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At least 145 records · Page 8Linked to original sources
PubMed1986

Stimulus-secretion coupling in bovine parathyroid cells. Dissociation between secretion and net changes in cytosolic Ca2+.

The relationship between the concentration of cytosolic free Ca2+ ([Ca2+]i) and secretion of parathyroid hormone (PTH) was investigated in isolated bovine parathyroid cells using the fluorescent Ca2+ indicator, quin 2. Increasing the concentration of extracellular Ca2+ from 0.5 to 2.0 mM caused a 3-fold increase in [Ca2+]i (from 183 +/- 4 to 568 +/- 21 nM) which was associated with a 2-4-fold decrease in secretion of PTH. Decreasing extracellular Ca2+ to about 1 microM caused a corresponding fall in [Ca2+]i to 60-90 nM. Extracellular Ca2+-induced changes in [Ca2+]i were not affected by omission of extracellular Na+. Depolarizing concentrations of K+ (30 mM) depressed [Ca2+]i at all concentrations of extracellular Ca examined, and this was associated with increased secretion of PTH. Ionomycin (0.1 or 1 microM) increased [Ca2+]i at extracellular Ca2+ concentrations of 0.5, 1.0, and 2.0 mM, but inhibited secretion of PTH only at Ca concentrations near the "Ca2+ set point" (1.25 microM). In contrast, dopamine, norepinephrine (10 microM each), and Li+ (20 mM) potentiated secretion of PTH without causing any detectable change in [Ca2+]i. The results obtained with these latter secretagogues provide evidence for a mechanism of secretion which is independent of net changes in [Ca2+]i. The phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) did not alter [Ca2+]i or secretion of PTH at low (0.5 mM) extracellular Ca2+ concentrations. At 2.0 mM extracellular Ca2+, however, TPA (20 nM or 1 microM) depressed [Ca2+]i and potentiated secretion of PTH. The addition of TPA prior to raising the extracellular Ca2+ concentration reduced the subsequent increase in [Ca2+]i. The results show that the effects of TPA on secretion in the parathyroid cell are not readily dissociated from changes in [Ca2+]i and suggest that some TPA-sensitive process, perhaps involving protein kinase C, may be involved in those mechanisms that regulate [Ca2+]i in response to changes in extracellular Ca2+.

Aminoquinolines↗
PubMed1995

Spontaneous quantal transmitter secretion from myocytes and fibroblasts: comparison with neuronal secretion.

When exogenous ACh is loaded into the cytoplasm of cultured amphibian myocytes and fibroblasts, the cells undergo spontaneous quantal ACh secretion, as detected by the appearance of pulsatile membrane currents in Xenopus myocytes which are manipulated into contact with the cells. These currents resemble in many ways the miniature endplate currents (MEPCs) observed at developing neuromuscular synapses formed on these Xenopus myocytes. Analyses of the frequency, amplitude, and time course of these currents suggests similarity in the cellular mechanisms involved in the packaging and secretion of ACh quanta in fibroblasts, myocytes, and developing neurons. The size of the ACh packets released by the non-neuronal cells were found to be very similar to the size of the neuronal ACh quanta, which are thought to result from the exocytotic release of synaptic vesicles. Moreover, the kinetics with which the ACh packets are discharged from all three cell types are comparable, although the speed of secretion in non-neuronal cells is somewhat slower and more irregular. The spontaneous quantal ACh secretion from neurons and myocytes was decreased by reducing cytosolic Ca2+ level and enhanced by activation of protein kinase C with phorbol ester, but secretion from fibroblasts was unaffected by both treatments. The spontaneous secretion from fibroblasts did show some sensitivity to a rise in cytosolic Ca2+ after treatment with a Ca2+ ionophore. These observations support the hypothesis that the basic machinery for transmitter secretion operating in neurons derive from a more ubiquitous mechanism used for constitutive secretion and membrane trafficking in non-neuronal cells, and neuronal differentiation involves expression of additional unique components for the regulation of the spontaneous quantal secretion.

Acetylcholine↗
PubMed1994

PrtD, the integral membrane ATP-binding cassette component of the Erwinia chrysanthemi metalloprotease secretion system, exhibits a secretion signal-regulated ATPase activity.

