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PubMed1989

Autocrine-paracrine inhibition of growth hormone and prolactin production by GH3 cell-conditioned medium.

In previous work we have shown that perifused GH3 cells exhibit spontaneously accelerating growth hormone (GH) and prolactin (PRL) secretory rates. This behavior contrasts with GH and PRL secretion rates that are decreasing or stable over the same 3-d period in static cell culture. We now report that GH3 cells maintained in serum-supplemented medium produce an autocrine-paracrine factor(s) which inhibits GH secretion in plate culture; PRL release is frequently reduced as well. The inhibitory effect of conditioned medium on GH secretion was concentration dependent, whereas PRL release was stimulated at low and inhibited at high concentrations over the same range. Extensive dialysis of conditioned medium using membranes with a molecular weight cut-off of 12,000-14,000 did not remove GH inhibition but produced a retentate that stimulated PRL secretion. Heat-inactivation of conditioned medium did not abolish inhibition of GH release but did remove the PRL-stimulatory effect. IGF-I added to fresh culture medium did not reproduce the GH-inhibitory effects of conditioned medium. We conclude that GH3 cell secretory behavior in perifusion and plate culture systems may be partially explained by the production of an autocrine-paracrine factor: its accumulation in plate culture inhibits GH and PRL secretion whereas its removal, by perifusing medium, allows GH and PRL secretion to accelerate.

Animals↗
PubMed1980

Local production of prostaglandins in relation to mammary function at the onset of lactation in the goat.

1. Arterial and mammary venous concentrations of prostaglandins F alpha (PGF alpha), E (PGE) and the PGF alpha metabolite, 13,14-dihydro-15-oxoPGF alpha (DHK-PGF alpha) were studied during late pregnancy and the onset of lactation in conscious goats. Mammary secretion concentrations of PGF alpha and DHK-PGF alpha were determined, and mammary blood flow, arterial plasma progesterone concentrations and milk composition were also studied. 2. A significant output of PGF alpha from the mammary gland into mammary venous blood was observed during late pregnancy; this output ceased near term. 3. Mammary output of DHK-PGF alpha into venous blood began about 6 days prepartum, suggesting an increasing capacity of the gland to metabolize PGF alpha. 4. The concentration of PGF alpha in mammary secretion increased from about 4 days pre-partum, that of DKH-PGF alpha from about 12 days pre-partum. 5. It is concluded that although total mammary output of PGF alpha decreases during late pregnancy and early lactation, the rate of mammary synthesis of PGF alpha increases and the PGF alpha is increasingly secreted into milk and metabolized to DHK-PGF alpha within the mammary gland. 6. Unilateral treatment of one mammary gland in goats with the PGF 2 alpha analogue, Cloprostenol, at two dose levels from 2-3 days pre-partum to 1-2 days post-partum prevented the changes in milk [Na] that occur at term in untreated glands. At the higher dose, the normal rise in milk [citrate] was abolished and milk yield was reduced; these effects persisted after cessation of treatment. 7. It is suggested that PGF alpha may play a local inhibitory role in mammary gland function during late pregnancy. It is further suggested that PGF alpha could be the factor, or one of the factors, proposed by Linzell & Peaker (1974) to be responsible for local control of mammary epithelial permeability and possibly also for secretory rate.

Animals↗
PubMed1987

Insulin secretion and clearance. Comparison after oral and intravenous glucose.

