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PubMedDate not supplied

Hydrogen peroxide-induced broncho- and vasoconstriction in the isolated perfused and ventilated guinea pig lung.

The effect of hydrogen peroxide on perfusion flow, airway conductance (Gaw) and dynamic compliance (Cdyn of isolated perfused and ventilated guinea pig lungs was investigated. Hydrogen peroxide (50 microM in the perfusion buffer) induced a decrease in Gaw and Cdyn and perfusion flow during 5 min. of exposure. Hydrogen peroxide also caused an increase in the levels of thromboxane in the perfusate of the lung. The constrictor effects as well as the formation of thromboxane were inhibited by the cyclooxygenase inhibitor ibuprofen (50 microM). The thromboxane/prostaglandin endoperoxide receptor antagonist L-670,596 (1 microM) abolished the effects of hydrogen peroxide on perfusion flow, Gaw and Cdyn, but did not affect the formation of thromboxane. The thromboxane-synthetase inhibitor carboxyheptylimidazole (100 microM) reduced both the hydrogen peroxide-induced formation of thromboxane and vaso- and bronchoconstriction, suggesting a predominant role for thromboxane A2 versus prostaglandin H2 in these effects. A role for platelet-activating factor in mediating the effect of hydrogen peroxide could not be supported, as the platelet-activating factor receptor antagonist WEB 2086 (10 microM) did not affect hydrogen peroxide induced vaso- and brochoconstriction. The results of this study show that hydrogen peroxide induces thromboxane A2 mediated vaso- and bronchoconstriction in the isolated perfused and ventilated guinea pig lung. Platelet-activating factor does not appear to play a significant role in the hydrogen peroxide-induced vaso- and bronchoconstriction. Our results also suggest that the perfused guinea pig lung is more sensitive to hydrogen peroxide than the perfused rat lung.

Animals↗
PubMed1994

The effects of endothelin peptides in the rabbit isolated perfused kidney.

1. Endothelin-1 (21-amino acids) and pre-pro endothelin-1 (39-amino acids) produced a concentration-dependent increase in perfusion pressure when infused through the renal artery of rabbit isolated perfused kidney. Addition of phosphoramidon to the medium caused a potentiation in the vasoconstrictor response to endothelin-1 and greatly, but not completely, inhibited vasoconstriction induced by pre-pro-endothelin-1. 2. Addition of indomethacin to the medium did not alter the vasoconstrictor effects of the peptides. 3. Methylene blue in the medium caused a highly significant potentiation in the vasoconstrictor response to endothelin-1. 4. A short-term infusion of endothelin-1 through the renal artery elicited a decrease in urine flow which returned to control levels after perfusing the kidney with Krebs buffer, but prolonged infusion of the peptide produced an irreversible increase in urine flow. 5. Phosphoramidon, methylene blue and indomethacin failed to alter the effect of endothelin-1 on urine flow. 6. From these results it was concluded that phosphoramidon-sensitive endothelin-converting enzyme, probably localized in microvasculature of the kidney, can convert pre-pro-endothelin-1 to endothelin-1 which is responsible for the vasoconstrictor effect of pre-pro-endothelin-1 in addition to its possible direct vasoconstrictor effect on kidney vasculature. Moreover, the endothelin-1 degradating enzyme in kidney should be a phosphoramidon-sensitive metalloproteinase(s). The results also indicated the release of EDRF but not prostanoids by endothelin-peptides in the rabbit isolated perfused kidney.

Animals↗
PubMed1989

[Studies on the metabolism of antiepilepserine in isolated perfused rat liver].

The metabolism of antiepilepserine, 3,4-methylene dioxycinnamyl piperidine, was studied in isolated perfused rat liver. Two metabolites were separated and purified by means of HPLC. They were identified as 3,4-methylene dioxycinnamyl hydroxypiperidine and 4-hydroxy-3-methoxycinnamyl piperidine by UV and MS. The latter was further confirmed by chemical synthesis. The pharmacokinetics of antiepilepserine in isolated perfused liver was also studied. Parameters obtained include a first order elimination constant, k = 0.0157 +/- 0.0043 min-1, and a half-life, t 1/2 = 46.7 +/- 11.9 min, (n = 6). The amount of antiepilepserine lost during the perfusion could not be compensated by the increased amount of metabolites. Antiepilepserine was found to be tightly bound and stored in the liver. This might be one of the explanations of the first pass effect of antiepilepserine after oral administration.