We have overproduced, partially purified, and characterized PrtD, the ATP-binding cassette (ABC) integral membrane component from the metalloproteases secretion system of the Gram-negative phytopathogenic bacterium Erwinia chrysanthemi. These metalloproteases are secreted independently of the general export pathway encoded by the sec genes. They are secreted via a C-terminal secretion signal and by a secretion apparatus composed of two inner membrane proteins, PrtD and PrtE, and one outer membrane protein PrtF. PrtD is specifically labeled by 8-azido-ATP both in whole membrane vesicles and upon purification. The purified protein displays a low level of P-type ATPase activity. This activity is almost completely and specifically inhibited by the cognate C-terminal secretion signal of the PrtG and PrtB metalloproteases (half inhibition at 0.1 microM) but not by a C-terminal secretion signal of a protein not secreted by the Prt translocator. A mutant PrtD protein bearing a point mutation in the ATP binding site (conserved lysine 370 of the Walker A box changed to arginine) has also been purified. It displays a lower level of ATPase activity which correlates with the lower level of secretion of the metalloproteases by a strain expressing this mutated protein.

ATP-Binding Cassette Transporters↗
PubMed1998

IL-10 as an autocrine regulator of CSF secretion by monocytes: disparate effects on GM-CSF and G-CSF secretion.

In previous studies of endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) production, we found several differences in the secretion pattern within and between different cell systems; for example, CSF secretion by endothelial cells is not affected by any major downregulatory factors, whereas monocyte CSF secretion is modulated by several mechanisms. In this study, we characterized the factors that inhibit CSF secretion by monocytes. Three cytokines have inhibitory effects: interleukin (IL)-4, IL-10, and IL-13. Among these, IL-4 and IL-10 have higher potency than IL-13. IL-4 and IL-13 affect GM-CSF and G-CSF secretion to the same extent. In contrast, exogenously added IL-10 has a stronger inhibitory effect on GM-CSF secretion than on G-CSF secretion. We also found that monocytes produce IL-10 with an autocrine downregulatory effect, and that this autocrine IL-10 reaches concentrations at which in most cases only GM-CSF (not G-CSF) secretion is significantly affected. We postulate that the disparate effect of IL-10 on monocyte secretion of the two CSFs reflects their physiological functions, with GM-CSF being mainly a proinflammatory cytokine working in the local compartment and G-CSF functioning mainly as a cell recruiting factor.

Granulocyte Colony-Stimulating Factor↗
PubMed1991

Nocturnal growth hormone secretion does not affect diurnal variations in arginine and glucose-stimulated insulin secretion.

There is a diurnal variation in insulin secretion, with higher values in the morning (AM) than in the afternoon (PM). This study tested the hypothesis that nocturnal human growth hormone (hGH) secretion might be the mechanism producing this diurnal variation in insulin secretion. Six healthy normal-weight men were studied on four occasions: twice in the early morning (AM) and twice in the afternoon (PM). Oral methscopolamine (Pamine), an anticholinergic agent that blocks hGH release, was administered at bedtime prior to the AM study or before breakfast for the PM study. An index of insulin secretion in all four tests was obtained from measurement of the acute release of insulin in response to two intravenous (IV) boluses of arginine, one given basally and the other given after raising glucose levels to approximately 150 mg/dL above the baseline. Insulin secretion was significantly greater in the morning than in the afternoon in both control and methscopolamine-pretreated subjects. The mean peak hGH was reduced in subjects pretreated with oral methscopolamine. Drug treatment reduced insulin secretion proportionally in the morning and afternoon. These results suggest that the diurnal insulin response to stimulation with arginine during a hyperglycemic clamp persists despite complete suppression of hGH by anticholinergic blockade, and that the diurnal insulin secretion is not caused by sleep- or meal-induced GH secretion.

Adult↗
PubMed1986

Interaction of acetylcholine and gastric inhibitory polypeptide on endocrine and exocrine rat pancreatic secretion: augmentation of acetylcholine-induced amylase and volume secretion by the insulinotropic action of gastric inhibitory polypeptide.

