may be increased. This effect of barbiturates on choleresis appears to be independent of microsomal enzyme induction. Barbiturates increase the uptake, storage and excretion of various dyes, for example sulfobromophthalein. Phenobarbital increases bilirubin clearance by the liver; it enhances bilirubin-UDP-glucuronyl transferase activity; whether the influence on bilirubin clearance is related to the effect on the enzyme is unknown. The influence of phenobarbital on biliary lipids is markedly different from one species to the other. In the rhesus monkey and in the rat, the relative concentration of cholesterol is decreased; in the hamster it is increased, and in man it appears largely unaffected. These effects of phenobarbital have been utilized in the treatment of chronic unconjugated hyperbilirubinemia and of certain cholestatic syndromes. Phenobarbital alone has been useful, so far, in the treatment of cholesterol gallstones.

Despite wide variations in bile secretion and biliary tract capacitance, the pressure in the bile ducts is fairly constant. Recent studies have demonstrated that both inhibitory and excitatory nerves regulate the activity of the sphincter of Oddi. In the present study, it was consistently found that the resistance by the choledochoduodenal junction to a constant flow, within the physiologic range of hepatic bile output, is reduced when the hydrostatic pressure in the gallbladder and bile ducts is increased from 0 to 10, 0 to 15, and 0 to 20 cmH2O. This response was eliminated by tetrodotoxin or infiltration of the junction between the common bile duct and the cystic duct by mepivacaine, a local anesthetic. The results suggest a homeostatic mechanism during the interprandial periods, when the activity of the sphincter of Oddi is regulated by the distending pressure in the biliary tract. This reflex regulation is mediated by modulation of the activity of inhibitory nerves running along the common bile duct.

Male Sprague-Dawley rats were treated ip on Day 0 with 0, 20, 50, or 100 micrograms/kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and biliary tree permeability was evaluated on Days 2, 4, 7, 10, 14, or 20 by segmented retrograde intrabiliary injection of [3H]sucrose or [14C]mannitol. Seven days after 100 micrograms/kg TCDD, the percentage recovery in bile of both [3H]sucrose (73.9 +/- 4.2 vs 27.6 +/- 7.6, control vs TCDD, means +/- SE) and [14C]mannitol (22.7 +/- 2.2 vs 12.1 +/- 2.2) was decreased, demonstrating that the permeabilities of both the intracellular (canalicular) and paracellular pathways were increased. Seven days after 50 micrograms/kg TCDD, the recovery of [3H]sucrose was decreased (73.5 +/- 5.4 vs 39.0 +/- 2.8) but the recovery of [14C]mannitol was not (25.5 +/- 1.5 vs 22.9 +/- 1.9). Thus, an increase in paracellular permeability is obtained at a lower dose of TCDD. In rats treated with 100 micrograms/kg TCDD on Day 0, co-treatment with chlordecone (15 mg/kg/day on Days 2-6) or thyroxine (50 micrograms/kg on Day 2) had no effect. Pregnenolone-16 alpha-carbonitrile (75 mg/kg/day on Days 4-6) treatment increased [14C]mannitol recovery in both TCDD and control groups; its effect must not be specific. Methimazole given in drinking water (0.5%) on Days -7 through 7 reversed the increased permeability effects of TCDD (100 micrograms/kg) without affecting the biliary tree permeability ([14C]mannitol recovery) of control animals.

There is evidence that increased availability of taurine enhances the proportion of taurine-conjugated bile acids in bile. To explore the possibility that taurine treatment could also influence hepatic cholesterol and bile acid metabolism, we fed female hamsters for 1 week and measured both the biliary lipid content and the microsomal level of the rate-limiting enzymes of cholesterol and bile acid synthesis. In these animals the cholesterol 7 alpha-hydroxylase activity was significantly greater in respect to controls (P less than 0.05). The total HMG-CoA reductase activity, as well as that of the active form, was similarly increased. The stimulation of 7 alpha-hydroxycholesterol synthesis was associated with an expansion of the bile acid pool size in taurine-fed animals. Taurine feeding was observed to induce an increase in bile flow as well as in the rate of excretion of bile acids, whereas the secretion rate of cholesterol in bile was decreased. As a consequence, the saturation index was significantly lower in taurine-fed animals (P less than 0.05). The possible mechanisms through which taurine exhibits the modification of the enzyme activities and of the biliary lipid composition are discussed.