Insulin secretion and clearance in response to the administration of oral and intravenous glucose was investigated in nine normal men. C-peptide metabolic kinetics were calculated by analysis of individual C-peptide decay curves after the bolus injection of biosynthetic human C-peptide. Glucose was administered to the subjects on three occasions: as a 75-g oral dose, a 75-g i.v. infusion, and an intravenous glucose infusion at a variable rate adjusted to mimic the peripheral glucose levels obtained after the oral glucose load (matching experiment). Glucose, insulin, and C-peptide concentrations were measured for the subsequent 5 h. The glucose level after the oral glucose load (115.9 +/- 2.6 mg/dl, mean +/- SE) closely approximated that after the matching experiment (120.5 +/- 2.5 mg/dl) but was significantly lower than after 75 g i.v. glucose (127.7 +/- 3.4 mg/dl, P less than .05). Analysis of the areas under the peripheral concentration curves (60-360 min) showed that the responses of both insulin (52.7 +/- 5.6 and 46.5 +/- 4.5 pmol.ml-1.300 min-1) and C-peptide (252.7 +/- 27.5 and 267.0 +/- 21.6 pmol.ml-1.300 min-1) were not significantly different after the oral and 75-g i.v. glucose studies, respectively, whereas in the matching experiment, both the insulin (26.1 +/- 3.9 pmol.ml-1.300 min-1) and C-peptide (178.0 +/- 18.9 pmol.ml-1.300 min-1) responses were lower (P less than .05) than in the other two studies. Insulin secretory rates were derived from peripheral C-peptide concentrations with an open two-compartment model and individually derived model parameters. (ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1975

Transport and electrical phenomena in resting and secreting piglet gastric mucosa.

1. Gastric mucosae were isolated from piglets (0-5 days old) and mounted in a chamber where electrical properties and secretory function could be measured. Unlike many previously reported mammalian in vitro preparations, pig gastric mucosae were stable and physiologically responsive for many hours after isolation. 2. With similar Ringer solutions bathing both surfaces, the isolated piglet gastric mucosa maintained a p.d. with the mucosal surface 30-35 mV negative with respect to the serosal surface. Limitation of access of Na+ from the mucosal bathing solution to the tissue (e.g. replacement of Na+ on mucosal side with choline or treatment with 10- minus 5 M amiloride) produced a decrease in p.d. and increase in mucosal resistance consistent with an hypothesis of Na+ transport from mucosa to serosa. 3. Isotopic flux measurements (36Cl and 24Na) and net H+ secretory rate were performed during open and short-circuit conditions, while the tissue was at rest and after stimulation of HCl secretion by 6 times 10- minus 5 M histamine. Up to 90% of the respective short-circuit current for resting or secreting mucosae was accounted for as the algebraic sum of Cl minus, H+ or Na+ fluxes. 4. The net transport of Na+ which occurred from mucosa to serosa during rest (ca. 4-7 muequiv/cm2.hr) was somewhat reduced during HCl secretion (ca. 2-7 muequiv/cm2.hr). This active transport of Na+ was more resistant to anaerobiosis than was H+ or Cl minus transport. 5. An active transport component of Cl minus from serosa to mucosa was clearly demonstrable in the non-secreting preparations (ca. 3-9 muequiv/cm2.hr). Active Cl minus transport was stimulated three- to fourfold after H+ secretion was stimulated by histamine. Anaerobiosis promptly reduced Cl minus and H+ transport. An exchange diffusion component was demonstrated for Cl minus which appeared to be prominent during H+ secretory activity and was considerably diminished in resting mucosae. 6. Large changes in mucosal resistance were associated with conditions of rest, histamine stimulation and anaerobic conditions; mean values were 113, 74 and 197 omega.cm2, respectively. Electrical conductance of the isolated gastric mucosa was due primarily to partial ionic conductance of Cl minus (60-65%) and Na+ (10-15%). The partial conductance of H+ was extremely low. The observed increase in tissue conductance associated with H+ secretory activity and the changes in the long-time constant p.d. transient to a current pulse are discussed in terms of the relative contribution of the serosal and mucosal plasma membrane surfaces.

Anaerobiosis↗
PubMed1979

Intrarenal renin and autoregulation of renal plasma flow and glomerular filtration rate.