Exocrine pancreatic secretion is under partial control of endocrine pancreatic hormones. We studied the interaction of three doses of acetylcholine (Ach), a stimulator of exocrine and endocrine pancreatic secretion, with one dose of gastric inhibitory polypeptide (GIP) which is strongly insulinotropic, but has no effect on exocrine pancreatic secretion. The effects of Ach and GIP on insulin secretion from the rat pancreas were additive at 0.05 X 10(-6) M Ach and slightly, but not significantly less than additive at 0.25 or 2.5 X 10(-6) M Ach. GIP had an augmenting effect on amylase and volume secretion from the pancreas, when pancreatic secretion was stimulated by 2.5 X 10(-6) M Ach, but not by 0.05 or 0.25 X 10(-6) M. Exogenous rat insulin could exert an effect similar to that of GIP, although a higher dose was required. Atropine inhibited the effect of Ach on exocrine and endocrine pancreatic secretion, but not the insulinotropic action of GIP. It is hypothesized that GIP could play a role in regulating exocrine pancreatic secretion by its insulinotropic action.

Acetylcholine↗
PubMed2003

Mastoparan-induced insulin secretion from insulin-secreting betaTC3 and INS-1 cells: evidence for its regulation by Rho subfamily of G proteins.

Mastoparan, a tetradecapeptide from wasp venom, stimulates insulin secretion from the islet beta-cells, presumably via activation of trimeric G proteins. Herein, we used Clostridial toxins, which selectively modify and inactivate the Rho subfamily of G proteins, to examine whether mastoparan-induced insulin secretion also involves activation of these signaling proteins. Mastoparan, but not mastoparan 17 (an inactive analog of mastoparan), significantly stimulated insulin secretion from betaTC3 and INS-1 cells. Preincubation of betaTC3 cells with either Clostridium difficille toxin B, which inactivates Rho, Cdc42, and Rac, or Clostridium sordellii toxin, which inactivates Ras, Rap, and Rac, markedly attenuated the mastoparan-induced insulin secretion, implicating Rac in this phenomenon. Mastoparan-stimulated insulin secretion was resistant to GGTI-2147, a specific inhibitor of geranylgeranylation of Rho G proteins (e.g. Rac), suggesting that mastoparan induces direct activation of Rac via GTP/GDP exchange. This was confirmed by a pull-down assay that quantifies the binding of activated (i.e. GTP-bound) Rac to p21-activated kinase. However, glucose-induced insulin secretion from these cells was abolished by toxin B or GGTI-2147, suggesting that the geranylgeranylation step is critical for glucose-stimulated secretion. Mastoparan significantly increased the translocation of cytosolic Rac and Cdc42 to the membrane fraction. Confocal light microscopy revealed a substantial degree of colocalization of Rac (and, to a lesser degree, Cdc42) with insulin in beta-cells exposed to mastoparan. Further, stable expression of a dominant negative (N17Rac) form of Rac into INS-1 cells resulted in a significant reduction in mastoparan-stimulated insulin secretion from these cells. Taken together, our findings implicate Rho G proteins, specifically Rac, in mastoparan-induced insulin release.

Animals↗
PubMed2003

Insulin constitutively secreted by beta-cells is necessary for glucose-stimulated insulin secretion.

Four hypotheses have been posited on the role of insulin in glucose-stimulated insulin secretion; available evidence has supported insulin as being 1) essential, 2) a positive modulator, 3) a negative modulator, or 4) not necessary. Because circulating insulin levels in mice, before or after intraperitoneal glucose injection, are sufficient to elicit insulin responses in insulin-sensitive tissues, it is likely that beta-cell insulin receptors are continuously exposed to stimulating concentrations of insulin. To determine whether constitutively secreted insulin is necessary for glucose-stimulated insulin secretion, CD1 male mouse islets were incubated for 30 min at 4 degrees C in the absence (control) or presence of anti-insulin (1 micro g/ml) or anti-IgG (1 micro g/ml). Then islets were exposed to 3, 11, or 25 mmol/l glucose or to 20 mmol/l arginine. Nontreated islets exhibited first- and second-phase glucose-stimulated insulin secretion. Control and anti-IgG-treated islets, after a 5-min lag phase, increased their insulin secretion in 25 mmol/l glucose. Anti-insulin-treated islets secreted insulin at a basal rate in 3 or 25 mmol/l glucose buffers. Insulin secretion stimulated by 20 mmol/l arginine was the same in islets pretreated with either antibody and showed no lag phase. Taken together, these data suggest that constitutively secreted insulin is required and sufficient for beta-cells to maintain sensitivity to glucose.

