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PubMed1976

A compartmental model for bilirubin kinetics in isolated perfused rat liver.

Bilirubin kinetics were studied in an isolated, perfused rat liver system using unconjugated (14C) bilirubin (UC(14C)B) and delta-amino (4-14 C) levulinic acid (A(14 C)LA) to derive a suitable compartmental model. Plasma disappearance of UC(14C)B, plasma appearance of conjugated (14c) bilirubin (C(14C)B) and biliary excretion of C(14C)B were followed for 90-120 min following injection of UC(14C)B. Hepatic content of labeled bilirubin 12 min after the injection of UC(14C)B was determined directly in five separate perfusion experiments. UCB was found to reflux back to plasma from liver in two experiments using A(14C)LA. Bilirubin binding to red blood cells (6-8% of the perfusate level) and the components of the perfusion apparatus (4-6% of perfusate level) was estimated by performing a control experiment without the liver. A six compartment model was necessary and adequate to explain the experimental data and current knowledge of bilirubin metabolism: (1) UCB bound to red blood cells and the perfusion apparatus, (2) plasma UCB, (3) liver UCB, (4) liver CB, (5) plasma CB, and (6) bile CB. The proposed model could serve as a reference point for studies of bilirubin kinetics in whole animals for normal and abnormal states.

Aminolevulinic Acid↗
PubMed1982

Characterization of carnitine transport in isolated perfused adult rat hearts.

Carnitine transport was characterized in isolated perfused adult rat hearts. Carnitine uptake consisted of both a saturable (carrier-mediated) and nonsaturable (diffusion) component. Perfusion with 0.05 mM mersalyl acid, a sulfhydryl binding agent, inhibited the carrier-mediated transport but did not inhibit diffusion. The saturable transport system exhibited Michaelis-Menten kinetics with a maximum velocity of 154 nmol . g dry wt-1 . h-1 and an apparent Michaelis constant of 24 microM. D-carnitine competitively inhibited L-carnitine transport with an apparent inhibitor dissociation constant of 500 microM. Anoxia and K+ arrest resulted in only a slight inhibition of the saturable transport, suggesting that transport is not adenosine 5'-triphosphate (ATP) dependent. At physiological concentrations of extracellular carnitine (44 microM), total carnitine uptake rate was about 100 nmol . g dry wt-1 . h-1, 80% of which was by carrier-mediated transport. This rate of uptake would require about 60 h to replace the total cellular carnitine. Loss of tissue carnitine also appeared to be a slow process. These results suggest that carnitine is transported across the sarcolemma by both diffusion and carrier-mediated transport.

Animals↗
PubMed1981

Dietary effects on pancreatic exocrine function. Experiments on the isolated perfused rat pancreas.

Studies of the response of the isolated perfused rat pancreas to three doses of secretin (5.0, 10.0, 18.75 U/h) and CCK (0.6, 1.5, 2.4 U/h) show that a 35-day administration of a carbohydrate-rich (60% carbohydrate, 3% fat, 20% protein) or fat-rich (34% fat, 11.3% carbohydrate, 29.8% protein) diet increases the sensitivity of the gland to these hormones compared to a standard diet (50.5% carbohydrate, 4% fat, 19% protein). The maximal secretory flow on stimulation by secretin and on a combined stimulation by secretin (2.5 U/h) plus CCK (1.8 U/h) is significantly (p less than 0.05 and p less than 0.01, respectively) lower in both experimental diets than in controls, whereas the maximal protein and enzyme secretion is diminished only in the secretin plus CCK-stimulated pancreas of rats fed a fat-rich diet. A carbohydrate-rich diet results in a relative increase in amylase secretion and decrease in lipase and chymotrypsinogen output. Compared to controls, the fat-rich diet leads to a stronger secretion of lipase and chymotrypsinogen and to a reduced amylase secretion. This adaptation of the exocrine pancreatic function is rather due to changes in the organ itself than to an altered hormonal stimulation.

Amylases↗
PubMed1998

Localization and production of angiotensin II in the isolated perfused rat heart.