Animals↗
PubMed1995

Surgical workshop on liver surgery using isolated perfused livers in moulded casts of the upper abdomen.

The basic training in liver surgery on isolated perfused livers used at the workshop in the First Surgical Course of the Alps--Adriatic Hepatobiliary School is presented. The methods for the excision, preservation, perfusion and preparation of the liver are described, as is the manner of manufacturing the upper abdomen moulded casts, into which an isolated perfused liver is placed for training. The methods proved to be sufficiently successful, enabling participants to perform basic liver surgery like an intraoperative ultrasound investigation, as well as liver dissection techniques, liver suturing, segmental resection and even hepatectomy. Some technical improvements are proposed for future surgical workshops, such as washing out the blood from the liver, and a triple perfusion.

Abdomen↗
PubMed1984

Gastrin release from isolated perfused rat stomach after vagotomy.

Postvagotomy hypergastrinemia persists in the isolated perfused rat stomach, but its cause is unknown. The possible role of cholinergic nervous pathways was investigated in the isolated vascularly perfused rat stomach after vagotomy. Atropine and hexamethonium, but not propranolol, inhibited postvagotomy hypergastrinemia. A nervous mechanism involving acetylcholine was further suggested by the inhibitory action of methionine-enkephalin on gastrin release after vagal section. Methacholine, a muscarinic receptor agonist, only weakly stimulated gastrin release from vagotomized stomachs when compared with shamoperated controls, indicating that a cholinergic drive was already in place. Immunocytochemical studies of antral tissue following vagotomy indicated that numbers of gastrin-containing cells (G-cells) were not increased after vagotomy but exhibited reduced intensity of gastrin staining when compared with control stomachs. It was concluded that basal hypergastrinemia may result from increased stimulation of a normal G-cell population by a cholinergic mechanism at the ganglionic level.

Animals↗
PubMedDate not supplied

On the glomerular mechanism of the renal protein excretion. Studies in the isolated perfused rat kidney.

The glomerular permeability of the isolated perfused kidney is manifold higher than in vivo, although structural changes at the glomerular filtration barrier are not described. It has been proposed that in vivo high molecular weight plasma proteins are concentrated at the glomerular endothelium forming an additional filtration barrier ('concentration polarization'). To test this hypothesis, isolated rat kidneys were perfused with substrate-enriched Krebs-Henseleit solutions containing albumin (50 g/l) or albumin/globulin (40/10 g/l), or with plasma. The pO2 was 675 mm Hg. Furthermore, experiments were carried out with the addition of erythrocytes with and without a reduced O2 supply (pO2 35 mm Hg). Independent of the composition of the perfusate a continuously increasing glomerular permeability was observed immediately after perfusion was started. After about 10 min, a steady state value for the glomerular permeability was reached. The addition of globulin to the perfusate or perfusion with plasma did not prevent the initial increase of the permeability. However, after addition of 5% erythrocytes to the perfusate the increase of permeability was much less pronounced. Neither the reduction of the O2 supply nor the addition of erythrocytes to a higher concentration than 5% had any further effect on the glomerular permeability. These data show that concentration polarization of high molecular weight proteins does not take place at the endothelium of the glomerulus. Independent of their ability to carry O2 erythrocytes play an important role in the glomerular filtration process.

Albumins↗
PubMed1981

Paracetamol and the isolated perfused kidney: metabolism and functional effects.

1. Renal metabolism of paracetamol has been studied in the isolated perfused rat kidney. 2. The major metabolites of paracetamol normally observed in vivo were present in low concentrations in the urine of the isolated perfused rat kidney. 3. Paracetamol was bound covalently to kidney protein in a linear relationship to dose up to 31.9 mM paracetamol in the perfusate. 4. Using Michaelis-Menten kinetics, the apparent Km of 5.5 mM and Vmax of 139 nmol/h/g wet wt. for renal paracetamol oxidation were observed. 5. Concn. of paracetamol greater than 14.2 mM induced immediate diuresis and diminished sodium reabsorption. Lower concn. were without effect on function.