Animals↗
PubMed2006

Postprandial suppression of glucagon secretion depends on intact pulsatile insulin secretion: further evidence for the intraislet insulin hypothesis.

Type 2 diabetes is characterized by an approximately 60% loss of beta-cell mass, a marked defect in postprandial insulin secretion, and a failure to suppress postprandial glucagon concentrations. It is possible that postprandial hyperglucagonemia in type 2 diabetes is due to impaired postprandial insulin secretion. To address this, we studied eight adult Goettingen minipigs before and after an approximately 60% reduction in beta-cell mass induced by alloxan. Pigs were studied fasting and after ingestion of a mixed meal. Insulin and glucagon secretion were determined by deconvolution of blood hormone concentrations measured at 1-min intervals. The relationship between insulin and glucagon release was analyzed using cross-correlation and forward versus reverse cross-approximate entropy. We report that glucagon and insulin were secreted in approximately 4-min pulses. Prealloxan, postprandial insulin secretion drove an approximately 20% suppression of glucagon concentrations (P < 0.01), through inhibition of glucagon pulse mass. The alloxan-induced approximately 60% deficit in beta-cell mass lead to an approximately 70% deficit in postprandial insulin secretion and loss of the postprandial insulin-driven suppression of glucagon secretion. We conclude that postprandial hyperglucagonemia in type 2 diabetes is likely due to loss of intraislet postprandial suppression of glucagon secretion by insulin.

Animals↗
PubMed1998

Quantitating secretion rates of individual cells: design of secretion assays.

To observe events occurring in the microenvironment surrounding individual cells, a mathematical framework has been developed describing the behavior of a compound following its secretion by a single cell. This description is based on the diffusional and binding processes taking place in the vicinity of the cell surface. It allows prediction of the rate of capture and accumulation of a secreted compound around a single cell. This concept provides the basis for the design of two experimental assays for measuring single-cell secretion rates: (1) Cells are immobilized in hydrogel microbeads which contain capture sites for the secreted compound; and (2) artificial receptors are bound directly to the cell surface which are capable of binding molecules secreted by individual cells. This general methodology is developed in the specific case of the model organism Saccharomyces cerevisiae secreting a heterologous protein, but can be applied to any cell/secreted protein combination. Binding studies have shown that approximately 2 x 10(5) of these artificial receptors can be attached to the surface of a single yeast cell. At this surface density of a putative artificial receptor, it is predicted that single-cell secretion rates of 47 molecules/cell/sec of a 150 kDa protein can be detected. Simulations indicate that a microbead loaded with 5 x 10(6) capture antibodies will result in detection of secretion of this protein at rates as low as 4 molecules/cell/sec.

Animals↗
PubMed2005

Automated in situ measurement of cell-specific antibody secretion and laser-mediated purification for rapid cloning of highly-secreting producers.

Cloning of highly-secreting recombinant cells is critical for biopharmaceutical manufacturing, but faces numerous challenges including the fact that secreted protein does not remain associated with the producing cell. A fundamentally new approach was developed combining in situ capture and measurement of individual cell protein secretion followed by laser-mediated elimination of all non- and poorly-secreting cells, leaving only the highest-secreting cell in a well. Recombinant cells producing humanized antibody were cultured serum-free on a capture matrix, followed by staining with fluorescently-labeled anti-human antibody fragment. A novel, automated, high-throughput instrument (called LEAP) was used to image and locate every cell, quantify the cell-associated and secreted antibody (surrounding each cell), eliminate all undesired cells from a well via targeted laser irradiation, and then track clone outgrowth and stability. Temporarily sparing an island of helper cells around the clone of interest improved cloning efficiency (particularly when using serum-free medium), and helper cells were easily eliminated with the laser after several days. The in situ nature of this process allowed several serial sub-cloning steps to be performed within days of one another, resulting in rapid generation of clonal populations with significantly increased and more stable, homogeneous antibody secretion. Cell lines with specific antibody secretion rates of > 50 pg/cell per day (in static batch culture) were routinely obtained as a result of this cloning approach, often times representing up to 20% of the clones screened.

