Reduction in hepatic endothelin-1 clearance in cirrhosis

2003 ◽  
Vol 105 (2) ◽  
pp. 227-234 ◽  
Author(s):  
Anh Thu TRAN DUC ◽  
Andreas J. SCHWAB ◽  
André SIMARD ◽  
Louis VILLENEUVE ◽  
Jocelyn DUPUIS
Keyword(s):  
Binding Site ◽  
Kinetic Modelling ◽  
Hepatic Clearance ◽  
Reversible Binding ◽  
Endothelin 1 ◽  
Multiple Indicator Dilution ◽  
Etb Receptor ◽  
Multiple Indicator ◽  
A Minor ◽  
Receptor Antibodies

Circulating endothelin-1 (ET-1) levels are increased in cirrhosis. The liver is an important site for circulating ET-1 clearance through the ETB receptor. We evaluated ET-1 kinetics in cirrhosis to determine if a reduced liver clearance contributes to this process. Cirrhosis was induced by carbon tetrachloride in rats. Hepatic ET-1 clearance was measured in isolated perfused livers using the single bolus multiple indicator-dilution technique. Plasma ET-1 levels doubled in cirrhosis from 0.49±0.04 fmol/ml (mean±S.E.M.) to 1.0±0.18 fmol/ml (P<0.01). Liver ET-1 extraction was reduced from 81±1% (mean±S.E.M.) in controls to 50±6% in cirrhosis (P<0.01). Kinetic modelling revealed a major irreversible binding site for ET-1 that is blocked by the selective ETB receptor antagonist BQ788 and a minor non-specific reversible binding site that cannot be blocked with BQ788 or the selective ETA antagonist BQ123. Reduced hepatic clearance correlated with the biochemical markers of cirrhosis, portal vein perfusion pressure (r=-0.457; P<0.001) and the increase in ET-1 levels (r=-0.462; P=0.002). Immunohistofluorescence with specific anti-(ETB receptor) antibodies revealed a preponderant distribution of ETB receptors on hepatic stellate cells, which was increased in cirrhosis. We conclude that cirrhosis reduces ET-1 clearance probably by capillarization of hepatic sinusoids and reduced access to ETB receptors. This relates to the severity of cirrhosis and may contribute to the increase in circulating ET-1 levels.

Differential uptake of endothelin-1 by the coronary and pulmonary circulations

1992 ◽  
Vol 73 (2) ◽  
pp. 557-562 ◽  
Author(s):  
S. Rimar ◽  
C. N. Gillis
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Pulmonary Circulation ◽  
Enzyme Inhibitor ◽  
Isolated Heart ◽  
Mean Transit Time ◽  
Converting Enzyme ◽  
Endothelin 1 ◽  
Multiple Indicator Dilution ◽  
Multiple Indicator ◽  
Heart Preparation

Substantial removal of the vasoconstrictor peptide endothelin-1 (ET-1) by the pulmonary circulation has been reported to occur in perfused guinea pig and rat lungs. We examined the uptake of ET-1 by coronary and pulmonary circulations of the rabbit by measuring single-pass extraction of ET-1 in the isolated heart and lung. In separate experiments, each organ was perfused at 30 ml/min with Krebs-albumin (3%) solution. A bolus of 125I-ET-1 and [14C]dextran in 0.3 ml Krebs-albumin solution was injected, and extraction of endothelin (EET), relative to that of an intravascular reference indicator, [14C]dextran, was determined by multiple indicator-dilution technique. EET was 5 +/- 2% (SE) in the heart and 49 +/- 4% in the lung. Increasing flow rate in the lung preparation to approximate the mean transit time in the heart preparation did not significantly alter EET. Despite insignificant uptake of ET-1, the coronary circulation extracted an angiotensin-converting enzyme inhibitor (351A) and metabolized a synthetic angiotensin-converting enzyme substrate (benzoyl-phenyl-alanyl-proline), both properties of the normal pulmonary circulation. We therefore conclude that there is no significant ET-1 uptake in the coronary vascular bed.