Autoregulatory responses of renal plasma flow (RPF) and glomerular filtration rate (GFR) to reductions in renal artery pressure (RAP) were studied in both kidneys of two-kidney, one-clamp dogs and in dogs treated with deoxycorticosterone acetate (DOCA; 25 mg/kg) plus high sodium diets with and without renal arterial clamping. In non-DOCA-treated animals, unilateral renal artery constriction resulted in a significant difference (P = 0.004) in renal renin activity (RRA) between the clamped (171 +/- 37 ng AI.mg-1.h-1) and the contralateral (57 +/- 23 mg AI.mg-1.h-1) kidneys with no change in their relative autoregulatory ability. In dogs treated with DOCA/high sodium there were no differences in RRA between the clamped and contralateral kidneys. The dogs treated with DOCA/high sodium were able to autoregulate both RPF and GFR even though their RRA was only 5.4 ng AI.mg-1.h-1. DOCA/high sodium treatment, however, reduced basal RPF (22%) and GFR (23%) below those in non-DOCA-treated animals. Analysis of the autoregulatory ability of individual kidneys showed no relationship to either RRA or renin secretory rates. These results support the conclusion that the renin-angiotensin system is not necessary component in the autoregulation of RPF or GFR.

Animals↗
PubMed1999

Heterogeneity in glutamic acid decarboxylase expression among single rat pancreatic beta cells.

AIMS/HYPOTHESIS: An isoform of glutamic acid decarboxylase, (GAD)65 has been identified as a pancreatic beta-cell autoantigen in Type I (insulin dependent) diabetes mellitus. We investigated the expression of GAD isoforms among single rat beta cells in culture, under different conditions and the correlation between GAD65 expression and insulin secretion-rate. RESULTS: Independent of culture conditions, 100 % of fresh and cultured beta cells express GAD67. In contrast, considerable heterogeneity in GAD65 expression among single beta cells was observed. After 2 days in culture in 2.6 mmol/l glucose, only 24 % of the beta cells express GAD65. This percentage increases to 39 % in 5.6 mmol/l glucose and to 54 % and 56 % in 11.6 mmol/l and 20.6 mmol/l glucose, respectively. Moreover, reducing glucose concentration from 11.6 to 2.5 mmol/l for 2 days, reduces GAD65 expression by nearly 30 %. After 11 days in culture with 11.6 mmol/l glucose, 50 % of beta cells continue expressing GAD65, this percentage is further increased to nearly 75 % by including either nerve growth factor or dibutyryl cyclic AMP or both in the culture medium. When beta cells are challenged for 1 h with 20.6 mmol/l glucose, 67 % respond forming insulin-immunoplaques. More than two-thirds of insulin-secretors are GAD65-positive, in contrast to only 11 % of the non-secreting cells. Moreover, 87 % of beta cells that have a high insulin secretory rate express GAD65. CONCLUSION/INTERPRETATION: These results show that the most active beta cells, which secrete more insulin, also express GAD65 and that manipulating extracellular glucose may modify the expression of the enzyme and possibly the autoimmune attack in Type I diabetes.

Animals↗
PubMed1984

Cholera-induced mucin secretion from rat intestine: lack of effect of cAMP, cycloheximide, VIP, and colchicine.

Purified cholera enterotoxin (20-50 micrograms) and dialyzed cholera filtrate (50-125 mg) increased net glycoprotein synthetic and secretory rates in rat intestinal epithelium. Specific goblet cell mucin secretion was increased 5- to 10-fold. However, other agents that increase intestinal cAMP and accelerate glycoprotein synthesis did not enhance mucin secretion. This was true for dibutyryl cAMP (10(-3) and 10(-2) M) with or without theophylline (10(-3) M) and isoproterenol (10(-4) M) with or without dibutyryl cAMP (10(-3) M). Hyperosmotic mannitol (450 mosmol/l), which increases fluid secretion but does not affect cAMP, and vasoactive intestinal peptide (2 X 10(-7) M), which increases both fluid secretion and cAMP, both failed to increase mucin secretion, implying that fluid "washout" of mucin adherent to the mucosal surface is not responsible for cholera-induced mucin secretion. Cycloheximide, an inhibitor of cholera diarrhea in vivo (20 mg/kg) or in vitro (1 mM), effectively abolished [3H]leucine incorporation into protein but did not affect cholera-induced mucin secretion. Colchicine (10-50 mg/kg) given to block microtubule assembly was similarly without effect on mucin secretion. These findings suggest that there is a dissociation of electrolyte/fluid and mucin secretory processes and cast doubt on the widely accepted notion that all cholera effects are mediated via the well-known adenylate cyclase-cAMP mechanism.