We used a modification of the isolated perfused rat heart, in which coronary effluent and interstitial transudate were separately collected, to investigate the localization and production of angiotensin II (Ang II) in the heart. During combined renin (0.7 to 1.5 pmol Ang I/mL per minute) and angiotensinogen (6 to 12 pmol/mL) perfusion (4 to 8 mL/min) for 60 minutes (n=3), the steady-state levels of Ang II in interstitial transudate in two consecutive 10-minute periods were 4.3+/-1.5 and 3.6+/-1.5 fmol/mL compared with 1.1+/-0.4 and 1.1+/-0.6 fmol/mL in coronary effluent (mean+/-half range). During perfusion with Ang II (n=5), steady-state Ang II in interstitial transudate was 32+/-19% of arterial Ang II compared with 65+/-16% in coronary effluent (mean+/-SD, P<.02). During perfusion with Ang I (n=5), Ang II in interstitial transudate was 5.1+/-0.6% of arterial Ang I compared with 2.2+/-0.3% in coronary effluent (P<.05). The tissue concentration of Ang II in the combined renin/angiotensinogen perfusions (per gram) was as high as the concentration in interstitial transudate (per milliliter). Addition of losartan (10(-6) mol/L) to the renin/angiotensinogen perfusion (n=3) had no significant effect on the tissue level of Ang II, whereas losartan in the perfusions with Ang I (n=5) or Ang II (n=5) decreased tissue Ang II to undetectably low levels. The results indicate that the heart is capable of producing Ang II and that this can lead to higher levels in tissue than in blood plasma. Cardiac Ang II does not appear to be restricted to the extracellular fluid. This is in part due to AT1-receptor-mediated cellular uptake of extracellular Ang II, but our results also raise the possibility of intracellular Ang II production.

Angiotensin II↗
PubMed1983

Metabolism of circulating adenosine by the porcine isolated perfused lung.

Adenosine uptake was studied in the piglet isolated perfused lung by means of the single-circulation paired-tracer dilution technique. Adenosine was efficiently taken up from the pulmonary vascular bed, and the process was potently inhibited by dipyridamole. Following uptake, adenosine was incorporated into intracellular nucleotides, and at low perfusate concentrations, little or none of the incorporated radioactivity returned to the circulation. At higher concentrations, cellular uptake was saturable and products of intracellular catabolism (inosine and hypoxanthine) were returned to the circulation. Perfusion of low concentrations of adenosine after inhibition of pulmonary adenosine kinase led to a proportional decrease in the retention of nucleotides and to a release of inosine and hypoxanthine. A small proportion of adenosine was metabolised extracellularly by adenosine deaminase; this activity was not released from perfused lungs and is apparently an ecto-enzyme.

Adenine Nucleotides↗
PubMed1995

Pharmacologic characterization of endothelin receptor responses in the isolated perfused rat lung.

Endothelin receptor subtypes were characterized in isolated perfused rat lungs using the peptide ETA-receptor antagonists BQ 610 and BQ 123, the nonpeptide mixed ETA-/ETB-receptor antagonist bosentan, and the ETB-receptor agonist IRL 1620. Intra-arterial injection of 1 nmol IRL 1620 caused an enhanced reduction in pulmonary conductance compared with 1 nmol endothelin (ET-1) or 0.33 nmol IRL 1620. Pretreatment of lungs with BQ 610, BQ 123, or bosentan aggravated the bronchoconstriction induced by 1 nmol ET-1 so that it was comparable to that induced by 1 nmol IRL 1620. Although perfusion with 1 nmol IRL 1620 had only minor effects on vascular conductance, 1 nmol ET-1 caused a marked decrease in this parameter. This vasonconstriction was prevented by BQ 610, BQ 123, or bosentan. High concentrations of the stable prostacyclin metabolite, 6-keto-PGF1 alpha, were found in the perfusate of lungs treated with 1 nmol IRL 1620 or 1 nmol ET-1. The ET-1-induced release of 6-keto-PGF1 alpha was blocked by bosentan, but not by BQ 610. ET-1, but not IRL 1620, provoked the release of thromboxane B2. The main effect of ETA-receptor stimulation is vasoconstriction, whereas ETB-receptor stimulation causes bronchoconstriction. Both actions, however, are attenuated by the other receptor, i.e., the ETA-induced vasoconstriction is attenuated by ETB-receptor-induced release of vasodilators such as prostacyclin, whereas the ETB-receptor-induced bronchoconstriction is attenuated by an unknown ETA-receptor-dependent bronchodilatory mechanism.

