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  • 1
    Electronic Resource
    Electronic Resource
    Reduction of thyroid hormone levels by methylsulfonyl metabolites of polychlorinated biphenyl congeners in rats (1998)
    Springer
    Archives of toxicology 72 (1998), S. 541-544 
    Details
    ISSN: 1432-0738
    Keywords: Key words Polychlorinated biphenyl ; Methylsulfonyl metabolite ; Total thyroxine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Male Sprague-Dawley rats received four consecutive intraperitoneal doses of four kinds of methylsulfonyl (MeSO2) metabolites of polychlorinated biphenyl (PCB) congeners: 3-MeSO2-2,2′,3′,4′,5,6-hexachlorobiphenyl (3-MeSO2-CB132); 3-MeSO2-2,2′,3′,4′, 5,5′-hexachlorobiphenyl (3-MeSO2-CB141); 3-MeSO2-2,2′,4′,5,5′,6-hexachlorobiphenyl (3-MeSO2-CB149) and 4-MeSO2-2,2′,4′,5,5′,6-hexachlorobiphenyl (4-MeSO2-CB149). The congeners were major MeSO2-PCBs determined in human milk, liver and adipose tissue, and the aim was to determine their effect on thyroid hormone levels. All four tested MeSO2 metabolites (20 μmol/kg once daily for 4 days) reduced serum total thyroxine levels by 22–44% at a much lower dose than phenobarbital (PB; 431 μmol/kg once daily for 4 days) on days 2, 3, 4 and 7 after the final doses. Total triiodothyronine levels were reduced 37% by treatment with 4-MeSO2-CB149 at day 7. A 30% increase in thyroid weight was produced by 3-MeSO2-CB141 treatment. Total cytochrome P450 content was increased by 3-MeSO2-CB132, 3-MeSO2-CB141 and 3-MeSO2-CB149, but not by 4-MeSO2-CB149. Thus, it is likely that the 3-MeSO2-hexachlorobiphenyls and 4-MeSO2-CB149 could influence the thyroid hormone metabolism by different mechanism(s). The results show that tested 3- and 4-MeSO2 metabolites of PCB congeners reduce thyroid hormone levels much more than PB in rats. Our finding suggests that the metabolites may act as endocrine-disrupters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050540
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  • 2
    Electronic Resource
    Electronic Resource
    Internalization of basic fibroblast growth factor at the mouse blood–brain barrier involves perlecan, a heparan sulfate proteoglycan (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 83 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In this study, the internalization mechanism of basic fibroblast growth factor (bFGF) at the blood–brain barrier (BBB) was investigated using a conditionally immortalized mouse brain capillary endothelial cell line (TM-BBB4 cells) as an in vitro model of the BBB and the corresponding receptor was identified using immunohistochemical analysis. The heparin-resistant binding of [125I]bFGF to TM-BBB4 cells was found to be time-, temperature-, osmolarity- and concentration-dependent. Kinetic analysis of the cell-surface binding of [125I]bFGF to TM-BBB4 cells revealed saturable binding with a half-saturation constant of 76 ± 24 nm and a maximal binding capacity of 183 ± 17 pmol/mg protein. The heparin-resistant binding of [125I]bFGF to TM-BBB4 was significantly inhibited by a cationic polypeptide poly-L-lysine (300 µm), and compounds which contain a sulfate moiety, e.g. heparin and chondroitin sulfate-B (each 10 µg/mL). Moreover, the heparin-resistant binding of [125I]bFGF in TM-BBB4 cells was significantly reduced by 50% following treatment with sodium chlorate, suggesting the loss of perlecan (a core protein of heparan sulfate proteoglycan, HSPG) from the extracellular matrix of the cells. This type of binding is consistent with the involvement HSPG-mediated endocytosis. RT-PCR analysis revealed that HSPG mRNA and FGFR1 and FGFR2 (tyrosine-kinase receptors for bFGF) mRNA are expressed in TM-BBB4 cells. Moreover, immunohistochemical analysis demonstrated that perlecan is expressed on the abluminal membrane of the mouse brain capillary. These results suggest that bFGF is internalized via HSPG, which is expressed on the abluminal membrane of the BBB. HSPG at the BBB may play a role in maintaining the BBB function due to acceptance of the bFGF secreted from astrocytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.01129.x
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  • 3
    Electronic Resource
    Electronic Resource
    COMPARATIVE STUDY ON α1-ADRENOCEPTOR ANTAGONIST BINDING IN HUMAN PROSTATE AND AORTA (1994)
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 21 (1994), S. 0 
    Details