Animals↗
PubMed1995

Differential regulation of sympathetic neuron neuropeptide Y and catecholamine content and secretion.

Cultured principal neurons of the superior cervical ganglion (SCG), which coexpress high levels of catecholamines and neuropeptide Y (NPY), were used as a model to simultaneously examine whether sympathetic neuronal peptide and transmitter content or secretion are differentially regulated. Accumulation of NPY immunoreactivity and the dopamine metabolites DOPAC and HVA in SCG neuronal conditioned culture medium was used as an index of NPY and catecholamine secretion, respectively. Release of NPY and catecholamines was linear with time; SCG neurons exhibited a basal NPY secretory rate of approximately 0.9-3 fmol NPY immunoreactivity/10(4) cells/hr, and basal DOPAC plus HVA accumulation was about 10-20 pmol total metabolites/10(4) cells/hr. While sympathetic neuronal NPY and total catecholamine cell content increased more than 6-10-fold by 14 d of culture, secretion remained constant. Depolarization stimulated the rate of NPY secretion 18-fold, whereas medium catecholamine metabolite levels increased 3-fold. Activation of intracellular signaling pathways was shown to be an important point of regulation of sympathetic neuron peptide and transmitter content and secretion. Differential regulation of SCG neuron NPY and catecholamine expression was second messenger system specific. Activation of the protein kinase A pathway with the cAMP analog dibutyryl cAMP, or the adenylyl cyclase activator forskolin, produced a concentration-dependent, sustained stimulation of NPY secretion; maximal stimulation resulted in decreased cellular NPY content. Parallel stimulated neuronal catecholamine release was observed, but in contrast to NPY, total cellular catecholamine content was also increased. Regulation of the protein kinase C pathway with phorbol myristate acetate (PMA) stimulated SCG neuronal NPY secretion to a lesser degree than activation of protein kinase A, but did not alter cellular NPY levels. PMA minimally stimulated catecholamine release and content. NPY secretion induced by the calcium ionophore A23187 was paralleled by a concomitant decrease in cellular NPY. A23187 decreased catecholamine release, but did not change cellular total catecholamine levels. The magnitude of the secretory responses of sympathetic neurons to these regulators was far greater than changes in NPY or catecholamine content, biosynthesis or mRNA levels, suggesting that release is a primary site of regulation. The independent regulation of sympathetic neuronal NPY and catecholamine content and release is consistent with the fundamental differences in the biosynthetic pathways, vesicular compartmentalization, uptake and metabolism of neuropeptides and neurotransmitters.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Do D-1 dopamine receptors mediate dopamine-induced pancreatic exocrine secretion in anesthetized dogs?

Characterization of dopamine (DA) receptor subtypes was examined on the canine exocrine pancreas using selective DA receptor agonists and antagonists in the isolated and blood-perfused pancreas of anesthetized dogs. Each drug was injected i.a. in a single bolus fashion. Graded doses of DA (0.01-3 mumol) produced dose-dependent increases in the secretory rate of pancreatic juice, with a maximum effect at approximately 1 mumol. SCH23390 (3-30 nmol), a selective D-1 DA receptor antagonist, caused a progressive parallel shift to the right in the dose-response curve for DA-induced pancreatic secretion without changes in the maximal response. High doses of RS-sulpiride (0.3-3 mumol) or haloperidol (1-3 mumol), a mixed D-1/D-2 DA receptor antagonist, also caused a rightward shift in the DA dose-response curve. However, domperidone (3 mumol), a selective D-2 DA receptor antagonist, did not antagonize the DA-induced pancreatic exocrine secretion. A modified Schild analysis of the data indicates that SCH23390 is approximately 2 and 3 orders of magnitude more potent than RS-sulpiride and haloperidol, respectively. In addition, the stimulatory effects of DA (0.01-3 mumol), SKF38393 (0.1-10 mumol, a selective D-1 DA receptor agonist) and LY171555 (1-10 mumol, a selective D-2 DA receptor agonist) on pancreatic secretion were demonstrated. The rank order of agonist potency was DA greater than SKF38393 greater than LY171555. The secretory response to LY171555 was inhibited completely by pretreatment with SCH23390 (30 nmol).(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1988

Verapamil impairs secretion of stimulated atrial natriuretic factor in humans.