Influence of phenobarbital on the hepatic handling of [3H]vitamin D3 in the dog

1986 ◽  
Vol 251 (5) ◽  
pp. G627-G635 ◽  
Author(s):  
M. Gascon-Barre ◽  
S. Vallieres ◽  
P. M. Huet
Keyword(s):  
Enzyme Induction ◽  
Vitamin D3 ◽  
Hepatic Clearance ◽  
Correlation Coefficients ◽  
Hepatic Uptake ◽  
Indicator Dilution ◽  
Strong Positive Correlation ◽  
Dihydroxyvitamin D3 ◽  
Multiple Indicator Dilution ◽  
Multiple Indicator

The effect of phenobarbital (PB) on the hepatic handling of vitamin D3 (D3) and its metabolism to 25-hydroxyvitamin D3 [25(OH)D3] was studied in eight mongrel dogs. The hepatic uptake and clearance of [3H]D3 were evaluated by the multiple indicator-dilution curve technique, and the formation of [3H]25(OH)D3 was evaluated by sampling the hepatic effluent. The hepatic enzyme induction was assessed in six dogs by the 14CO2 breath excretion test. The results show that the hepatic uptake of [3H]D3 was not significantly affected but that its hepatic clearance was significantly increased during PB treatment. The [3H]25(OH)D3 production was increased during PB administration by a factor of 3–5 times over the pre- or post-PB period. Evaluation of the enzyme induction produced by PB revealed that two of the dogs studied had a blunted response to PB; furthermore, these dogs were the only animals that showed no increase in [3H]25(OH)D3 production during PB treatment and that in the presence of similar serum PB, endogenous 25(OH)D3 and 1,25-dihydroxyvitamin D3 pools, and hepatic uptake and clearance of [3H]D3. Strong positive correlation coefficients were observed between the breath excretion of 14CO2 and the [3H]25(OH)D3 production during PB treatment, whereas no correlation was present in the absence of PB. These observations show that, in most animals, PB is accompanied by an increased hepatic clearance of [3H]D3 and by an increased production of [3H]25(OH)D3. The data obtained during the present study also show that the response to PB is heterogeneous and that some animals escaped PB-mediated enzyme induction.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary removal and production of endothelin in the anesthetized dog

1994 ◽  
Vol 76 (2) ◽  
pp. 694-700 ◽  
Author(s):  
J. Dupuis ◽  
C. A. Goresky ◽  
D. J. Stewart
Keyword(s):  
Blue Dye ◽  
Blood Samples ◽  
Endothelin 1 ◽  
Multiple Indicator Dilution ◽  
Significant Difference ◽  
Anesthetized Dogs ◽  
Multiple Indicator ◽  
Pulmonary Arterial ◽  
Arteriovenous Difference ◽  
Dilution Curves

The single-bolus multiple-indicator-dilution technique was used to evaluate pulmonary removal of tracer 125I-labeled endothelin-1 in seven anesthetized dogs. Simultaneously, pulmonary arterial and aortic blood samples were obtained and assayed to determine the levels of immunoreactive endothelin-1. When 125I-endothelin-1 was compared with a plasma vascular reference (Evans blue dye), there was a single passage mean extraction of 31 +/- 8%. In contrast, there was no significant difference between immunoreactive endothelin-1 levels measured in blood samples from the pulmonary artery and the aorta (1.26 +/- 0.58 and 1.37 +/- 0.50 pg/ml, respectively; P = 0.47). The absence of an arteriovenous difference for bulk endothelin-1 across the lungs in the presence of tracer data indicating a substantial uptake implies that an amount of endothelin-1 quantitatively more or less equal to that removed is produced by the lung. The shapes of the dilution curves suggest that the tracer endothelin uptake by the lung is a one-way process without vascular reentry of tracer. We conclude that the dog lung is an important site for both uptake and release of endothelin-1.