Acetaminophen↗
PubMed1981

In situ immune complex formation in isolated perfused kidney using homologous antibody.

The pathogenesis of Heymann nephritis (HN), a morphologic and immunohistologic model for the human membranous glomerulonephropathy, is controversial. To determine the presence of the offending antigen in glomeruli, the specific disease-producing brush border antibody (BBAb) of homologous origin was infused into isolated perfused rat kidney. The antibody was obtained from the acid eluates of kidneys from rats with severe HN and purified using ion exchange and gel filtration chromatography. Its molecular size and IgG nature were ascertained by gel filtration, sucrose density gradient ultracentrifugation, and immunoelectrophoresis, and its specificity by indirect immunofluorescence. Isolated perfused kidneys were perfused with 0.5 to 10 mg. of BBAb; three control groups of kidneys were perfused with buffer only, normal rat IgG, and BBAb absorbed with a renal cortical fraction FX1A, respectively. The ischemia time ranged from 24 to 34 minutes. Localization of BBAb was noted in glomerular capillaries and mesangium and in the walls of blood vessels of many sizes. Normal rat IgG and absorbed BBAb did not show any localization. These results show that the putative antibody of HN when injected into a perfused, bloodless, ischemic kidney combines specifically with an antigen which under the above conditions can be demonstrated in the glomerular capillaries and other blood vessels. Although this represents in situ immune complex formation, which may be suspected of occurring in active HN, the conditions of the isolated perfused kidney under which this occurs are clearly unphysiologic. Whether it indeed takes place in the physiologic in vivo state will require further studies.

Animals↗
PubMedDate not supplied

Hyperthermic isolation-perfusion with melphalan, a preliminary appraisal of local and general effects in malignant melanoma.

Ten hyperthermic isolation-perfusions with melphalan were performed for invasive malignant malenoma of the limbs. Four cases at stage II and with in transit metastases (up to 15 cm in diameter) had a complete regression. However, no improvement of survival was noticed: 4 out of 5 stage II patients who died, within 1 year after perfusion, developed a generalized disease. Systemic chemotherapy was administered in 3 patients after perfusion, but they died from distant metastases. The need for an adequate adjuvant treatment added to isolation perfusion is discussed.

Aged↗
PubMed2005

Reduced activation of immunomodulatory transcription factors during positive end-expiratory pressure adjustment based on volume-dependent compliance in isolated perfused rabbit lungs.

BACKGROUND: Repeated alveolar collapse and cyclic alveolar overdistension with associated activation of inflammatory signalling cascades contribute to ventilator-induced lung injury (VILI). The appropriate positive end-expiratory pressure (PEEP) which prevents or ameliorates VILI is unknown. In the isolated perfused lung, repeated adjustments of PEEP based on the continuously analysed intratidal compliance-volume curve have previously been shown to result in full end-expiratory alveolar recruitment and low risk of cyclic alveolar overdistension. Accordingly, we tested the hypothesis that such ventilatory management reduces intrapulmonary activation of the immunomodulatory transcription factors nuclear factor kappaB (NF-kappaB), activator protein 1 (AP-1) and cAMP-responsive element binding protein (CREB) which induce the expression of various chemokines and cytokines. METHODS: Isolated perfused rabbit lungs were randomly allocated to one of three groups: zero end-expiratory pressure (ZEEP) to induce repeated alveolar collapse (n=6), high PEEP to induce cyclic alveolar overdistension (n=6) and repeated PEEP adjustments based on intratidal compliance-volume curve analysis by the slice method to minimize repeated alveolar collapse and overdistension (n=9). All lungs were ventilated with a tidal volume of 6 ml kg(-1) bodyweight for 120 min. Thereafter, activation of transcription factors NF-kappaB, AP-1 and CREB in lung tissue was analysed by electrophoretic mobility shift assay. RESULTS: High PEEP was associated with the highest activation of NF-kappaB and AP-1 and repeated PEEP adjustments with the lowest activation when compared with the other two study groups (P<0.001). In contrast, activation of CREB did not differ between groups. Activated NF-kappaB and AP-1 protein complexes consisted mainly of the transactivators p50/p65 and c-Fos/Jun, respectively. CONCLUSIONS: In isolated perfused rabbit lungs, repeated adjustments of PEEP based on the continuously analysed intratidal compliance-volume curve were associated with less activation of early steps of inflammatory signalling cascades than ventilation with ZEEP or high PEEP.