Analysis of Variance↗
PubMed1985

Metabolic studies of a podophyllotoxin derivative (VP16) in the isolated perfused liver.

The metabolism of VP16 was studied in isolated perfused rat liver. The rate of elimination into the medium and excretion in bile were determined by h.p.l.c. with u.v. detection. With high VP16 concentrations (180 micrograms/ml medium), the elimination half-life of the compound was prolonged markedly (156 v. 45 min for lower doses), the percentage recovered in bile was more than halved and drug accumulation in the hepatic tissue was three times greater. These findings indicate saturation of metabolism and of biliary elimination during high-dose treatment. The presence of glucuronides in the bile of VP16 perfused livers indicates that VP16 undergoes conjugation with glucuronic acid. Formation of picro isomer of VP16 in the liver also occurs.

Animals↗
PubMed1961

Regional isolation perfusion in the treatment of advanced malignant disease.

Regional isolation perfusion with an alkylating agent was carried out in a small community hospital, using readily available equipment, ten times in nine cases of advanced malignant disease. Visible regression of tumor, either grossly or histologically, occurred in seven patients and decided subjective improvement occurred in five patients. The long range effect of the procedure could not be determined in the present series, not enough time having elapsed. Side effects included jaundice in four patients, massive necrosis of the tumor in one patient, nausea and vomiting in three patients, postoperative edema in five patients, wound infection in two patients, Horner's syndrome in one patient, temporary alopecia in three patients, and depression of hemoglobin level in seven patients, of the leukocyte count in four patients and of the platelet count in four patients.A feature of the procedure used in the present series was a system of monitoring the escape of alkylating agent into the systemic circulation.

Antineoplastic Agents↗
PubMedDate not supplied

The metabolism of styrene oxide in the isolated perfused rat liver. Identification and quantitation of major metabolites.

Isolated perfused rat livers rapidly metabolized 14C-styrene oxide. A large proportion of the administered radioactivity was excreted in the bile as a single compound that was identified as S-(1-phenyl-2-hydroxyethyl)glutathione by comparison with an authentic synthetic standard. The circulating perfusate was found to contain approximately equal amounts of styrene glycol, mandelic acid, and the glutathione derivative.

Animals↗
PubMed1988

Inflammation-induced vasodepression detected ex vivo in the isolated perfused hindlegs in mice.

The ex vivo vasoreactivity of isolated perfused hindleg blood vessels upon norepinephrine is strongly decreased in mice with anaphylactic or dextran-induced paw oedema. In the presence of the carrageenin paw oedema vasoreactivity is only slightly or not influenced. The decrease of vasoreactivity can be observed in the leg with the paw oedema but, to a somewhat lesser extent, in an animal's leg without paw oedema, i.e., general vasodepression occurs. The development of vasodepression can already be seen a few minutes after inflammation induction. It partly parallels the development of paw swelling, but, to a certain extent, overlasts the disappearance of the oedema. Vasodepressing factors (VDFs) released from the site of inflammation are obviously responsible for the vasodepression. Contrary to the rat, no vasodepression could be demonstrated by using angiotensin II as the vasoconstrictor in the dextran mouse paw oedema model.

Anaphylaxis↗
PubMed1985

[Kallikrein secretion by the isolated perfused rat kidney. Role of perfusion pressure and the renin-angiotensin system].

