The initial uptake of copper by the liver in the dog

1968 ◽  
Vol 46 (5) ◽  
pp. 771-784 ◽  
Author(s):  
Carl A. Goresky ◽  
Thomas H. Holmes ◽  
Andrew Sass-Kortsak
Keyword(s):  
Plasma Concentrations ◽  
Hepatic Uptake ◽  
Constant Infusion ◽  
Multiple Indicator Dilution ◽  
Dog Plasma ◽  
Major Organ ◽  
Before And After ◽  
Multiple Indicator ◽  
Wet Weight ◽  
Initial Uptake

The initial uptake of 64Cu and serum and tissue copper levels were examined in the dog. Plasma disappearance curves, multiple indicator dilution studies of initial hepatic uptake, and constant infusion experiments were carried out, at various doses, before and after preloading with cupric acetate. Over a range of plasma concentrations of direct-reacting copper extending to levels far above those encountered under physiological circumstances, little evidence of saturation of the initial hepatic uptake was evident. The countertransport of labeled copper was produced by administering unlabeled copper. The tissue levels of copper in the liver of the normal dog were, unexpectedly, found to be comparatively high, to average 82 μg/g wet weight. Attempts to produce manyfold increases in this copper content by daily intravenous copper administration failed because the doses of copper which would have been necessary to produce the increases, doses which would not have caused major toxic effects in the rat, were lethal for the dog. This low tolerance for copper loading presumably reflects the preexisting high copper concentration in the liver, the major organ which takes up exogenously administered copper. The degree of preloading which could be achieved produced no perceptible change in initial hepatic uptake. The copper levels in the liver are of the order of those found in some patients with Wilson's disease. Despite this, none of the other abnormalities which characterize this disease have been encountered in dogs.

Hepatic uptake of hippurate: a multiple-indicator dilution, perfused rat liver study

1998 ◽  
Vol 274 (1) ◽  
pp. G10-G20 ◽  
Author(s):  
Tsutomu Yoshimura ◽  
Andreas J. Schwab ◽  
Lei Tao ◽  
Ford Barker ◽  
K. Sandy Pang
Keyword(s):  
Benzoic Acid ◽  
Rat Liver ◽  
Hepatic Uptake ◽  
Indicator Dilution ◽  
Monocarboxylate Transporter ◽  
Maximal Velocity ◽  
Perfused Rat Liver ◽  
Hepatic Transport ◽  
Multiple Indicator Dilution ◽  
Multiple Indicator

The hepatic transport of hippuric acid (HA), a glycine-conjugated metabolite of benzoic acid that exhibits only modest plasma albumin binding (binding association constant of 2.1 × 103M−1), was studied in the single-pass perfused rat liver (12 ml/min), using the multiple indicator dilution (MID) technique. The venous recovery of [3H]HA on portal venous injection of a MID dose containing a mixture of a set of noneliminated reference indicators and [3H]HA revealed a survival fraction of unity, corroborating the lack of disappearance of bulk HA from plasma. When the outflow recovery was fitted to the barrier-limited model of Goresky et al. (C. A. Goresky, G. G. Bach, and B. E. Nadeau. J. Clin. Invest. 52: 991–1009, 1973), the derived influx ( P in S ) and efflux ( P out S ) permeability-surface area products were found to be dependent on the concentration of HA (1–930 μM); P in S and P out S were ∼3.5 times the plasma flow rate at low HA concentration, but decreased with increasing HA concentration. All values, however, greatly exceeded the expected contribution from passive diffusion, because the equilibrium distribution ratio of chloroform to buffer for HA was extremely low (0.0001 at pH 7.4). The tissue equilibrium partition coefficient ( P in/ P out, or ratio of influx to efflux rate constants, k 1/ k −1) was less than unity and decreased with concentration. The optimized apparent Michaelis-Menten constant and maximal velocity were 182 ± 60 μM and 12 ± 4 nmol ⋅ s−1 ⋅ g−1, respectively, for influx and 390 ± 190 μM and 29 ± 13 nmol ⋅ s−1 ⋅ g−1, respectively, for efflux. In the presence ofl-lactate (20 mM), however, P in S for the uptake of HA (174 ± 3 μM) was reduced. Benzoic acid (10–873 μM) was also effective in reducing hepatic uptake of HA (5.3 ± 0.9 μM). These interactions suggest that MCT2, the monocarboxylate transporter that mediates the hepatic uptake of lactate and other monocarboxylic acids, may be involved in HA transport.