Butorphanol, levo-N-cyclobutylmethyl-3,14 beta-dihydroxy-morphinan, is a new agonist-antagonist type analgetic agent which is 4 to 8 times more potent than morphine in experimental animals and man. Butorphanol and morphine were evaluated in mice and dogs for their gastrointestinal and biliary tract smooth muscle effects. Morphine decreased the propulsion of a charcoal meal through the gastrointestinal tract of the mouse in a dose related manner with the maximal inhibition obtainable being 90%. Butorphanol produced a maximal inhibition of motility of only 40% with very high doses producing less of an inhibitory effect than lower doses. In dogs, morphine caused a dose-dependent increase in duodenal smooth muscle activity and a dose-dependent decrease in bile duct flow. A clinically effective i.v. dose of morphine (0.1 mg/kg) produced a statistically significant spasmogenic effect on dog biliary tract and gastrointestinal smooth muscle, while a clinically effective equianalgetic i.v. dose of butorphanol (0.025 mg/kg i.v.) had little or not effect on the biliary or gastrointestinal systems. These findings indicate that at equianalgetic doses, butorphanol should produce less constipation and less biliary tract and gastrointestinal smooth muscle spasm than morphine.

Effect of the infusion of glycodeoxycholate (GDC), taurocholate (TC) and dehydrocholate (DHC) on bile flow and on bile salt, biliary lipid and bile pigment secretion, has been studied in pentobarbital-anesthetized rabbits. GDC increased bile flow the most, while DHC increased it more than TC. The different choleretic actions of these bile salts cannot be explained by means of variations in their capacity to form micelles. Only GDC and TC were able to stimulate biliary lipid secretion, which suggests that both bile salts increase the formation of mixed micelles. GDC and TC to a lesser extent increased bile pigment excretion, DHC being without effect. These results favour the hypothesis that micellar binding could be an important factor responsible for the effect of bile acids on bile pigment excretion and should not be completely ruled out.

The effects of the phenothiazine derivative metopimazine on the spontaneous or induced activities of guinea-pig isolated stomach and of the rabbit biliary and intestinal tracts were studied. A predominant inhibitory effect was observed except for the circular muscle layers of the duodenum and colon where activation appeared. Evidence from in vitro experiments suggest that metopimazine exerts an inhibitory action partly through a direct effect on smooth muscle cells and partly by reducing stimulated acetylcholine release (at least in the stomach). Finally the involvement of a non-adrenergic, non-cholinergic inhibitory system is postulated.

The spasmolytic activity of 3-butoxy-1-phenoxy-propanol-(2) (febuprol) on the biliary tract is demonstrated in two different experimental arrangements in anesthetized dogs. This effect on the spasm provoked by morphine or prostigmine is illustrated by measuring the alteration of pressure in the choledochal duct. The spasmolytic efficacy of febuprol is significant and indicates a favourable secondary therapeutic effect of this substance.

To study the mechanism of salicylate-induced choleresis in rhesus monkeys, we utilized animals with indwelling common bile duct catheters under phencyclidine anesthesia. Bile flow, [14C]erythritol clearance (an estimate of canalicular flow), and bile acid secretion were measured during baseline and for 1 1/2 hr during salicylate infusion. Bile flow increased from 91.2 +/- 7.3 ml/24 hr (SEM) to 180.1 +/- 8.0 ml/24 hr (P less than 0.001) with salicylate infusion and [14D]erythritol clearance from 114.5 +/- 8.9 ml/24 hr to 222.3 +/- 10.7 ml/24 hr (P less than 0.001), but bile acid secretion was unchanged, suggesting increased bile acid-independent canalicular bile flow. Salicylate concentration in bile averaged 1.48 +/- 0.08 mmol/liter, and salicylate concentration in extra bile produced by salicylate was unlikely to result in chloeresis of the magnitude observed. [3H]inulin bile-plasma ratios, measured in these same studies, were unchanged after salicylate administration, suggesting that permeability of the biliary tree was not altered. Bile lipid secretion, like bile acid secretion, was unchanged after salicylate administration, so no change occurred in the lithogenic index of the bile. These results demonstrate that salicylate is a potent choleretic in rhesus monkeys because of enhancement of bile acid-independent bile flow. Salicylate produced no change in the lithogenic index of the bile.

