Hydrocortisone treatment increases the sensitivity and responsiveness to cholecystokinin in rat pancreas

1989 ◽  
Vol 257 (3) ◽  
pp. G364-G370 ◽  
Author(s):  
M. Otsuki ◽  
Y. Okabayashi ◽  
T. Nakamura ◽  
M. Fujii ◽  
S. Tani ◽  
...  
Keyword(s):  
Ionophore A23187 ◽  
Pancreatic Acini ◽  
Cck Receptors ◽  
Cyclic Monophosphate ◽  
Dna Contents ◽  
Wet Weight ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Hydrocortisone Treatment

The effects of hydrocortisone treatment on the secretory abilities of pancreatic acini to various secretagogues were studied. Rats were given subcutaneous injections of hydrocortisone at doses of 1.25, 2.5, or 5.0 mg/kg body wt once daily for 7 days. Hydrocortisone led to a small dose-dependent increase in pancreatic wet weight per 100 g body wt, which was associated with an increase in both total protein and DNA contents. In acini prepared from hydrocortisone-treated rats, both the responsiveness and the sensitivity to cholecystokinin octapeptide (CCK-8) was increased. The concentration dependence of cellular Ca2+ mobilization in response to CCK-8 was also shifted to lower concentrations in acini from hydrocortisone-treated rats compared with control rat acini. In vivo administration of hydrocortisone caused a significant increase in the affinity of 125I-CCK-8 binding to high-affinity receptors. The secretory responsiveness to carbamylcholine and bombesin, but not to secretin, was also increased but without any change in the sensitivity. Moreover, the hydrocortisone treatment increased the secretory responsiveness of acini to the Ca2+ ionophore A23187 and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate but did not to an adenosine 3',5'-cyclic monophosphate analogue, 8-bromoadenosine 3',5'-cyclic monophosphate. The present observations suggest that in vivo glucocorticoid administration affects both the CCK receptors and a postreceptor loci.

Amylase secretion by isolated pancreatic acini after chronic cholecystokinin treatment in vivo

1983 ◽  
Vol 244 (6) ◽  
pp. G683-G688 ◽  
Author(s):  
M. Otsuki ◽  
J. A. Williams
Keyword(s):  
Amylase Secretion ◽  
Response Curves ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Subcutaneous Injections ◽  
Cck Receptors ◽  
Wet Weight ◽  
Initial Content ◽  
And Control

Rats were given subcutaneous injections of synthetic cholecystokinin octapeptide (CCK8, 5 micrograms/kg) in a depot carrier twice daily for 7–14 days. The pancreatic wet weight increased by 20.6 and 30.9% in the rats treated with CCK8 for 7 and 14 days, respectively. The increase in pancreatic weight was associated with an increase in the amount of protein per DNA, indicating hypertrophy of the acinar cells, and with an increase in the total amount of pancreatic DNA. Moreover, CCK administration also increased the amylase content per DNA. In acini prepared from CCK8-treated rats, responsiveness to CCK8 was increased when amylase release was expressed relative to DNA but was decreased when calculated as the percentage of the initial content in the acini. The dose-response curves for CCK8 were similarly shaped in both CCK8-treated and control rats, but they were shifted 3- to 10-fold toward higher concentrations of CCK8 after 7 and 14 days of CCK8 treatment. There were no major changes in the affinity and capacity of CCK receptors determined by studying the binding of radioiodinated CCK, suggesting that alterations in pancreatic amylase release were due to changes at a postreceptor loci. In support of this hypothesis, the secretory response to carbachol, known to act on a different receptor but by a common intracellular mechanism, was altered in a manner identical to the response to CCK8. Thus chronic stimulation with CCK sufficient to induce pancreatic hypertrophy does not greatly alter CCK receptors and induces only moderate postreceptor desensitization.