Animals↗
PubMed1998

Macromolecular assembly and secretion across the bacterial cell envelope: type II protein secretion systems.

A decade ago, Pugsley and colleagues reported the existence of a large region of Klebsiella DNA, distinct from the Klebsiella gene encoding pullulanase, which was necessary for secretion of this enzyme to the cell surface in Escherichia coli (d'Enfert et al., 1987a,b). The pul genes it contained proved to be the tip of an iceberg. The sequences reported before 1992 (d'Enfert et al., 1987a,b; d'Enfert & Pugsley, 1989; Pugsley & Reyss, 1990; Reyss & Pugsley, 1990) included only one gene (pulD) that matched any sequence in the data base; a 220 amino acid residue segment of PulD was 32% identical with a portion of the filamentous phage-encoded protein, pIV. But by the time the sequence of the 18.8 kb DNA fragment that contained the pul genes had been completed (Possot et al., 1992), reports of sets of homologous genes in several species of Gram-negative plant and animal pathogens had appeared. For the most part, these gene clusters were cloned by their ability to complement mutants that produced, but failed to secrete, proteins normally found in the extracellular milieu; when tested, the mutants showed reduced pathogenicity or were totally avirulent. The secreted proteins included hydrolytic enzymes such as cellulase and pectinase from plant pathogens, and proteases and toxins from animal pathogens. The multi-gene family necessary for secretion of these enzymes is now known as the type II system or the main terminal branch (MTB) of the general secretion pathway (GSP). As summarized by Pugsley et al. (1997), the current tally includes type II systems from Klebsiella oxytoca (pul), Erwinia chrysanthemi and carotovora (out), Xanthomonas campestris (xps), Pseudomonas aeruginosa (xcp), Aeromonas hydrophila (exe), and Vibrio cholerae (eps). A second type II system (sps) necessary for deposition of the S-layer on the cell surface in A. hydrophila is more similar to the X. campestris than A. hydrophila genes (Thomas & Trust, 1995). The biggest surprise has been the discovery of a complete set of type II secretion genes in E. coli K12. The E. coli genes are not expressed under normal growth conditions, and a search is underway to find inducing conditions and secretion substrates (Francetic & Pugsley, 1996). Impressive progress has already been made in defining components of the pathway. What remains to be understood in mechanistic detail is how this protein secretion system functions.

Bacterial Proteins↗
PubMed1976

[Comparative study on the effect of anticholinergic substances on basic gastric secretion as well as on gastric secretion stimulated by pentagastrin or hypoglycemia (author's transl)].

The effect of orally administered ipratropiumbromide and propanthelinbromide on the basic gastric secretion as well as on the gastric secretion stimulated by pentagastrin or hypoglycemia due to application of insulin was tested intraindividually in a double blind comparative study. Drug dosage and time after the drug effect was measured varied. In addition the anticholinergic effect of ipratropiumbromide on the basic as well as on the gastric secretion stimulated by pentagastrin was compared to that of oxacepam. The inhibitory effect of ipratropiumbromide on the basic gastric secretion as well as on the secretion stimulated by pentagastrin and hypoglycemia is more pronounced than that of propanthelinbromid. The effect on the basic secretion reached its peak 450 min after drug application whereas the maximal effect on pentagastrin stimulated secretion showed earlier. The effect described was only seen with a dose of the anticholinergic drug of at least 30 mg. A combination of ipratropiumbromide+oxacepam has no effect stronger than ipratropiumbromide alone. On the contrary, it rather seems to have an augementative effect on pentagastrin stimulated gastric secretion that may be compensated completely by ipratropiumbromide. On the basic of these results a direct influence of anticholinergic substances on the parietal cell is discussed.