The effect of the long-acting somatostatin analogue Sandostatin (SMS 201-995) on intestinal absorption and propagation (mouth-to-caecum transit time; MCTT), on pancreatic secretion and on gall bladder contraction after direct (secretin-pancreozymin test) and indirect stimulation (Lundh meal), and on meal-induced responses of seven gastrointestinal regulatory peptides has been investigated. In a double-blind cross-over study, 9 healthy volunteers completed two 7-day periods with subcutaneous injections of either placebo or 25 micrograms SMS 201-995 twice daily. Mean faecal fat excretion was increased to 19.2 g/day and MCTT was three times longer during the SMS period. After duodenal infusion of a mixture containing D-galactose, D-xylose and triglycerides, SMS 201-995 significantly reduced the serum concentrations of D-galactose but increased serum levels of D-xylose. After 6 days of pretreatment, SMS 201-995 completely suppressed duodenal trypsin, lipase and bilirubin increases in response to endogenous stimulation by a Lundh meal. Concomitantly, cholecystokinin (CCK) release and gall bladder contraction were almost abolished. Compared with placebo, SMS 201-995 significantly diminished pancreatic amylase, trypsin and lipase output after stimulation with CCK, while the secretion of fluid and bicarbonate in response to secretin was unchanged. This inhibition of enzyme response was significantly more marked after a single injection of the analogue than after pretreatment for 7 days and did not reach the level of exocrine pancreatic insufficiency. CCK-induced gall bladder contraction was significantly inhibited by a single dose of 25 micrograms SMS 201-995 but not after 7 days of pretreatment with the somatostatin analogue.

The distribution and excretion of an intravenously injected, radioactive biliary contrast medium (Ioglycomate) were studied in the mini-pig after the induction of choledochal, thoracic duct and gall bladder fistulae. The investigations were carried out with free lymph and bile flow during artificial cholestasis and after occluding both ureters. Following intravenous injection of 0.24 to 1.0 ml. Bilivistan, there was a cholersis up to six times original value. Ther thoracic duct lymph showed only a small volume rise. The lymphatic circulation played no significant quantitative role in contrast distribution of Ioglycomate in the animal, nor did it influence the blood clearance curves. During normal bile flow, only 1.3% of the injected dose appeared in the thoracic duct within three hours, and during acute biliary obstruction, only 2.6%. The investigations have indicated a biliary transport maximum Ioglycomate in the mini-pig of 2.9 mg./min./kg. body weight. If the excretory capacity of the liver is exceeded and during cholestasis there is compensatory excretion of the biliary contrast medium through the kidneys.

The interaction of various cholecystokinin (CCK) peptides with the protein inhibitor (PK-I) of cyclic AMP dependent protein kinase (A-PK) has been studied. The order of the affinities (ED50) for relaxation of hog biliary muscle by a series of C-terminal peptides of CCK correlated with the order of the potencies for A-PK-catalyzed phosphorylation of the sarcoplasmic reticulum enriched fraction (SR-F) in the muscle. CCK-4 peptide inhibited the PK-I of A-PK. The apparent Km value of the peptide was 11.5 microM. Scatchard plot analysis for the binding of [14C]CCK-6 peptide to the PK-I showed a dissociation constant (Kd) of 11.2 microM. These results indicated that the Kd value agreed with the ED50 value of CCK-6 and the Km value of CCK-4. It is proposed that a receptor for CCK C-terminal peptides is probably a component in the PK-I; binding of the peptides to this site usually results in the relaxation by these allosteric inhibitors of the PK-I.

The study was undertaken to assess the effects of glucagon on biliary tract opacification during intravenous cholangiography. Two series of infusion cholangiograms were obtained at two investigating centres designated A and B. In series A, 41 patients had ioglycamide infusions at a rate of 0.2833 g min-1 over 1 h. In series B, 31 patients had ioglycamide infusions at a rate of 0.3886 g min-1 over 30 min. Radiographs were taken in both series, immediately at the end of the infusion, 10 min later and 30 min after the infusion. Two mg of intravenous glucagon was injected into alternate cases in both series A and B immediately after the first radiograph was taken at the completion of the ioglycamide infusion. Two observers in each series than assessed the radiographic opacification of the biliary system without prior knowledge of which patients had received the glucagon. Delineation of the biliary system was considered better in both series in those patients who received glucagon when compared with the controls. Gallbladder opacification was definitely increased in series A in those receiving glucagon, and a similar tendency was shown in series B. The amount of contrast in the upper intestine was increased in series A in the glucagon group, but not in series B. It is concluded that glucagon improves visualisation of the biliary tract, especially the gallbladder at infusion cholangiography.