Determination of glomerular permselectivity to neutral dextrans in the dog

1983 ◽  
Vol 245 (4) ◽  
pp. F485-F495
Author(s):  
C. Whiteside ◽  
M. Silverman
Keyword(s):  
Renal Vein ◽  
Renal Plasma Flow ◽  
Constant Infusion ◽  
Solute Flux ◽  
Left Renal Artery ◽  
Multiple Indicator Dilution ◽  
Transit Times ◽  
Multiple Indicator ◽  
T Values

The multiple-indicator-dilution (MID) technique was used to separate solute flux (Js) across the glomerular and postglomerular capillaries in vivo. Anesthetized mongrel dogs (n = 20) during mannitol diuresis received a pulse of extracellular indicators including 125I-albumin (plasma reference), [14C]inulin (glomerular reference), creatinine (interstitial reference), and a neutral [3H]dextran (specific mol wt between 10,000 and 24,000 dalton) in the left renal artery. Left renal venous and ureteric outflows were rapidly sampled. 3H-labeled dextrans 10,000-15,500 had renal vein mean transit times (t) greater than those of 125I-albumin, indicating postglomerular extraction. 3H-labeled dextrans greater than 15,500 had t values identical to those of 125I-albumin, indicating only unidirectional glomerular extraction. The glomerular fractional dextran extractions relative to simultaneously injected [14C]inulin (ED/Ei) were calculated from urine and renal vein outflow curves and ranged from 0.98 +/- 0.02 to 0.33 +/- 0.12 (SD) for mol wt 10,000 +/- 24,000. ED/Ei values were quantitatively identical to constant-infusion fractional clearances of the same dextrans. Renal plasma flow (RPF) was then deliberately reduced two-to threefold in the same dog. ED/Ei as measured by the MID technique remained unchanged during graded reduction in RPF. In constant-infusion experiments RPF was reduced from 5.78 to 2.77 ml X s-1 X 100 g-1 and GFR from 50.4 to 36.3 ml X min-1, but the fractional neutral dextran clearances remained constant. The predominance of convective solute flux across the dog glomerulus permitted calculation of glomerular reflection coefficients 0.03 +/- 0.06 to 0.85 +/- 0.03 (SD) for neutral 3H-labeled dextrans 10,000-24,000 dalton.

Pulmonary vascular extraction and distribution of antipyrine with alveolar flooding

1995 ◽  
Vol 269 (5) ◽  
pp. H1811-H1819
Author(s):  
W. O. Cua ◽  
V. Bower ◽  
C. Tice ◽  
F. P. Chinard
Keyword(s):  
Tritiated Water ◽  
Indicator Dilution ◽  
Limiting Factor ◽  
Multiple Indicator Dilution ◽  
Transit Times ◽  
Before And After ◽  
Multiple Indicator ◽  
Dilution Experiments ◽  
Orthogonal Distribution

Transport characteristics of antipyrine (AP), 22Na+, and tritiated water (THO) were assessed in dog lungs by multiple indicator-dilution experiments in vivo with anesthesia and in isolated perfused preparations before and after alveolar flooding. In controls, outflow patterns of AP and THO were nearly identical. In flooding, AP and THO patterns separated. THO upslopes decreased and mean (t) and modal (tmax) transit times increased as flooding increased; AP initial upslopes remained relatively unchanged but t increased, whereas tmax decreased. Patterns of 22Na+ were unchanged. The results indicate 22Na+ limitation at the endothelium, AP limitation only at the epithelium, and no THO limitation. A mathematical model is based on axial and orthogonal distribution of AP and THO. With alveolar flooding, diffusional distance may be a limiting factor in this distribution.

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)

The Effect of Neostigmine on Twitch Tension and Muscle Relaxant Concentration during Infusion of Mivacurium or Vecuronium

1995 ◽  
Vol 83 (1) ◽  
pp. 83-87. ◽  
Author(s):  
Janos Szenohradszky ◽  
Marie Lau ◽  
Ronald Brown ◽  
Manohar L. Sharma ◽  
Dennis M. Fisher
Keyword(s):  
Cholinesterase Activity ◽  
Plasma Concentrations ◽  
Neuromuscular Function ◽  
Plasma Cholinesterase ◽  
Constant Infusion ◽  
Plasma Cholinesterase Activity ◽  
Limited Efficacy ◽  
Before And After ◽  
Neuromuscular Effect