Animals↗
PubMed1988

Carbaryl metabolism is inhibited by cimetidine in the isolated perfused rat liver and in man.

The potential for cimetidine to alter the metabolism of carbaryl has been investigated in the isolated perfused rat liver and in man. In the isolated perfused rat liver, carbaryl was removed by a high intrinsic clearance process, which was inhibited in a dose dependent fashion by cimetidine in the concentration range of 60-240 micrograms/ml. The pharmacokinetic profile in one subject for orally administered carbaryl was altered following administration of cimetidine (200 mg every eight hours for three days). The peak carbaryl level occurred 25 minutes later and was increased by twofold, due to a 46% reduction in apparent oral clearance. The observations indicate that cimetidine can inhibit the metabolism of carbaryl in both rat and man. These data suggest that administration of cimetidine to individuals exposed to carbaryl could result in enhanced toxicity.

Adult↗
PubMed1979

Glomerular albumin filtration: a comparison of micropuncture studies in the isolated perfused rat kidney with in vivo experimental conditions.

Glomerular albumin filtration was investigated in the isolated perfused rat kidney and compared with in vivo experiments. Applying micropuncture techniques, we obtained samples from the glomerulus or adjacent early proximal convoluted tubules (EPT) of cortical nephrons and analyzed them for albumin using ultramicrodisc electrophoresis. By determining albumin in glomerular filtrate, we could calculate the sieving coefficient (EPTalb/Palb) directly. The control in vivo value was 0.27 +/- 0.05 X 10(-3) (N = 11). In the isolated perfused rat kidney, the sieving coefficient was 2.1 +/- 0.8 X 10(-3), N = 18 (30 g/liter albumin in perfusate) and 2.3 +/- 0.8 X 10(-3), N = 13 (50 g/liter albumin in perfusate), which is approximately eight times the control in vivo value. With elevated renal venous pressure (20 cm H2O), it increased further to 5.4 +/- 1.6 X 10(-3), N = 8. In all experiments, GFR and proximal transit times were similar to the in vivo controls. Although no major morphologic changes could be detected in any instance, the albumin filtration was greatly elevated. These data confirm the role of a functional barrier in the prevention of glomerular albumin filtration.

Albuminuria↗
PubMedDate not supplied

Effects of epinephrine and perfusion pressure on the peak aortic pressure development and glucose transport in the isolated perfused heart of normal and diabetic rats.

The effects of increased perfusion pressure and epinephrine stimulation on the contractile parameters and glucose transport in the isolated perfused hearts of control and ketotic diabetic rats were studied. An increase in perfusion pressure from 60 mm Hg to 100 mm Hg resulted in increases in coronary flow and peak aortic pressure development in control and diabetic hearts. The responses of the diabetic heart were similar to the control. Epinephrine produced lower increments in peak aortic pressure development in control and diabetic hearts under the higher perfusion pressure. Glucose uptake, although stimulated about 4-fold in both control and diabetic hearts on increasing the perfusion pressure, was still lower in the diabetic heart. Epinephrine stimulated glucose uptake in both control and diabetic hearts at 60 mm Hg, but the control heart showed a greater response. At 100 mm Hg perfusion pressure, the stimulatory effect of epinephrine on glucose uptake was abolished in both control and diabetic hearts. The results of this study show that the contractile and glucose stimulatory effects of epinephrine were influenced by the perfusion pressure. Epinephrine did not correct the impairment in glucose transport in the diabetic heart.

Animals↗
PubMed1984

Metabolism of valine and 3-methyl-2-oxobutanoate by the isolated perfused rat kidney.