Glutathione depletion inhibits amylase release in guinea pig pancreatic acini

1983 ◽  
Vol 244 (3) ◽  
pp. G273-G277
Author(s):  
W. F. Stenson ◽  
E. Lobos ◽  
H. J. Wedner
Keyword(s):  
Guinea Pig ◽  
Reduced Glutathione ◽  
Glutathione Depletion ◽  
Amylase Secretion ◽  
Ionophore A23187 ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Stimulus Secretion Coupling ◽  
Dose Dependent ◽  
Higher Doses

Isolated guinea pig pancreatic acini were specifically depleted of glutathione by treatment with 2-cyclohexene-1-one (2-CHX-1). Untreated acini contained 4.3 +/- 0.6 micrograms of glutathione per milligram protein. Incubation with 1 mM 2-CHX-1 for 5 min at 37 degrees C depleted glutathione to 17% of control values; 5 mM 2-CHX-1 depleted glutathione to less than 4% of control values. Incubation with 2-CHX-1 also impaired the ability of the isolated acini to secrete amylase in response to stimulation with carbachol and the ionophore A23187. The depletion of glutathione and the inhibition of amylase secretion by 2-CHX-1 were both dose dependent and time dependent. Incubation of acini with 2 mM 2-CHX-1 for 15 min at 37 degrees C reduced glutathione levels to 6.6% of control and reduced carbachol-stimulated amylase release to 63% of control. Higher doses of 2-CHX-1 or longer incubations resulted in greater depletion of glutathione and greater inhibition of carbachol-induced amylase release. These data indicate that specific depletion of glutathione impairs the ability of isolated acini to secrete amylase in response to physiological and pharmacologic stimuli and suggest that glutathione has a role in stimulus-secretion coupling in the exocrine pancreas.

Leukotriene D4 induces MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells

1996 ◽  
Vol 271 (6) ◽  
pp. L1014-L1022 ◽  
Author(s):  
R. Rajah ◽  
S. E. Nunn ◽  
D. J. Herrick ◽  
M. M. Grunstein ◽  
P. Cohen
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Smooth Muscle Cells ◽  
Igf Binding Proteins ◽  
Leukotriene D4 ◽  
Igf Binding ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Insulin Like Growth Factors

We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene D4 (LTD4) is comitogenic with insulin-like growth factors (IGF) in airway smooth muscle (ASM) cells. This synergistic effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-produced inhibitory IGF-binding proteins (IGFBP). In this report, we analyzed the conditioned media (CM) from LTD4-treated human ASM cells (ASM-LTD4-CM) by Western ligand blotting and demonstrated a marked LTD4-induced reduction in the levels of the intact IGFBP (predominantly IGFBP-2) secreted by these cells. The IGFBP-2 in the ASM-LTD4-CM was identified as lower-molecular-weight fragments by Western immunoblotting. Incubation with 125I-labeled IGFBP demonstrated that an IGFBP protease was induced in the ASM cells in response to LTD4 treatment. Immunodepletion of ASM-LTD4-CM with anti-matrix metalloproteinase (MMP)-1 antibodies demonstrated a dose-dependent reduction of IGFBP proteolysis. Tissue inhibitor of MMP-1 and Batimastat (synthetic) inhibited proteolysis of IGFBP. Immunoblotting the ASM-LTD4-CM with anti-MMP-1 demonstrated a dose-dependent increase in MMP-1 protein. Similar results were also obtained by immunocytochemistry. Collectively, these observations demonstrate that MMP-1 is an IGFBP protease induced by leukotrienes that plays a significant role in modulating IGF action in ASM cells. A similar mechanism may be applicable in vivo in the airways of patients with asthma.