Adult↗
PubMed2001

mRNA stability and the secretion signal of HrpA, a pilin secreted by the type III system in Pseudomonas syringae.

Gram-negative bacteria that are pathogenic for animals or plants utilise a specialised Type III secretion system to inject effector proteins into their eukaryotic target cells. The basis for selection of the proteins to be translocated via type III systems is still enigmatic. No clearly defined consensus amino acid sequence that could serve as a specific secretion signal has been identified, and the hypothesis that an mRNA secondary structure acts as the signal has several shortcomings. We have localised a secretion signal that is sufficient to ensure the secretion of the pilin HrpA, a substrate and an indispensable extracellular component of the type III secretion machinery of Pseudomonas syringae pv. tomato DC3000, to the first 15 codons. Transcription of hrpA starts at a single site 42 bp upstream of the first codon. Gene swapping experiments revealed that altering the continuity of the 5' non-translated leader with the region including the secretion signal radically decreased accumulation of the hrpA transcript. These results indicate that an mRNA secondary structure, possibly formed in this region, is important for efficient expression of the gene. The proposed secondary structure is not, however, indispensable for the secretion of HrpA and it does not couple secretion and translation.

5' Flanking Region↗
PubMed1987

Intrahypothalamic microinfusion of corticotropin-releasing factor inhibits gastric acid secretion but increases secretion volume in rats.

Bilateral microinfusion of synthetic ovine corticotropin releasing factor (oCRF; 0-4.0 microgram/rat [0-856 pmol/rat]) into the paraventricular nucleus or the ventromedial nucleus of the rat hypothalamus inhibited gastric acid secretion in a dose-related manner. Unexpectedly, these microinfusions both decreased acid concentration and increased secretion volume; total acid output (acid concentration multiplied by secretion volume) was strongly inhibited. In the lateral hypothalamus. CRF microinfusion also both decreased acid concentration and increased secretion volume, but total acid output did not change. oCRF microinfusion into the caudate-putamen did not significantly affect any measure of gastric acid secretion even at the highest dose used. The increased secretion volume seen after oCRF microinfusion is unique; all other centrally acting inhibitors of gastric acid secretion decrease secretion volume. It is possible that hypothalamic CRF may influence gastric secretory function.

Animals↗
PubMed1989

Extracellular Na+ removal enhances granule secretion in platelets--evidence that Na+/H+ exchange is inhibitory to secretion induced by some agonists.

The effect of extracellular Na+ [( Na+]e) removal on agonist-induced granule secretion in platelets in relation to [pH]i and [Ca2+]i changes was investigated. Substitution of [Na+]e with choline+ of K+ resulted in a significant enhancement of 5HT secretion induced by thrombin, collagen, U46619 and the protein kinase C activators, PMA and diC8. Increases in [Ca2+]i induced by thrombin and U46619 were slightly inhibited or unaffected in these buffers, but [pH]i increases induced by thrombin, U46619, PMA and diC8 were abolished and a drop in [pH]i (0.05 0.1 units below resting) was observed. Although preincubation with potassium acetate produced a big drop in [pH]i and greatly increased secretion with all the agonists, particularly in the absence of [Na+]e, clear evidence that [pH]i rises due to Na+/H+ exchange are inhibitory to secretion was obtained only with thrombin. Thus, (i) NH4Cl, which restored the increase in [pH]i in the absence of [Na+]e reduced the potentiated secretory response to thrombin, (ii) no increase in thrombin-induced secretion was observed when Na+ was replaced with Li+, which allowed a normal increase in [pH]i and (iii) ethyl isopropyl amiloride (EIPA) abolished the [pH]i rise and potentiated thrombin-induced secretion. With collagen and U46619, the results suggest that removal of [Na+]e per se rather than inhibition of Na+/H+ exchange results in enhanced secretion. It is concluded that [Na+]e per se and [pH]i elevations via Na+/H+ exchange both have important inhibitory roles in the control of platelet granule secretion.

Blood Platelets↗
PubMed1989

Determinants of bile secretion: effect of bile salt structure on bile flow and biliary cation secretion.