The effects of exogenously applied prostaglandins on the contractile responses of the gallbladder and sphincter of Oddi isolated from guinea pigs were examined in normal and indomethacin-treated preparations. Indomethacin reduced the tone and the contractile responses to transmural stimulation and to exogenously applied ACh of the gallbladder, while the tone and contractile responses of the sphincter of Oddi were little affected by indomethacin. Prostaglandins E1, E2 and F2 alpha potentiated the contractile responses of the gallbladder to transmural stimulation and ACh, and furthermore, treatment with indomethacin enhanced the potentiating effects of prostaglandins E1 and E2 but not the effect of PGF2 alpha. The reduced tone and contractility of the gallbladder were restored to the control level by addition of PGE1 and PGE2 but not by PGF2 alpha. These results suggest that endogenous PGE1 and PGE2 may play an important role in neurogenic control of contractility of the gallbladder, but not of the sphincter of Oddi.

The effects of taurine (2-aminoethanesulfonic acid) and its homologue, homotaurine (3-aminopropanesulfonic acid), on biliary and fecal excretion of bile acids were investigated in dietary hyperlipidemic rats. Taurocholic acid was a major component in the bile of rats on laboratory chow and the ratio between glycine and taurine conjugated bile acids (G/T ratio) was 0.14. In feces, more free bile acids were present than in bile and the G/T ratio increased to 1.49. The biliary bile acid level increased approximately 2-fold in rats fed a diet containing 0.5% cholesterol and 1.0% cholic acid for 10 days. The glycine conjugated bile acid level increased approximately 7.5-fold, so that the G/T ratio was reversed to 1.17. the level of fecal bile acids increased approximately 19-fold while the G/T ratio remained at 1.43. Taurine or homotaurine (500 mg/kg/d each) was orally administered for 10 d concurrently with the cholesterol diet. Taurine suppressed elevation in the glycine conjugated bile acid level so the bile acid composition was roughly similar to that of the rats on laboratory chow and the G/T ratio became 0.06. In fecal excretion, the bile acid level increased significantly 1.2-fold over that of the control and the G/T ratio was 0.45. Homotaurine did not significantly alter the biliary bile acid level or the composition. These results indicated that taurine stimulated the excretion of bile acids, resulting in a reduction in serum cholesterol. Homotaurine did not influence bile acid metabolism.

The earliest lesion in rabbits dosed orally with 2 mg of sporidesmin per kg of body weight was necrosis of occasional hepatocytes 1 day after dosing. The most consistent lesion was a severe necrotizing cholangitis of medium and large-sized intrahepatic and extrahepatic bile ducts, first seen 2 days after dosing. Similar lesions were also present in the gall bladder of some rabbits. Expansion of portal triads with fibrous tissue and proliferating bile ductules progressed to pseudo-lobulation by 21 days. Other hepatic changes observed irregularly included large infarcts at the periphery of some lobes, and multiple small foci of coagulation necrosis in midzonal and periportal regions. Vascular necrosis and thrombosis, invariably adjacent to necrotic bile ducts, was presumably responsible for the hepatic necrosis. Serum cholesterol and total bilirubin concentrations and GGT activity reached peaks 15 days after dosing and were useful indicators of the severity of biliary lesions. Serum ID activity was the most useful indicator of hepatic necrosis following oral dosing with sporidesmin. The similarity between hepatobiliary lesions observed in sheep and rabbits with experimental sporidesmin toxicity suggests that the rabbit would be a useful model for studying methods of treatment and prevention of "facial eczema" in ruminants.

Continuous biliary pressure and electromyographic activity of the sphincter of Oddi and gastrointestinal tract were recorded in conscious opossums following administration of analgesic drugs. Morphine, meperidine, and pentazocin increased significantly the duration of the migrating motor complex (MMC) cycle. Periods of 1-2 minutes of intense burst of spike potentials were seen in the sphincter of Oddi and duodenum following administration of morphine (8 experiments), meperidine (6 experiments), and pentazocin (3 experiments). The biliary pressure in the control studies was similar to that following administration of all analgesics in the animals with gallbladder and following instillation of tramadol, metamizol, and acetylsalicylic acid in animals with no gallbladder. However, the biliary pressure was significantly higher following administration of morphine, meperidine, and pentazocin in the animals with no gallbladder. It is concluded from this study that morphine, meperidine, and pentazocin may cause important disturbances in the motility of the sphincter of Oddi and gastrointestinal tract. These myoelectric disturbances may cause an increase in the biliary pressure in animals that have been subjected to cholecystectomy, but not in animals with intact gallbladder. The gallbladder may accommodate the bile produced by the liver during periods of sphincter of Oddi dysfunction and thus impede an increase in the biliary pressure.