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. Specific binding of [3H]-prazosin in prostatic and aortic membranes of humans was saturable and of high affinity (prostate: apparent dissociation constant, Kd= 0.35 ± 0.03 nmol/L; aorta: Kd= 0.26 ± 0.03 nmol/L). The density of [3H]-prazosin binding sites (Bmax) for prostate and aorta was 546 ± 31 and 61.6 ± 1.6 fmol/mg protein, respectively.2. Prazosin, YM617, naftopidil and urapidil competed with [3H]-prazosin for the binding sites in a dose-dependent manner in the prostate and aorta of humans. The binding affinities of these antagonists in both tissues were compared, based on the inhibition constant, Ki. Both prazosin and urapidil showed similar affinity to [3H]-prazosin binding sites in human tissue, whereas YM617 and naftopidil showed approximately a 12 and two times higher affinity, respectively, to α1-adrenoceptor sites of prostate than aorta.3. The chloroethylclonidine treatment reduced partially the Bmax values for specific [3H]-prazosin binding in the prostate and aorta of humans with little effect on the Kd values.4. These data suggest that YM617 is a relatively selective antagonist of human prostatic α1-adrenoceptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1440-1681.1994.tb02534.x
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  • 4
    Electronic Resource
    Electronic Resource
    DOWN-REGULATION OF ANGIOTENSIN II RECEPTORS IN HYPERTROPHIED HUMAN MYOCARDIUM (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 23 (1996), S. 0 
    Details
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. Specific [125I]-angiotensin II (AngII) binding in normal and hypertrophied human myocardial membranes was saturable and of high affinity. Low concentrations of unlabelled AngII and saralasin competed with [125I]-AngII for the binding sites in these tissues. Thus, saturable [125I]-AngII binding in human myocardium exhibited pharmacological specificity that characterized high affinity receptors for AngII.2. There was little difference in the apparent dissociation constant (Kd) values for [125I]-AngII binding between normal and hypertrophied human myocardium, whereas the maximal number of binding sites (Bmax) was significantly (51%) lower in the hypertrophied group. Further, PD123177, a selective antagonist of the AT2 receptor subtype, showed three orders of magnitude higher affinity for [125I]-AngII binding sites in both normal and hypertrophied myocardium than losartan, a selective antagonist of the AT1 receptor subtype; the Hill coefficients for these drugs were close to one.3. A significant decrease in Bmax and Kd values for (—)-[125I]-iodocyanopindolol binding between normal and hypertrophied human myocardium rarely occurred.4. The present study suggests that both normal and hypertrophied human myocardium predominantly contains the AT2 receptor subtype and that these receptors are down-regulated in hypertrophied tissues.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1440-1681.1996.tb02771.x
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacodynamics and Pharmacokinetics of Iganidipine (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Cardiovascular drug reviews 14 (1996), S. 0 
    Details
    ISSN: 1527-3466
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3466.1996.tb00227.x
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  • 6
    Electronic Resource
    Electronic Resource
    Inhibition of cell-cell communication by methylsulfonyl metabolites of polychlorinated biphenyl congeners in rat liver epithelial IAR 20 cells (1998)
    Springer
    Archives of toxicology 72 (1998), S. 178-182 
    Details
    ISSN: 1432-0738
    Keywords: Key words Polychlorinated biphenyl ; Methylsulfonyl metabolite ; Gap junction intercellular communication ; IAR 20 rat liver epithelial cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of three polychlorinated biphenyl (PCB) congeners and their six methylsulfonyl (MeSO2)-metabolites on cell communication have been investigated in the scrape-loading/dye-transfer assay in IAR 20 rat liver epithelial cells. The results demonstrated that at non-cytotoxic concentrations 2,2′,4′,5-tetrachlorobiphenyl, 2,2′,4′,5,5′-pentachlorobiphenyl (2,2′,4′,5,5′-pentaCB), 2,2′,4′,5,5′,6-hexachlorobiphenyl (2,2′,4′,5,5′, 6-hexaCB), and their 3- and 4-MeSO2 derivatives completely inhibited the cell communication within 1 h. 4-MeSO2-2,2′,4′,5,5′-pentaCB and 4-MeSO2-2,2′,4′,5, 5′,6-hexaCB appeared to inhibit the cell communication at slightly lower concentration than their parental PCB congeners and 3-MeSO2 derivatives. The results show that 3- and 4-MeSO2 derivatives of the PCB congeners tested inhibit gap junction intercellular communication at about the same potency as their parental compounds. Since inhibition of cell communication is often observed after treatment with many tumor promoters, our findings suggest that the metabolites may also act as tumor promoters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050484