The effect of five bile salts, deoxycholate, chenodeoxycholate, cholate, ursodeoxycholate, and ursocholate, possessing (in decreasing order) different hydrophobicity, on bile flow and biliary secretion of total calcium, magnesium, sodium, and potassium was studied in 10 patients with T-tubes. Each subject was infused intraduodenally with one or two bile salts, given separately, to produce a selective enrichment of biliary bile salts with the infused bile salt. The choleresis induced per 1-mumol increase of bile salt output was greater during the secretion of 7 beta-hydroxylated bile salts, ursodeoxycholate (0.029 ml), and ursocholate (0.027 ml), followed in decreasing order by deoxycholate (0.023 ml), chenodeoxycholate (0.019 ml), and cholate (0.009 ml). Deoxycholate stimulated the greatest increase in cation secretion per unit increase in bile salt output, followed by chenodeoxycholate and cholate. The two 7 beta-hydroxylated bile salts induced greater cation secretion than did their 7 alpha-epimers. Whereas biliary concentration of divalent cations differed depending on the structure and concentration of the infused bile salt, the concentration of monovalent cations was constant for any species and concentration of infused bile salt. Relationships between bile salt and divalent cation concentration indicate that 1 mumol of secreted biliary deoxycholate, the most hydrophobic bile salt, associates with the greatest amount of calcium (0.046 mumol) and magnesium (0.022 mumol), followed by chenodeoxycholate (0.020 and 0.010 mumol, respectively) and cholate (0.012 and 0.008 mumol, respectively). The capacity of ursodeoxycholate and ursocholate to associate with calcium and magnesium seems to be less than that of their 7 alpha-epimers. These data suggest that of the common bile salts, the more hydrophobic bile salts stimulate bile flow and cation secretion better than the more hydrophilic bile salts, whereas ursodeoxycholate and ursocholate are more effective than their more hydrophobic 7 alpha-epimers. Whereas different bile salts seem to influence the secretion of sodium and potassium mainly by virtue of their choleretic properties, the effect of bile salt structure on biliary secretion of calcium and magnesium suggests the presence of a secretory link that might be consistent with cation-bile salt binding.

Bile↗
PubMed1990

Concentrative biliary secretion of ceftriaxone. Inhibition of lipid secretion and precipitation of calcium ceftriaxone in bile.

The hepatic transport of ceftriaxone, a third-generation cephalosporin, was characterized in the rat and hamster; its effect on bile flow and bile acid-induced biliary lipid secretion was also measured. In anesthetized rats with biliary fistulae, the Tmax was about 5 mumol.min-1.kg-1, and in the hamster the Tmax was about 1 mumol.min-1.kg-1. The compound was not biotransformed. At high secretion rates, the concentration of cephalosporin in bile increased to 27 mmol/L, a concentration far exceeding the solubility product of its calcium salt [2 x 10(-6) (mol/L)2], which precipitated from bile. In the rat, ceftriaxone induced choleresis (22 microL/mumol ceftriaxone, the expected value for a dianionic compound). In the isolated perfused rat liver, ceftriaxone had a fractional hepatic extraction rate averaging 3%; the compound was concentratively secreted into bile, the bile-perfusate ratio ranging from 35-250. Ceftriaxone inhibited phospholipid and cholesterol secretion induced by endogenous or exogenous bile acids; the rate of inhibition was linearly proportional to the canalicular secretion rate of ceftriaxone. Hepatic transport of ceftriaxone had no influence on hepatic secretion of ursodeoxycholyltaurine. In contrast, the net hepatic transport of ursodeoxycholic acid, ursodeoxycholyltaurine, or cholyltaurine inhibited ceftriaxone transport in a dose-dependent manner. It is concluded that ceftriaxone and bile acids share a common mechanism for hepatic transport in the rat and also interact in the processes involved in biliary lipid secretion. Biliary secretion of unbiotransformed ceftriaxone occurs at high concentrations; secondary Ca2+ entry results in the formation of supersaturated canalicular bile and subsequent precipitation as a calcium salt in the biliary tract. These data explain the formation of biliary sludge that occurs in patients undergoing high-dose ceftriaxone therapy.

Animals↗