The adaptation of the secretory rate of atrial natriuretic factor to repeated adequate stimuli and the influence of the calcium antagonist verapamil on the release of atrial natriuretic factor were investigated in 16 patients. In eight patients (Group 1) right atrial pressure was abruptly increased by rapid right ventricular pacing for 4 min (stimulation I). After a 15 min interval, the identical stimulation was repeated (stimulation II). Eight patients (Group 2) underwent the same protocol but received 5 mg of verapamil intravenously after stimulation I. Pacing increased right atrial pressure in both groups identically by 70%. In Group 1, release of atrial natriuretic factor caused by the second stimulation (median 290 pg/ml over basal) was significantly (2.5-fold) larger than atrial natriuretic factor release induced by the first stimulation (median 116 pg/ml over basal). In the verapamil-treated patients (Group 2), the effect of right atrial pressure increase on release of atrial natriuretic factor was abolished after stimulation II. In both groups, changes in plasma concentrations of cyclic guanosine monophosphate corresponded to changes in atrial natriuretic factor concentrations. Thus, the myoendocrine cells are apparently capable of a fast upward regulation of their response to repeated secretory stimuli. Verapamil appears to block the stimulatory effect of a sudden increase in right atrial pressure upon release of atrial natriuretic factor.

Adult↗
PubMedDate not supplied

Subtypes of adenosine receptors on pancreatic exocrine secretion in anaesthetized dogs.

Characterization of adenosine receptor subtypes was examined on the canine exocrine pancreas using selective adenosine receptor agonists and antagonists in the isolated and blood-perfused pancreas of anaesthetized dogs. Each drug was injected intra-arterially in a single bolus fashion. Graded doses of CGS21680 (1-300 nmol/kg), a selective adenosine A2A receptor agonist, produced dose-dependent increases in the secretory rate of pancreatic juice, with a maximum effect at approximately 30 nmol/kg. However, CPA (1-300 nmol/kg), a selective adenosine A1 receptor agonist, did not cause the pancreatic secretion. CGS21680 (3-30 nmol/kg) and secretin (0.01-0.03 pmol/kg) increased the bicarbonate concentration in pancreatic juice and decreased the protein concentration. CCK-8 (0.1-0.3 pmol/kg) increased the protein concentration but did not alter the bicarbonate concentration. DMPX (5-50 nmol/kg), a weak adenosine A2A receptor antagonist, caused a progressive parallel shift to the right in the dose response curve for CGS21680-induced pancreatic secretion without changes in the maximal response. DPCPX (100 nmol/kg), a selective A1 adenosine receptor antagonist, did not antagonize the CGS21680-induced pancreatic secretion. Schild analysis of the data indicated that the apparent pA2 value for DMPX was 8.3 using CGS21680 as the agonist. The slope of the Schild regression line was not different from 1. When a phosphodiesterase IV inhibitor rolipram (0.1 nmol/kg) was added, pancreatic secretion induced by CGS21680 (10 nmol/kg) and secretin (0.03 pmol/kg) were potentiated, but not that of CCK-8 (0.3 pmol/kg). These results suggest the existence of adenosine A2A receptors in the exocrine cells of the dog pancreas involved in the water and bicarbonate secretory response.

Adenosine↗
PubMed1991

Effects of the phorbol ester phorbol 12-myristate 13-acetate (PMA) on islet-cell responsiveness.