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  • 7
    Electronic Resource
    Electronic Resource
    Study on Brain Interstitial Fluid Distribution and Blood-Brain Barrier Transport of Baclofen in Rats by Microdialysis (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1838-1844 
    Details
    ISSN: 1573-904X
    Keywords: baclofen ; blood-brain barrier ; microdialysis ; organic anion transport system ; probenecid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. This study was performed to examine the distribution in the brain interstitial fluid (ISF) and the blood-brain barrier (BBB) transport of baclofen in rats by a microdialysis technique. Methods. Following an i.v. bolus administration and/or the constant i.v. infusion of baclofen to the microdialysis cannula-bearing anesthetized rats, the concentrations of baclofen in the hippocampal ISF, whole brain tissue, cerebrospinal fluid (CSF), and plasma were determined by high-performance liquid chromatography (HPLC). Data were kinetically analyzed to estimate the transport parameters, i.e., the influx clearance (CLin) from plasma to brain and the efflux rate constant (keff) from brain to plasma, and the steady-state volume of distribution in the brain (Vd). Results. The concentrations of baclofen in ISF, whole brain tissue, and CSF at the pseudo-steady state were almost 30-fold lower than the plasma unbound concentration, suggesting the restricted distribution of baclofen in the brain. The estimated values of CLin and keff were 0.00157 ± 0.00076 ml/min/g of brain and 0.0872 ± 0.0252 min−1, respectively. The efflux clearance (CLout) calculated by multiplying keff by Vd (0.816 ± 0.559 ml/g of brain) was 0.0712 ± 0.0529 ml/min/g of brain, and it was significantly 40-fold greater than the CLin value and fully greater than the convective flow in ISF. Furthermore, no significant concentration gradient was observed between ISF and CSF. These results suggest that the CLout value mainly reflects the efflux clearance through the BBB. Additionally, the hippocampal ISF/plasma concentration ratio of baclofen was markedly increased by both systemic administration of probenecid and its direct instillation into ISF. Conclusions. The restricted distribution of baclofen in the brain ISF may be ascribed to the efficient efflux from the brain through the BBB which is regulated possibly by a probenecid-sensitive organic anion transport system.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016263032765
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  • 8
    Electronic Resource
    Electronic Resource
    Correlation Between the Plasma Concentration of Mepirodipine and Its Occupancy of Ca2+ Antagonist Receptors in Rats (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 1346-1349 
    Details
    ISSN: 1573-904X
    Keywords: Ca2+ antagonist ; plasma concentration ; receptor occupancy ; heart ; brain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The relationship between the plasma concentration of mepirodipine (1,4-dihydropyridine Ca2+ antagonist) and its occupancy of cardiac and cerebral Ca2+ antagonist receptors in rats has been characterized by a radioreceptor assay technique using ( + )-[3H]PN 200-110. Oral administration of mepirodipine in rats produced a dose-dependent and sustained decrease in the number of specific ( + )-[3H]PN 200-110 binding sites in both tissues, and the effect was more pronounced in the cardiac tissue than in the cerebral cortex. The occupancy of cardiac and cerebral Ca2+ antagonist receptors by mepirodipine correlated well with its plasma concentration, whereas a 20-fold higher plasma concentration of this drug was necessary to occupy Ca2+ antagonist receptors in the cerebral cortex. Thus, these data suggest that mepirodipine occupies Ca2+ antagonist receptors in cardiovascular tissue selectively over those in brain tissue.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018982116273
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  • 9
    Electronic Resource
    Electronic Resource
    Receptor Occupancy in Myocardium, Adrenal Cortex, and Brain by TH-142177, a Novel AT1 Receptor Antagonist in Rats, in Relation to Its Plasma Concentration and Hypotensive Effect (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 911-917 
    Details
    ISSN: 1573-904X