Cholecystokinin downregulates receptors for vasoactive intestinal peptide and secretin in rat pancreatic acini

1990 ◽  
Vol 258 (3) ◽  
pp. G395-G403
Author(s):  
S. Katsushima ◽  
H. Adachi ◽  
T. Honda ◽  
S. Sato ◽  
T. Kusui ◽  
...  
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Binding Sites ◽  
Specific Binding ◽  
Amylase Secretion ◽  
Affinity Binding ◽  
Pancreatic Acini ◽  
Cck Receptors ◽  
Cyclic Monophosphate ◽  
Apparent Decrease ◽  
Specific Antagonist

We examined the effect of cholecystokinin (CCK) on the receptors for vasoactive intestinal peptide (VIP) and secretin in rat pancreatic acini. CCK decreased the specific binding of 125I-VIP and 125I-secretin by 42 and 51%, respectively. This CCK-induced inhibition was caused by an apparent decrease in the capacity of high-affinity binding sites of VIP and secretin receptors. CR 1409, a specific antagonist of CCK, abolished CCK-induced binding inhibition, whereas 12-O-tetradecanoylphorbol-13-acetate, A23187, and cycloheximide did not affect the binding of the radioligands. Both N2,O2-dibutyryl guanosine 3',5'-cyclic monophosphate (Bt2cGMP) and nitroprusside inhibited the specific binding of 125I-VIP. This inhibition, however, was because of an apparent decrease in the capacity of low-affinity binding sites on VIP receptors. CCK-induced downregulation of VIP and secretin receptors was associated with the diminished acinar response to VIP or secretin-induced adenosine 3',5'-cyclic monophosphate accumulation and amylase secretion, whereas neither Bt2cGMP nor nitroprusside affected VIP-induced amylase secretion. Data suggest that CCK-induced downregulation is mediated by the initial interaction of CCK with CCK receptors followed by some postreceptor process, which appears unrelated to protein kinase C, calcium mobilization, decrease in protein synthesis, or cellular cGMP increases. This downregulation, at least in part, accounts for CCK-induced restricted stimulation of amylase secretion by VIP and secretin.

Regulation of bombesin receptors on pancreatic acini by cholecystokinin

1989 ◽  
Vol 256 (2) ◽  
pp. G291-G298
Author(s):  
M. Younes ◽  
S. A. Wank ◽  
R. Vinayek ◽  
R. T. Jensen ◽  
J. D. Gardner
Keyword(s):  
Guinea Pig ◽  
Response Curve ◽  
Binding Capacity ◽  
The Other ◽  
Single Class ◽  
Pancreatic Acini ◽  
Cck Receptors ◽  
Cyclic Monophosphate ◽  
High Affinity ◽  
Bombesin Receptors

When guinea pig pancreatic acini are first incubated with the COOH-terminal octapeptide of cholecystokinin (CCK-8), washed, and then reincubated with 125I-[Tyr4]bombesin (125I-[Tyr4]BN) there is a significant decrease in binding of 125I-[Tyr4]BN compared with that observed with pancreatic acini that have been first incubated with no additions. The CCK-8-induced decrease in binding is maximal after 90 min of first incubation is abolished by reducing the temperature of the first incubation from 37 to 4 degrees C or by adding L364,718 to the first incubation and cannot be reproduced by first incubating acini with A23187, 8-bromoadenosine 3',5'-cyclic monophosphate (8Br-cAMP), 8-bromoadenosine 3',5'-cyclic monophosphate (8Br-cGMP), or 12-O-tetradecanoylphorbol 13-acetate. 125I-[Tyr4]BN interacts with a single class of receptors on pancreatic acini, and first incubating acini with CCK-8 decreases the affinity of BN receptors for BN with no change in the maximal binding capacity. CCK-8 does not alter the rate at which bound 125I-[Tyr4]BN dissociates from pancreatic acini; therefore, CCK-8 must alter the rate at which the radiolabeled BN analogue associates with its receptor. Pancreatic acini possess two classes of CCK receptors: one has a high affinity for CCK-8; the other has a low affinity for CCK-8. The dose-response curve for CCK-8-induced inhibition of binding of 125I-[Tyr4]BN appears to to reflect occupation of low-affinity CCK receptors by CCK-8.(ABSTRACT TRUNCATED AT 250 WORDS)

EFFECTS OF GROWTH HORMONE, PROLACTIN AND THYROXINE ON BODY WEIGHT, SOMATOMEDIN-LIKE ACTIVITY AND IN-VIVO SULPHATION OF CARTILAGE IN HYPOPITUITARY DWARF MICE