Background An investigation suggested that neostigmine may not effectively antagonize mivacurium, presumably because neostigmine impairs mivacurium's metabolism. However, the effect of neostigmine on mivacurium's metabolism in vivo has not been reported. Therefore, the effect of neostigmine on neuromuscular function and plasma mivacurium concentrations during constant mivacurium infusion was determined. Methods Mivacurium was infused in five patients to maintain 90% depression of adductor pollicis twitch tension, then 50 micrograms/kg intravenous neostigmine was administered without altering the mivacurium infusion. Peak twitch tension after neostigmine, plasma cholinesterase activity, and mivacurium concentrations before and after neostigmine were measured. Five additional patients were given 50 micrograms/kg neostigmine to antagonize block due to continuous infusions of vecuronium. Results Neostigmine produced less antagonism of mivacurium (39 +/- 11%) than of vecuronium (54 +/- 9%, P < 0.05). Neostigmine decreased plasma cholinesterase activity and increased plasma concentrations of the trans-trans and cis-trans stereoisomers of mivacurium (P < 0.05). Conclusions Neostigmine is less effective at antagonizing the neuromuscular effect of mivacurium than that of vecuronium during constant infusion. Neostigmine increases plasma mivacurium concentrations, likely explaining its limited efficacy. Our results confirm that neostigmine impairs the metabolism of mivacurium in vivo and may explain the observation that neostigmine may not effectively antagonize mivacurium-induced block.

Cardiopulmonary and carotid baroreflex control of splanchnic and forearm circulations

1993 ◽  
Vol 264 (3) ◽  
pp. H777-H782 ◽  
Author(s):  
P. Escourrou ◽  
B. Raffestin ◽  
Y. Papelier ◽  
E. Pussard ◽  
L. B. Rowell
Keyword(s):  
Carotid Sinus ◽  
Lower Body Negative Pressure ◽  
Human Subjects ◽  
Venous Pressure ◽  
Plasma Concentrations ◽  
Venous Occlusion ◽  
Constant Infusion ◽  
Baroreflex Control ◽  
Carotid Sinus Stimulation ◽  
Before And After

The objective was to determine whether a rise in carotid sinus transmural pressure by neck suction (NS) would counteract vasoconstriction secondary to inhibition of discharge of arterial and cardiopulmonary baroreceptors by simultaneous lower body negative pressure (LBNP). NS alone was applied to seven normal human subjects at -40 mmHg for 400–600 ms at each heartbeat during a 6-min period. NS reduced mean arterial pressure (MAP) from 94 +/- 6 to 86 +/- 9 mmHg and heart rate (HR) from 64 +/- 5 to 60 +/- 4.7 beats/min but did not affect vascular resistance in the splanchnic region (flow by constant infusion of indocyanine green; assumed constant extraction) or in the forearm (venous occlusion plethysmography). The same NS stimulus was applied during 23 min of continuous LBNP at -40 mmHg. LBNP alone before NS significantly reduced central venous pressure (CVP) from 5 +/- 0.3 to 1 +/- 0.5 mmHg and raised splanchnic (+34%) and forearm (+70%) vascular resistances and HR (from 64 to 74 beats/min) without reducing MAP. NS plus LBNP reduced MAP from 103 +/- 8 to 95 +/- 6 mmHg and HR from 74 +/- 6 to 67 +/- 5 beats/min without changing CVP but did not alter vascular resistances, which remained elevated and constant throughout LBNP before and after NS. Increments in plasma concentrations of renin (240%), aldosterone (70%), epinephrine (112%), and norepinephrine (46%) accompanied LBNP and NS; a separate influence of NS was not discernible. We conclude that vasoconstriction in response to combined cardiopulmonary and aortic inhibition is not overpowered by carotid sinus stimulation.

Edrophonium Increases Mivacurium Concentrations during Constant Mivacurium Infusion, and Large Doses Minimally Antagonize Paralysis

1995 ◽  
Vol 82 (4) ◽  
pp. 912-918. ◽  
Author(s):  
Paul S. Hart ◽  
Peter M. C. Wright ◽  
Ronald Brown ◽  
Marie Lau ◽  
Manohar L. Sharma ◽  
...  
Keyword(s):  
Cholinesterase Activity ◽  
Plasma Concentrations ◽  
Plasma Cholinesterase ◽  
Constant Infusion ◽  
Dependent Manner ◽  
Plasma Cholinesterase Activity ◽  
Limited Efficacy ◽  
Before And After ◽  
Dose Dependent ◽  
Nondepolarizing Muscle Relaxant