The isolated perfused rat kidney (IPRK) releases kallikrein in urine and renin in perfusate. We have previously shown (Kidney Int 24: 58-65, 1983) and confirm here that kallikrein, as well as renin releases are influenced by changes in renal hemodynamics in this model: a rise in perfusion pressure (PP) from 80 to 98 mmHg increases renal perfusate flow (RPF) by 48 +/- 3 p. 100, inhibits renin release and stimulates kallikrein secretion to 234 +/- 84 p. 100 of control values (n = 8). Since the perfusate lacks angiotensinogen, we decided to study the effect on kallikrein of the reconstitution of the renin-angiotensin system in the IPRK by adding angiotensinogen + angiotensin converting enzyme (AG + ACE) to the perfusion medium. After AG + ACE, PP rose to 107 +/- 4 mmHg, RPF decreased by 82 +/- 3 p. 100 as a consequence of the vasoconstrictor effect of angiotensin II, and renin release was suppressed. Again kallikrein secretion was stimulated and increased to 333 +/- 153 p. 100 of control values (n = 4). It is concluded 1) that kallikrein release is influenced by changes in PP but not in RPF on the IPRK. 2) that reconstitution of the renin-angiotensin system by addition of AG + ACE to the perfusate leads to vasoconstriction, suppression of renin release and a marked increase in kallikrein secretion.

Animals↗
PubMed1977

[Changes in liver metabolism following a standardized skin burn and intraperitoneal injection of a burn toxin isolated from burned mice skin. Studies on rat liver using isolation perfusion].

Parameters of liver metabolism were studied in the isolated perfused rat liver 5 days after a standard skin burn or an i.p. injection of a specific cutaneous burn toxin. Decreased values of the energy quotient ATP/ADP compared with normal controls were found. The absolute content of adenonucleotides was unchanged. The excretion of glucose and urea was also decreased in both groups and glucose synthesis after a lactate load was only slightly stimulated. The results show a direct influence of a burn toxin on hepatic metabolism suggesting a possible disturbance of oxydative phosphorylation.

Adenine Nucleotides↗
PubMed1984

Regulation of the glycine cleavage system in the isolated perfused rat liver.

The catabolism of glycine in the isolated perfused rat liver was investigated by measuring the production of 14CO2 from [1-14C]- and [2-14C]glycine. Production of 14CO2 from [1-14C]glycine was maximal as the perfusate glycine concentration approached 10 mM and exhibited a maximal activity of 125 nmol of 14CO2 X g-1 X min-1 and an apparent Km of approximately 2 mM. Production of 14CO2 from [2-14C]glycine was much lower, approaching a maximal activity of approximately 40 nmol of 14CO2 X g-1 X min-1 at a perfusate glycine concentration of 10 mM, with an apparent Km of approximately 2.5 mM. Washout kinetic experiments with [1-14C]glycine exhibited a single half-time of 14CO2 disappearance, indicating one metabolic pool from which the observed 14CO2 production is derived. These results indicate that the glycine cleavage system is the predominant catabolic fate of glycine in the perfused rat liver and that production of 14CO2 from [1-14C]glycine is an effective monitor of metabolic flux through this system. Metabolic flux through the glycine cleavage system in the perfused rat liver was inhibited by processes which lead to reduction of the mitochondrial NAD(H) redox couple. Infusion of beta-hydroxybutyrate or octanoate inhibited 14CO2 production from [1-14C]glycine by 33 and 50%, respectively. Alternatively, infusion of acetoacetate stimulated glycine decarboxylation slightly and completely reversed the inhibition of 14CO2 production by octanoate. Metabolic conditions which are known to cause a large consumption of mitochondrial NADPH (e.g. ureogenesis from ammonia) stimulated glycine decarboxylation by the perfused rat liver. Infusion of pyruvate and ammonium chloride stimulated production of 14CO2 from [1-14C]glycine more than 2-fold. Lactate plus ammonium chloride was equally as effective in stimulating glycine decarboxylation by the perfused rat liver, while alanine plus ammonium chloride was ineffective in stimulating 14CO2 production.

Acetoacetates↗
PubMed1978

Rates of removal and degradation of chylomicron remnants by isolated perfused rat liver.