1980 ◽  
Vol 85 (1) ◽  
pp. 35-47 ◽  
Author(s):  
A. T. HOLDER ◽  
M. WALLIS ◽  
P. BIGGS ◽  
M. A. PREECE
Keyword(s):  
Growth Hormone ◽  
Costal Cartilage ◽  
Tail Length ◽  
Bovine Growth Hormone ◽  
Dwarf Mouse ◽  
Dwarf Mice ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
In Vivo Uptake

SUMMARY Hypopituitary dwarf mice were found to have reduced levels of serum somatomedin-like activity compared with normal mice of the Snell strain. Treatment with bovine growth hormone for 3 and 7 days resulted in growth without significantly increased levels of serum somatomedin-like activity, as detected by in-vitro uptake of 35SO42− into normal rat cartilage; only after treatment for 14 days was somatomedin activity significantly raised. However, treatment for 2 days with bovine growth hormone, bovine prolactin or thyroxine resulted in a dose-dependent increase in in-vivo uptake of 35SO42− into dwarf mouse costal cartilage; growth hormone and thyroxine did not act synergistically. Ten days of treatment with growth hormone promoted a dose-dependent increase in both growth (increased weight gain and tail length) and in-vivo uptake of 35SO42−. Increase in tail length was correlated with uptake of 35SO42−. Thus, in-vivo uptake of 35SO42− into dwarf mouse costal cartilage provides a sensitive method for detecting a dose-related effect of growth hormone.

scholarly journals Folate protects against oxidative modification of human LDL

2001 ◽  
Vol 86 (6) ◽  
pp. 637-639 ◽  
Author(s):  
Emi Nakano ◽  
John A. Higgins ◽  
Hilary J. Powers
Keyword(s):  
Lag Time ◽  
Oxidative Modification ◽  
Protective Effects ◽  
Unsaturated Lipids ◽  
Anti Oxidant ◽  
Total Homocysteine ◽  
Endogenous Antioxidants ◽  
Dose Dependent Increase ◽  
Dose Dependent

Elevated plasma total homocysteine is considered to be a graded risk factor for cardiovascular disease. Folate, through its homocysteine-lowering potential, may therefore be protective. Folate, however, may have protective effects independent of homocysteine-lowering. We have measured the effects of folate on Cu-catalysed oxidative damage to the unsaturated lipids in human LDL. Experiments were carried out in the presence of citrate, and followed increases in absorption at 234 nm, which measures the amount of conjugated diene produced. There is a lag time during which endogenous antioxidants are oxidised, followed by rapid oxidation of lipid. Addition of 0–6 μM-5-methyltetrahydrofolate produced a dose-dependent increase in the lag time, suggesting that folate may have a direct anti-oxidant role in vivo, which is independent of any indirect effects through lowering of homocysteine levels.

scholarly journals Corticosteroid effect on murine hemopoietic precursor cells in vivo

Blood ◽  
1981 ◽  
Vol 57 (6) ◽  
pp. 1138-1139 ◽  
Author(s):  
E Niskanen ◽  
J Squires
Keyword(s):  
Colony Formation ◽  
Precursor Cells ◽  
Diffusion Chambers ◽  
Hemopoietic Precursor Cells ◽  
Granulocytic Colony ◽  
Dose Dependent Increase ◽  
Dose Dependent

Abstract The effect of methylprednisolone on murine hemopoietic colony formation in diffusion chambers implanted in mice was evaluated. A dose-dependent increase in granulocytic colony (CFU-DG) formation from murine marrow was observed. This effect could be abrogated by administration of progesterone. These studies suggest that the murine early granulocytic precursors (CFU-DG) have receptors that mediate proliferation-promoting signals triggered by glucocorticoids. Erythroid colony formation (CFU- DE) was not effected by methylprednisolone administration.