Collagenase-isolated rat islets were labelled for 2 h in myo-[2-3H]inositol solution supplemented with 2.75 mM-glucose. The phorbol ester phorbol 12-myristate 13-acetate (PMA; 0.1 or 1 microM) was also present in some experiments. After labelling, islets were washed and then perifused in 2.75 mM-glucose to establish basal [3H]inositol-efflux and insulin-secretory rates. Subsequently, the responses of these islets to stimulation with various agonists were assessed. Inositol phosphate accumulation was measured at the termination of the perifusion. In separate experiments, the cellular location of protein kinase C (PKC) after PMA pretreatment was measured by quantitative immunoblotting of membrane and cytosolic fractions. The following observations were made. (1) Labelling in 0.1-1 microM-PMA had no deleterious effect on total [3H]inositol incorporation during the 2 h labelling period. However, islets labelled for 2 h in 1 microM-PMA were unable to respond, in terms of increases in insulin release, to a 1 microM-PMA stimulus during the subsequent perifusion. (2) As compared with the responses of control islets labelled in 2.75 mM-glucose alone, islets labelled in the additional presence of 1 microM-PMA displayed a significant impairment in phosphoinositide (PI) hydrolysis, but an enhancement of both first-and second-phase insulin secretion, in response to subsequent 20 mM-glucose stimulation. (3) Decreasing extracellular Ca2+ level to 0.1 mM and including the Ca(2+)-channel antagonist nitrendipine (0.5 microM) along with 1 microM-PMA during the [3H]inositol-labelling period did not alter the response of the islets to the subsequent addition of 20 mM-glucose. Glucose-induced PI hydrolysis was still inhibited and 20 mM-glucose-induced insulin release was still enhanced. (4) A markedly amplified and sustained insulin-secretory response to 200 microM-tolbutamide in the presence of 2.75 mM-glucose was also obtained from 1 microM-PMA-pretreated islets. This contrasts sharply with the small and transient response to tolbutamide noted in control islets. (5) When present only during the perifusion phase of the experiments, nitrendipine (0.5 microM) abolished the amplified insulin-secretory responses to both 20 mM-glucose and 200 microM-tolbutamide noted in PMA-pretreated islets. (6) Prior labelling in 1 microM-PMA dramatically amplified the insulinotropic effect of 25 mM-K+ or 5 microM-A23187 stimulation. The amplified insulin-secretory response to K+, but not to A23187, was abolished by inclusion of nitrendipine during the perifusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Sham feeding for testing gastric secretory capacities before and after parietal cell vagotomy.

The usefulness of acid secretory data collected during a modified sham-feeding (MSF) test was examined in 50 patients suffering from duodenal ulcer before and after parietal cell vagotomy. In these patients basal acid output pentagastrin-stimulated acid output and MSF-stimulated acid output were measured. Preoperative MSF-stimulated acid output was found to be correlated with preoperative basal acid output, and postoperative MSF-stimulated acid output was correlated with both preoperative basal acid output and postoperative basal and pentagastrin-stimulated acid outputs. The addition of preoperative MSF-stimulated acid output to preoperative pentagastrin-stimulated acid output did not noticeably increase the close relationship between the latter and postoperative pentagastrin-stimulated acid output. It is concluded that basal and MSF-stimulated secretory rates overlap. Therefore, it is suggested that in both preoperative and postoperative conditions the addition of the sham-feeding test to the more simple basal and pentagastrin-stimulated studies could be discarded.

Adolescent↗
PubMed2002

Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma.