Anti-thyrotrophin receptor antibodies in Graves' disease as demonstrated directly by immunoprecipitation assay

1983 ◽  
Vol 102 (1) ◽  
pp. 49-56 ◽  
Author(s):  
Tjerk W. A de Bruin ◽  
Daan van der Heide ◽  
Maria C. Krol
Keyword(s):  
Binding Site ◽  
Tsh Receptor ◽  
Graves Disease ◽  
Immunoprecipitation Assay ◽  
Receptor Complexes ◽  
Auto Antibody ◽  
Receptor Antibodies ◽  
Normal Controls

Abstract. An immunoprecipitation assay was developed to determine the presence of antibodies against human TSH1 receptors. With this assay we were able to demonstrate that in comparison with sera from normal controls, 24 out of 30 (80%) sera from patients with untreated Graves' disease could immunoprecipitate more [125I]TSH-TSH receptor complexes. In 9 assays, an average of 14.1 ± 3.7% (sd) of the [125I]TSH-TSH receptor complexes was immunoprecipitated by the 30 Graves' sera vs 9.8 ± 3.0% by the normal pool serum (n = 23) (P < 0.001) and 7.7 ± 2.8% by the 22 normal sera (P < 0.001). One serum of the 24 positive Graves' sera was studied in detail. The results suggest that this serum contained an anti-TSH receptor auto-antibody directed towards a different determinant on the TSH receptor than the TSH binding site.

scholarly journals Necessity of dual blockade of endothelin ETA and ETB receptor subtypes for antagonism of endothelin-1-induced contraction in human bronchi

1996 ◽  
Vol 117 (6) ◽  
pp. 995-999 ◽  
Author(s):  
Takahiro Fukuroda ◽  
Satoshi Ozaki ◽  
Masaki Ihara ◽  
Kiyofumi Ishikawa ◽  
Mitsuo Yano ◽  
...  
Keyword(s):  
Receptor Subtypes ◽  
Endothelin 1 ◽  
Etb Receptor ◽  
Dual Blockade ◽  
Human Bronchi

Transcapillary exchange of molecular weight markers in the postglomerular circulation: application of a barrier-limited model

1982 ◽  
Vol 242 (5) ◽  
pp. F436-F446
Author(s):  
C. Trainor ◽  
M. Silverman
Keyword(s):  
Molecular Weight ◽  
Excluded Volume ◽  
Excluded Volume Effects ◽  
Multiple Indicator Dilution ◽  
Filtration Barrier ◽  
Transit Times ◽  
Multiple Indicator ◽  
Dilution Experiments ◽  
Volume Effects

The permselectivity of the postglomerular capillary wall was studied by performing pulse-injection multiple indicator-dilution experiments on dog kidneys in vivo, using simultaneous injection of T1824-labeled albumin (plasma reference), creatinine (extracellular reference), and one or two radioactively labeled indicators: raffinose (595 dalton), vitamin B12 (1,357 dalton), or inulin (approximately 5,000 dalton). The urine transit patterns superimposed for all these except albumin, suggesting equal permeability for these molecular weight markers at the level of the glomerular filtration barrier. But the renal vein mean transit times progressively decreased. Therefore, their apparent interstitial volumes of distribution decrease with increasing molecular weight. This could be due to several factors acting singly or in combination: reduced capillary permeability in the postglomerular microcirculation; restricted diffusion in the postglomerular interstitium; or excluded volume effects. Evidence suggested that the effect was due to a combination of permeability and exclusion volume effects. To assess the validity of this assumption, the barrier-limited model was compared with the experimental data. The results were analyzed (both hydropenic and mannitol-diuretic dogs) and best fits calculated using two independent parameters, permeability and excluded volume. For permeability (X10(-4) cm/s, mean +/- SD) the range of values was always greater than or equal to 15 for creatinine and raffinose, and greater than or equal to 12 for B12. The permeability for inulin was 6.9 +/- 1.4. When interstitial volume excluded was expressed as percentage of the volume available to creatine, the excluded volume was negligible for raffinose and B12 but 12 +/- 5% for inulin. During mannitol diuresis the permeability for creatinine and raffinose remained high, but the values tended to decrease for B12. The permeability of inulin decreased to 2.9 +/- 0.09. Mannitol diuresis increased the excluded volume of inulin but did not alter the creatinine, raffinose, or B12 value.

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