Chylomicron remnants are removed intact by isolated perfused rat livers and their lipid components are metabolized by the liver (Biochim. Biophys. Acta 488: 464, 1977). The present study provides quantitative information regarding these processes. When the lipoprotein concentration of the perfusate was constant, the removal of chylomicron remnants increases lineraly for 17 min. The rate of remnant removal was a hyperbolic function of the perfusate's remnant concentration. The removal rate had aV max of 28microgram cholesterol per g liver per min and an apparent Km of 64 microgram cholesterol per ml perfusate. Feeding the liver donors a diet containing 1% cholesterol or 4% cholesterol and 1% cholic acid failed to alter the hepatic removal rate. The cholesteryl ester removed from the remnants was hydrolyzed at a rate that was a small fraction of the removal rate (about 0.5% of removed cholesteryl ester per min). The rate of cholesteryl ester hydrolysis did not appear to approach saturation in the range studied. Studies of the lysosomal cholesteryl ester hydrolase suggested that this enzyme was not responsible for limiting the initial rate of hydrolysis, raising the possibility that the degradation rate is determined by the movement of the removed remnant to the site of hydrolysis.

Animals↗
PubMed1985

Effects of insulin treatment on ketone body production and carnitine-palmitoyl-transferase (CPT) activity in the isolated perfused liver from streptozotocin diabetic rats.

The aim of the present paper was to evaluate the effects of in vivo insulin treatment of streptozotocin (SZ) diabetic rats on the metabolism of the isolated, perfused liver. Perfused livers from SZ-diabetic rats showed a higher ketone body production and a higher mitochondrial carnitine-palmitoyl-transferase (CPT) activity than controls, while triglyceride (TG) output and free-fatty-acid (FFA) uptake were significantly reduced. In vivo insulin treatment normalized both the ketogenic capacity of the liver and CPT activity, while FFA uptake and TG production were still lower than in controls. A significant correlation was found between total ketone body output and CPT activity. We suggest that In vivo insulin treatment of SZ-diabetic rats can modulate the ketogenic capacity of the isolated, perfused liver.

Acyltransferases↗
PubMed1998

Effects of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) on haemodynamics and permselectivity of the isolated perfused rat kidney.

BACKGROUND: Vascular endothelial growth factor (VEGF) or vascular permeability factor (VPF) is a selective mitogen for endothelial cells; it increases microvascular permeability and has been shown to relax isolated canine coronary arteries by an endothelium-dependent mechanism. In many tissues VEGF/VPF is expressed after an appropriate stimulus, mostly hypoxia. In the kidney VEGF/VPF is constitutively expressed in glomerular podocytes and epithelia of collecting duct. Glomerular and peritubular capillary endothelia also constitutively express specific VEGF receptors. The in vivo function of renal VEGF/VPF is unknown. METHOD: In the present study the effects of human recombinant VEGF165 on renal haemodynamics and glomerular permselectivity was investigated in the isolated perfused kidney of the rat. RESULTS: In kidneys preconstricted by noradrenaline (NA 1.5 x 10(-7) mol/l) VEGF/VPF (155 pmol/l) caused an almost complete return of renal perfusion flow rate to pre-NA values (before NA 113 +/- 4%, after NA 100%, 15 min with VEGF/VPF 111 +/- 4%). Shortly after VEGF/VPF administration VEGF/VPF-induced relaxation commenced, and became significant after 2 min (15 min with VEGF/VPF vs without VEGF/VPF 111 +/- 4% vs 103 +/- 2%; P<0.05). In the presence of the NO-synthase inhibitor N(W)-nitro-L-arginine (L-NNA; 5 x 10(-5) mol/l) VEGF/VPF caused only small, transient relaxations (before NNA 109 +/- 5%, after NNA 100%, 15 min with VEGF 95 +/- 2%). The cyclooxygenase inhibitor diclofenac failed to inhibit the relaxing activity of VEGF/VPF (before NA 119 +/- 4%, after NA + diclofenac 100%, 15 min with VEGF/VPF 123 +/- 5%). VEGF demonstrated no significant increase in renal protein excretion rate (after NA pretreatment (= 100%): 12.5 min with VEGF/VPF vs without VEGF/VPF: 119 +/- 10% vs 132 +/- 11%, n.s.) (after NNA pretreatment (= 100%) 12.5 min with VEGF/VPF vs without VEGF/VPF 94 +/- 5% vs 96 +/- 4%; n.s.) or clearance quotient of albumin. Glomerular filtration rate was not influenced by VEGF/VPF in kidneys pretreated with NA (before NA 105 +/- 5%, after NA 100%, 12.5 min with VEGF/VPF 94 +/- 2%) or with NNA (before NNA 107 +/- 6%, after NNA 100%, 12.5 min with VEGF/VPF 96 +/- 2%). Fractional glucose and fractional sodium excretion showed flow-dependent changes. CONCLUSION: VEGF/VPF can contribute to the relaxing capacity of the renal vasculature. This relaxation is partly mediated by the NO/endothelium-derived relaxing factor (EDRF) pathway. In the isolated perfused rat kidney the glomerular permeability for albumin is not affected by VEGF/VPF.