BACKGROUND: Malignant pancreatic endocrine tumors (PETs) have a poor prognosis and existing antitumor treatments are unsatisfactory. Recent studies have shown somatostatin analogues to have antitumor growth effects in patients with malignant PETs; however, to the authors' knowledge, little information exists regarding their efficacy or effect on survival in patients with progressive malignant gastrinoma, the most common symptomatic malignant PET. The purpose of the current study was to study prospectively the efficacy, safety, and effect on survival of long-term treatment with octreotide in consecutive patients with progressive malignant gastrinoma. METHODS: Fifteen consecutive patients with malignant gastrinoma with progressive hepatic metastases were studied. All patients underwent conventional imaging studies (computed tomography scan, magnetic resonance imaging, ultrasound, and, if needed, selective angiography) and somatostatin receptor scintigraphy prior to treatment and at 3-6-month intervals while receiving treatment. The patients all were treated initially with octreotide, 200 microg every 12 hours, and at last follow-up were being maintained on long-acting release octreotide, 20-30 mg every month. Tumor size and/or number were used to classify patient responses as either no tumor response or tumor response (stabilization or decrease in size). Treatment response was correlated with tumor and clinical characteristics. RESULTS: Tumors in 8 of the 15 patients studied (53%) responded at 3 months, with 47% (7 of 15 patients) demonstrating tumor stabilization and 6% (1 of 15 patients) demonstrating a decrease in tumor size. The mean duration of response was 25.0+/-6.1 months (range, 5.5-54.1 months). Six of the eight responders were continuing to respond at the time of last follow-up. Tumor response did not correlate with any clinical parameter (e.g., tumor extent, fasting gastrin, or acid secretory rates). However, slow-growing tumors were more likely to respond prior to treatment (86% vs. 0%) (P < 0.0014). During follow-up (range, 4-8 years), 25% of the responders died compared with 71% of the nonresponders, a difference that approached statistical significance (P = 0.10). Two patients (13%) developed serious side effects that required the withdrawal of octreotide. CONCLUSIONS: Octreotide is an effective antitumor treatment in patients with progressive malignant gastrinoma. In approximately 50% of these patients octreotide has an antigrowth effect; treatment is associated with a low incidence of serious side effects compared with other antitumor treatments commonly used and, in contrast to many studies, the growth response is long-lasting. The results of the current study suggest that octreotide treatment should replace chemotherapy as the standard treatment for these patients, especially those patients with slow-growing tumors. Additional studies involving larger numbers of patients will be needed to determine a convincing effect on survival.

Adult↗
PubMedDate not supplied

Effects of gallbladder function on human bile: compositional and structural changes.

Water and electrolyte absorption leading to increased intraluminal concentrations of lipids and other solutes comprise the primary physiologic effect of the gallbladder. The dynamics of enterohepatic circulation can lead to confinement of up to 60% of the bile acid pool within the gallbladder during prolonged fasting. This bile acid sequestration markedly reduces both the bile salt secretory rate and total solute concentration in comparison with the nonfasting state producing hepatic bile that is more than normally dilute especially in comparison with gallbladder bile. These conditions favor formation of small low-density vesicles in hepatic bile which are more buoyant than the concentrated biliary micelles found in anatomically dependent regions of the gallbladder. Vesicle formation in hepatic bile may explain the "stratification" phenomenon often noted within the gallbladder. This observation could be accounted for by inhomogeneous mixing of the dissimilar lipid particles, i.e., vesicles and micelles. If vesicles are present and stratified as presumed, the overall cholesterol transporting capability of the total lipid particles, including these regionalized vesicles, would be considerably enhanced. The net effect of this process would lead to an overestimation of the true degree of metastable cholesterol supersaturation for the biliary micellar system within the gallbladder on the incorrect assumption of homogeneous mixing of lipids.

Bile↗
PubMedDate not supplied

Effects of ioglycamide on the hepatic transport of bilirubin and its mono- and diconjugates in the rat.

Bilirubin seems to share the biliary excretion pathway with other organic anions, but not with bile acids. We studied the effects of the organic anion ioglycamide, an iodinated contrast agent, on bilirubin metabolism in Wistar rats. This compound does not undergo conjugation and is characterized by a maximal biliary secretory rate (Tm). The results show that in spite of producing a 3-fold increase in bile flow, ioglycamide excretion under Tm conditions decreased the output of unconjugated bilirubin and its monoconjugate by approximately 90%. Diconjugated bilirubin decreased by only 50% and became by far the predominant pigment in bile (86.5 +/- 6.0% of total pigment vs. 61.0 +/- 4.0% in basal conditions, n = 12). Unconjugated and monoconjugated bilirubins changed in parallel suggesting that the former arises from the monoconjugates. In serum, diconjugated bilirubin augmented from trace amounts to 1.15 +/- 0.17 mumole per liter. Total conjugated pigments in serum increased from 5 to 85% of total bilirubin. Bile acid output remained unchanged. Pretreatment of rats with ioglycamide altered neither the activity of bilirubin UDP-glucuronyltransferase nor the ratio of diconjugate to monoconjugate formed at both low (25 microM) and high (164 microM) bilirubin concentrations. The observed biological effects of ioglycamide were dose-dependent and fully reversible. We suggest that ioglycamide interferes with the excretion of conjugated bilirubins ("bilirubinostasis"). The monoconjugates retained in the hepatocyte might then undergo more efficient transformation to diconjugates, the latter thus becoming the most important bile pigments in serum and bile.