Background Mivacurium, a nondepolarizing muscle relaxant, is metabolized by plasma cholinesterase. Although edrophonium does not alter plasma cholinesterase activity, we have observed that doses of edrophonium that antagonize paralysis from other nondepolarizing muscle relaxants are less effective with mivacurium. We speculated that edrophonium might after metabolism of mivacurium, thereby hindering antagonism of paralysis. Accordingly, we determined the effect of edrophonium on neuromuscular function and plasma mivacurium concentrations during constant mivacurium infusion. Methods We infused mivacurium to maintain 90% depression of adductor pollicis twitch tension and then gave edrophonium in doses ranging from 125-2,000 micrograms/kg without altering the mivacurium infusion. Peak twitch tension after edrophonium was determined to estimate the dose of edrophonium antagonizing 50% of twitch depression for antagonism of mivacurium; plasma cholinesterase activity and mivacurium concentrations before and after edrophonium were measured. Additional subjects were given 500 micrograms/kg edrophonium to antagonize continuous infusions of d-tubocurarine and vecuronium. Results With mivacurium, edrophonium increased twitch tension in a dose-dependent manner: the dose of edrophonium antagonizing 50% of twitch depression was 2,810 micrograms/kg. The largest dose of edrophonium (2,000 micrograms/kg) produced only 45 +/- 7% antagonism. Edrophonium, 500 micrograms/kg, antagonized mivacurium markedly less than it antagonized d-tubocurarine and vecuronium. Edrophonium increased plasma concentrations of the two potent stereoisomers of mivacurium 48% and 79%, these peaking at 1-2 min; plasma cholinesterase activity was unchanged. Conclusions Edrophonium doses that antagonize d-tubocurarine and vecuronium are less effective in antagonizing the neuromuscular effects of mivacurium during constant infusion. Edrophonium increases plasma mivacurium concentrations, partly or completely explaining its limited efficacy; the mechanism by which edrophonium increases mivacurium concentrations remains unexplained. Our results demonstrate that antagonism of mivacurium by edrophonium is impaired, and therefore we question whether edrophonium should be used to antagonize mivacurium.

Hepatic uptake of 3,5,3'-triiodothyronine: electrochemical driving forces

1992 ◽  
Vol 262 (6) ◽  
pp. G1104-G1112
Author(s):  
R. A. Weisiger ◽  
B. A. Luxon ◽  
R. R. Cavalieri
Keyword(s):  
Plasma Membrane ◽  
Active Transport ◽  
Driving Forces ◽  
Electrical Potential ◽  
Hepatic Uptake ◽  
Electrical Potential Difference ◽  
Multiple Indicator Dilution ◽  
Multiple Indicator ◽  
Basolateral Plasma Membrane ◽  
Uptake Process

We used the multiple indicator dilution technique to assess the electrochemical forces driving uptake of 3,5,3'-triiodo-L-thyronine (T3) across the basolateral plasma membrane in the single-pass perfused rat liver. With the use of 4 g/dl albumin solutions, the influx and efflux clearances were 0.020 +/- 0.005 and 0.0049 +/- 0.0017 (SE) ml.s-1.g liver-1, respectively, indicating that the total T3 concentration at equilibrium should be about four times greater in cytoplasm than in plasma. However, when the influx and efflux clearances were divided by the unbound (free) T3 concentration in the perfusate and cytosol, they were not different (3.76 +/- 0.26 vs. 4.30 +/- 0.38 ml.s-1.g liver-1), indicating that the uptake process does not generate a gradient of unbound T3 across the plasma membrane. To further test whether T3 uptake is driven by the electrical potential difference across the plasma membrane, liver cells were depolarized by isosmotic replacement of perfusate chloride with gluconate. There was no effect on uptake or efflux. To test whether uptake is coupled to influx of sodium, perfusate sodium was replaced with choline. Although there was a modest decline in both the influx and efflux clearances, there was no change in their ratio, as would be expected for sodium-coupled active transport. These results indicate that uptake of T3 across the basolateral hepatocyte membrane occurs by passive diffusion. We found no evidence to support concentrative, active transport by either electrogenic or sodium-coupled mechanisms.

Kinetics of Hepatic Uptake of Unconjugated Bilirubin

1976 ◽  
Vol 51 (2) ◽  
pp. 169-176 ◽  
Author(s):  
G. Paumgartner ◽  
J. Reichen
Keyword(s):  
Sodium Taurocholate ◽  
Compartment Model ◽  
Hepatic Uptake ◽  
Uptake System ◽  
Multiple Indicator Dilution ◽  
Half Saturation Constant ◽  
Carrier Mediated Transport ◽  
Multiple Indicator ◽  
Uptake Velocity ◽  
Kinetics Of

1. The uptake of bilirubin was studied in the perfused rat liver by a multiple-indicator dilution technique employing the three-compartment model of Goresky. 2. The kinetics of hepatic bilirubin uptake could be described by the Michaelis—Menten equation. 3. The maximal uptake velocity (Vmax.) and the apparent half-saturation constant (Km) were 4·4 ± 0·5 nmol s−1 g−1 of liver and 58 ±16 nmol/g of liver respectively, indicating that the hepatic uptake system for bilirubin under normal conditions is operating far below saturation. 4. Sodium taurocholate did not compete with bilirubin for hepatic uptake. 5. These findings are consistent with the concept that carrier-mediated transport is responsible for hepatocellular uptake of bilirubin and that bilirubin and bile acids enter the hepatocyte via separate pathways.

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