Animals↗
PubMed1990

Differential induction of 3-ethyl-2,6-dimethyl-4H-pyrido (1,2-alpha)pyrimidin-4-one metabolism by phenobarbital and 3-methylcholanthrene in microsomes and isolated perfused rat liver.

1. The in vitro metabolism of 3-ethyl-2,6-dimethyl-4H-[2-14C]pyrido(1,2-alpha)pyrimidin-4-one (PYPY) was studied in liver microsomes and isolated perfused liver of 3-methylcholanthrene (MC) or phenobarbital (PB)-treated, and untreated rats. 2. Hydroxylation of the alkyl substituents was the main metabolic pathway for PYPY in both in vitro systems of untreated, and MC-treated animals, but with different proportions of the metabolites. PB enhanced the rate of ring hydroxylation, especially in the microsomes, and the product of this reaction became the main metabolite of PYPY biotransformation. Ring hydroxylation reactions in the microsomes and in the isolated perfused liver led to different products. 3. Differences arose in the rate of some oxidative reactions measured in the two in vitro systems resulting in altered metabolic patterns. PB enhanced not only quantitative but qualitative differences in the two systems. 4. The altered metabolite profile observed with whole liver compared with the products of microsomes, and the enhanced amount of water-soluble metabolites due to PB treatment in experiments with perfused liver indicate the involvement of further metabolic processes, perhaps conjugation reactions, in PYPY metabolism in the perfused liver. 5. The differences observed in the inducibility of some oxidative reactions by MC and PB indicate the involvement of at least three distinct cytochrome P-450 isozymes in the metabolism of PYPY.

Animals↗
PubMedDate not supplied

Bile acid conjugation pattern in the isolated perfused rat liver during infusion of an amino acid formulation.

The influence of the taurine-containing amino acid mixture Trophamine on the pattern of bile acid conjugation was examined in the isolated perfused rat liver using cholic acid as the bile acid substrate. In all experiments, greater than 97% of the cholic acid appearing in bile was conjugated with taurine or glycine. The pattern of taurine and glycine bile acid conjugation, however, was dependent on the availability of taurine in the perfusate medium. Thus, in the absence of Trophamine infusion, the percentage of cholic acid conjugated with taurine (ie, taurocholate) declined throughout the course of the cholic acid infusion. Trophamine infusion increased the ratio of biliary taurocholate/glycocholate by 4.5-fold over that observed in the absence of the amino acid infusion. Increasing the amount of taurine in Trophamine by 2- or 5-fold resulted in a 1.8- and 4.3-fold increase, respectively, in the taurocholate/glycocholate ratio over that observed during the Trophamine infusion. Infusion of taurine alone, at an equimolar concentration of taurine as that in Trophamine, resulted in a similar taurocholate/glycocholate ratio as that observed during the Trophamine infusion. These data indicate that taurine availability, even in the presence of high concentrations of glycine and other amino acids in Trophamine, appears to be the most important factor in determining the pattern of bile acid conjugation in the isolated perfused rat liver.

Amino Acids↗