Animals↗
PubMedDate not supplied

Effect of complete sulfation of bile acids on bile formation in rats.

The effect of sulfation of common bile acids on the formation of bile was investigated in male rats by infusing them with the sulfate esters of cholic, chenodeoxycholic, deoxycholic, lithocholic or dehydrocholic acid in four step-wise, increasing doses. Each dose was infused for 30 min and bile collected every 10 min. Control studies were performed by using either albumin solution (the bile acid carrier) or corresponding nonsulfated bile acids at concentrations similar to those of the sulfated products. The secretion of sulfated bile acids was slower and less than that of nonsulfated bile acids, demonstrating transport maximum kinetics rather than the secretory rate maximum characteristic of nonsulfated bile acids. Sulfation significantly increased bile salt-independent bile flow and the choleretic potency of the bile acids tested. With the exception of deoxycholic acid, which had a slight stimulatory effect, bile acid sulfation generally prevented a rise in bile acid-dependent phospholipid and cholesterol secretion. In fact, it reduced biliary phospholipid and cholesterol secretion associated with the secretion of endogenous bile acids. These data are in agreement with the physicochemical properties of sulfated bile acids. They indicate that sulfation prevents the cholestatic action of nonsulfated bile acids, perhaps by increasing bile flow via a high choleretic potential and/or by stimulating bile acid-independent bile flow. The effect of sulfated bile acids on the secretion of biliary phospholipids may protect the canalicular membrane from the detergent properties of bile acids and may thus block the cholestasis which results from high, nonsulfated bile acid concentrations.

Animals↗
PubMed1998

Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat.

To test the hypothesis that impaired activity of the bile canalicular organic anion transporting system mrp2 (cmoat) is a key event in the etiology of 17alpha-ethinylestradiol (EE)-induced intrahepatic cholestasis in rats, EE (5 mg/kg subcutaneously daily) was administered to male normal Wistar (NW) and mrp2-deficient Groningen Yellow/Transport-deficient Wistar (GY/TR-) rats. Elevated plasma bilirubin levels in GY/TR- rats increased upon EE-treatment from 65 +/- 8.4 micromol/L to 183 +/- 22.7 micromol/L within 3 days, whereas bilirubin levels remained unaffected in NW rats. Biliary bilirubin secretion was 1.5-fold increased in NW rats but remained unaltered in GY/TR- rats. Plasma bile salt concentrations remained unchanged in both strains, although hepatic levels of the sinusoidal Na+-taurocholate cotransporting protein (ntcp) were markedly reduced. Biliary secretion of endogenous bile salt was not affected in either strain. A clear reduction of mrp2 levels in liver plasma membranes of NW rats was found after 3 days of treatment. The bile salt-independent fraction of bile flow (BSIF) was reduced from 2.6 to 2.0 microL/min/100 g body weight in NW rats with a concomitant 62% reduction of biliary glutathione secretion. The absence of mrp2 and biliary glutathione in GY/TR- rats did not prevent induction of EE-cholestasis; a similar absolute reduction of BSIF, i.e., from 1.1 to 0.6 microL/min/100 g bodyweight, was found in these animals. EE treatment caused a reduction of the maximal biliary secretory rate (S(RM)) of the mrp2 substrate, dibromosulphthalein (DBSP), from 1,040 to 695 nmol/min/100 g body weight (-38%) in NW rats and from 615 to 327 nmol/min/100 g body weight (-46%) in GY/TR- rats. These results demonstrate that inhibition of mrp2 activity and/or biliary glutathione secretion is not the main cause of EE-induced cholestasis in rats. The data indicate that alternative pathways exist for the biliary secretion of bilirubin and related organic anions that are also affected by EE.

Animals↗