    Keywords: angiotensin II receptor antagonist ; TH-142177 ; rat tissues ; ex vivo receptor occupancy ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To study the relationship between angiotensin II (All) receptor occupancy ex vivo in tissues plasma concentration and hypotensive effect of a novel All receptor antagonist, TH-142177 and losartan in rats. Methods. At 2, 8 and 24 hr after oral administration of TH-142177 and losartan in rats, All receptors in myocardium, adrenal cortex and cerebral cortex were determined by radioligand binding assay using [125I]Sar1,Ile8-AII. Plasma concentrations of both drugs and metabolite in rats were also measured using validated HPLC assays. Further, systolic blood pressure (SBP) in conscious renal hypertensive rats treated orally with TH-142177 and losartan were measured by using a tail cuff plethysmographic method. Results. Oral administration of TH-142177 (1.8 and 5.5 μmol/kg) and losartan (6.5 and 21.7 μmol/kg) in rats brought about dose-dependent decreases in [125I]Sar1,Ile8-AII binding sites (Bmax) in myocardium and adrenal cortex. The extent of receptor occupancy by both drugs in adrenal cortex was maximal at 2 hr later but that in myocardium at 8 hr later. Further, the receptor occupancy was more sustained in myocardium than adrenal cortex. The ex vivo binding affinity of TH-142177 for All receptors in these tissues was roughly three times higher than that of losartan. Also, cerebral cortical [125I]Sar1,Ile8-AII binding was significantly reduced by oral administration of losartan but not by TH-142177. The time course of All receptor occupancy by both drugs in adrenal cortex appeared to be in parallel with that of their plasma concentrations, while the time course in myocardium correlated with that of their hypotensive effects rather than plasma concentrations. Conclusions. TH-142177 produced a relatively selective and sustained occupancy ex vivo of All receptors in myocardium and adrenal cortex of rats with approximately three times greater potency than losartan. Its time course of myocardial receptor occupancy was in parallel with that of hypotensive effect rather than plasma concentration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011932800729
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  • 10
    Electronic Resource
    Electronic Resource
    In Vivo Specific Binding Characteristics and Pharmacokinetics of a 1,4-Dihydropyridine Calcium Channel Antagonist in the Senescent Mouse Brain (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 844-850 
    Details
    ISSN: 1573-904X
    Keywords: 1,4-dihydropyridine calcium channel antagonist ; (+)-[3H]PN 200-110 ; senescence-accelerated prone mouse ; brain concentration ; pharmacokinetics ; in vivo receptor binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To characterize the in vivo specific binding andpharmacokinetics of a 1,4-dihydropyridine (DHP) calcium channel antagonist, PN200-110, in the senescent brain, using senescence-accelerated pronemice (SAMP8) and senescence-resistant mice (SAMR1). Methods. Blood, brain, and heart samples were taken periodically fromSAMR1 and SAMP8 following intravenous injection of (+)-[3H]PN200-110, and the concentration of (+)-[3H]PN 200-110 in the plasmaand tissues was determined. In addition, the in vivo specific bindingof (+)-[3H]PN 200-110 in the brains of SAMR1 and SAMP8 wasmeasured periodically after intravenous injection of the radioligand. Results. There was very little significant difference between SAMR1and SAMP8 in terms of the half-life (t1/2), total body clearance (CLtot),steady-state volume of distribution (Vdss), and AUC for the plasmaconcentration of (+)-[3H]PN 200-110 after intravenous injection ofthe radioligand. The brain concentration (AUCbrain) for (+)-[3H]PN200-110 and the brain/plasma AUC ratio (AUCbrain/AUCplasma) weresignificantly lower in SAMP8 than in SAMR1, and the heartconcentration (AUCheart) and the heart/plasma AUC ratio (AUCheart/AUCplasma)were similar in both strains. Also, the brain/plasma unbound AUCratio (AUCbrain/AUCplasma-free) for (+)-[3H]PN 200-110 wassignificantly lower in SAMP8 than in SAMR1. The in vivo specific binding(AUCspecific binding, maximal number of binding sites: Bmax) of(+)-[3H]PN 200-110 was significantly lower in brain particulate fractionsof SAMP8 than SAMR1. Conclusions. The concentration and in vivo specific binding of(+)-[3H]PN 200-110 was significantly reduced in the senescent brain. Thesimultaneous analysis of the concentrations of centrally acting drugsand the in vivo specific binding in the brain in relation to theirpharmacokinetics may be valuable in evaluating their CNS effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007512426420
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