The acute intravenous toxicity of sodium arsenite and dichloro(2-chlorovinyl)arsine (lewisite) has been compared in rabbits to provide a quantitative and qualitative model for future assessment of treatments of lewisite poisoning. The LD50 of sodium arsenite was 7.6 mg.kg-1; that for lewisite was 1.8 mg.kg-1. On the basis of arsenic content the former was 6.5 times less toxic than the latter. Significant differences in tissue arsenic content and pathology were found between the 2 materials. Histologically, changes were observed in the lungs and gall bladder after lewisite injection but not after sodium arsenite. It was concluded that use of sodium arsenite is not a suitable substitute model for lewisite poisoning.

Hepatic bile acid synthesis is thought to be under negative feedback control by bile salts in the enterohepatic circulation, acting at the level of cholesterol 7 alpha-hydroxylase (C7 alpha H), the initial and rate-limiting step in the bile acid biosynthetic pathway. Bile salts also suppress the activity of the rate-limiting enzyme for cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA-R). The mechanisms of these regulatory effects are poorly understood, and one or both may be indirect. Previous data suggest that the hydrophilic-hydrophobic balance of bile salts, a major determinant of their cholesterol solubilizing properties, also determines their potency as regulators of bile acid and cholesterol synthesis. To further evaluate the relationship between the physicochemical and regulatory properties of bile acids, we altered the composition of the bile salt pool of rats by feeding one or more of seven different bile acids (1% w/w for 14 days). We then determined the mean hydrophilic-hydrophobic balance (hydrophobicity index) of the bile salts in bile, and correlated this with the specific activities of C7 alpha H and HMG-CoA-R, and of acyl-CoA:cholesterol acyltransferase (ACAT), a third hepatic microsomal enzyme which regulates cholesterol esterification. In all instances following bile acid feeding, conjugates of the fed bile acid(s) became the predominant bile salts in bile. Highly significant negative linear correlations (each P less than 0.0001) were found between the hydrophobicity indices of biliary bile salts and the activities of C7 alpha H (r = 0.79) or HMG-CoA-R (r = 0.63). By contrast, no significant correlation could be demonstrated between ACAT activity and the hydrophobicity index of biliary bile salts. The correlation between activities of HMG-CoA-R and C7 alpha H was also highly significant (r = 0.81; P less than 0.0001). No significant correlation existed between ACAT and either HMG-CoA-R or C7 alpha H. Microsomal free cholesterol was not consistently altered by bile acid feeding. Thus, the potency of circulating bile salts as suppressors of the enzymes regulating bile acid and cholesterol synthesis increases with increasing hydrophobicity. The hydrophobic-hydrophilic balance of the bile salt pool may play an important role in the regulation of cholesterol and bile acid synthesis.

Neuropeptide Y (NPY) is a recently discovered polypeptide found in neurons throughout the gastrointestinal tract and in especially high concentrations in the biliary tree. This study was designed to test the functional significance of these high concentrations in the biliary tree by determining the effect of intravenous NPY on sphincter of Oddi and gallbladder motility. In adult male prairie dogs a side-hole, pressure-monitored perfusion catheter was placed through a choledochotomy into the duodenum and positioned in the sphincter of Oddi. A perfusion catheter was also placed in the gallbladder fundus. Sphincter of Oddi and gallbladder pressures were recorded before and during intravenous infusions of NPY at doses of 10, 100, and 500 ng/kg/min. Each dose was administered to seven separate animals. No effects were seen at the 10 or 100 ng/kg/min doses. NPY at the 500 ng/kg/min dose significantly increased sphincter of Oddi phasic wave frequency, amplitude, and motility index (MI = F X A). In addition, gallbladder pressure was significantly increased after 20 min of intravenous infusion of NPY at the 500 ng/kg/min dose. No significant changes in blood pressure were noted. These data suggest that in the prairie dog, systemic intravenous infusion of NPY significantly increases sphincter of Oddi phasic wave activity and gallbladder pressure. These findings are similar to those observed with intravenous cholecystokinin but opposite of those seen with peptide YY in this species. We hypothesize that neuropeptide Y may be an important neurotransmitter or neuromodulator regulating bile flow.