scholarly journals METABOLIC ACTIVATION OF 2,6-DIMETHYLANILINE: MUTATIONAL SPECIFICITY IN THE GPT GENE OF AS52 CELLS

2018 ◽  
Vol 11 (9) ◽  
pp. 394
Author(s):  
Seo Hyun Moon ◽  
Min Young Kim
Keyword(s):  
Parent Compound ◽  
Chinese Hamster ◽  
Relative Survival ◽  
Metabolic Activation ◽  
Nested Polymerase Chain Reaction ◽  
Trypan Blue Exclusion ◽  
Polymerase Chain ◽  
Dose Dependent Increase ◽  
Dose Dependent

Objective: The purpose of the current work was to characterize the mechanisms of cytotoxicity and mutagenesis of a potential human bladder carcinogen 2,6-dimethylaniline (2,6-DMA).Methods: Chinese hamster ovary (CHO) AS52 cells were exposed to either human S9 activated 2,6-DMA for 6 h or its N-hydroxylamine and aminophenol metabolites for 1 h in serum-free medium. Cell survival was determined by trypan blue exclusion 24 h after treatment, and 6-thioguanine-resistant mutants at the xanthine-guanine phosphoribosyl transferase (gpt) gene locus were assessed with doses, of which relative survival is 30% or more. Nested polymerase chain reaction-based deletion analysis was also performed.Results: AS52 cells exhibited a dose-dependent increase in cytotoxicity and mutant fraction on treatment of 2,6-DMA and its metabolites but show a considerable variation in potency with aminophenol metabolites having the highest potency and parent compound at least; at the highest 2,6-dimethylaminophenol dose (10 μM), the mutant fraction in AS52 cells was 8-fold (13.2×10−5) greater than the spontaneous fraction of 1.62×10−5. Total deletion of the gpt gene sequences was found in 1 (4%) spontaneous and 2 (6%) the 6-thioguanine mutants generated by N-hydroxy-2,6-DMA.Conclusions: These findings indicate the mutagenicity of 2,6-DMA at the gpt gene, which is mediated through hydroxylamine and aminophenol metabolites, and contribute to the elucidation of mechanisms through which 2,6-DMA may exert its effects in vivo.

Regional differences in constitutive and induced ICAM-1 expression in vivo

1995 ◽  
Vol 269 (6) ◽  
pp. H1955-H1964 ◽  
Author(s):  
J. Panes ◽  
M. A. Perry ◽  
D. C. Anderson ◽  
A. Manning ◽  
B. Leone ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Regional Differences ◽  
Time Course ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Fourfold Increase ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Higher Doses

The aim of the present study was to characterize and compare the expression of intercellular adhesion molecule 1 (ICAM-1) on unstimulated and endotoxin-challenged endothelial cells in different tissues of the rat. ICAM-1 expression was measured using 125I-labeled anti-rat ICAM-1 monoclonal antibody (MAb) and an isotype-matched control MAb labeled with 131I (to correct for nonspecific accumulation of the binding MAb). Under baseline conditions, ICAM-1 MAb binding was observed in all organs. The binding of 125I-ICAM-1 MAb varied widely among organs, with the largest accumulation (per g tissue) in the lung, followed by heart (1/30th of lung activity), splanchnic organs (1/50th of lung activity), thymus (1/100th of lung activity), testes (1/300th of lung activity), and skeletal muscle (1/800th of lung activity). Endotoxin induced an increase in ICAM-1 MAb binding in all organs except the spleen. Endotoxin-induced upregulation of ICAM-1 was greatest in heart and skeletal muscle (5- to 10-fold), whereas the remaining organs exhibited a two- to fourfold increase in ICAM-1 expression. Maximal upregulation of ICAM-1 occurred at 9-12 h after endotoxin administration. A dose-dependent increase in ICAM-1 expression was elicited by 0.1-10 microgram/kg, with higher doses (up to 5 mg/kg) producing no further increment. Induction of ICAM-1 mRNA after endotoxin was observed in all tissues examined (lung, heart, intestine), peaked at 3 h, and then rapidly returned to control levels. These findings indicate that ICAM-1 is constitutively expressed on vascular endothelium in all organs of the rat and that there are significant regional differences in the magnitude and time course of endotoxin-induced ICAM-1 expression.

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