Metabolism of branched-chain amino and 2-oxo acids was studied in the isolated perfused kidney. Significant amounts of 2-oxo acids were released by perfused kidney with all concentrations of amino acids tested (0.1-1.0 mM each), despite the high activity of branched-chain 2-oxo acid dehydrogenase in kidney. As perfusate valine concentration was increased from 0.2 to 1.0 mM, [1-14C]valine transamination (2-oxo acid oxidized + released) increased roughly linearly; [1-14C]valine oxidation, however, increased exponentially. Increasing perfusate concentration of 3-methyl-2-oxo[1-14C]butanoate from 0 to 1.0 mM resulted in a linear increase in the rate of its oxidation and a rise in perfusate valine concentration; at the same time significant decreases occurred in perfusate isoleucine and leucine concentrations, with corresponding increases in rates of release of their respective 2-oxo acids. Comparison of rates of oxidation of [1-14C]valine and 3-methyl-2-oxo[1-14C]butanoate suggests that 2-oxo acid arising from [1-14C]valine transamination has freer access to the 2-oxo acid dehydrogenase than has the 2-oxo acid from the perfusate. The observations indicate that, when branched-chain amino and 2-oxo acids are present in perfusate at near-physiological concentrations, rates of transamination of the amino and 2-oxo acids by isolated perfused kidney are greater than rates of oxidation.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMedDate not supplied

The effect of tricyclic antidepressant drugs on the isolated perfused guinea-pig heart.

1. The effects of tricyclic antidepressants were studied on the isolated perfused guinea-pig heart simultaneously recording myocardial contractile force and cardiac electrogram. 2. Tricyclic antidepressants in a concentration 4 X 10(-5) mol/1 decreased cardiac contractile force and increased cardiac conduction time. 3. Doxepin had significantly greater negative inotropic effect than nortriptyline, protriptyline, desipramine, amitriptyline and imipramine (P less than 0.01). 4. There was no significant difference in the increase in P-R interval (P less than 0.5) and QRS width (P greater than 0.95) between the tricyclic antidepressants. 5. The isolated perfused guinea-pig heart can be used as a toxicological model for testing and treating cardiac arrhythmias induced by tricyclic antidepressants.

Animals↗
PubMed1999

Histological evaluation of proximal tubule cell injury in isolated perfused pig kidneys exposed to cold ischemia.

BACKGROUND: Ischemic injury of the renal allograft before transplantation is a major cause of impaired graft function. Proton nuclear spectroscopy provides a useful technique for evaluating proximal tubular activity. In addition to this technique, we proposed a histological grading system for quantifying proximal tubule alterations. METHODS: The aim of this study was to evaluate the histological lesions of tubule epithelial cells in the model of isolated perfused pig kidneys following 48 to 72 h of cold storage in Euro-Collins solution. Normothermic isolated perfused pig kidneys were randomized in three experimental groups : Group 1, control group; cold flush with cold heparinized solution followed by immediate reperfusion (n = 6); Group 2, 48 h of cold storage in Euro-Collins followed by reperfusion (n = 6); Group 3, 72 h of cold storage in Euro-Collins followed by reperfusion (n = 6). Proton nuclear spectroscopy of urine and biochemical studies were performed for whole renal functional evaluation during reperfusion. Optical and electron microscopy analyses of the reperfused kidneys were performed by four investigators and the degree of cell injury was assessed using 8 different criteria in a 5-scale numerical score. RESULTS: Numerical scores corroborate the results from NMR spectroscopy and differed significantly between the three groups studied. The degree of proximal tubule cell damage was increased with prolonged cold ischemia as shown particularly in Group 3. CONCLUSION: The results from this study showed that analysis of cell injury based on an histological grading system in the model of isolated perfused kidney allows the quantification of the degree of proximal tubule injury. Thus, such morphological system analysis could be a useful method for quantifying tubule cell injuries observed under various physiopathological conditions.

Animals↗
PubMed1991

Disposition of fluorescein-labelled dextran (150 kD) in isolated perfused livers from control and diabetic rats.

Isolated perfused livers were used to study the hepatic disposition of fluorescein-labelled dextran with a MW of 150 kD (FD-150), in control and streptozotocin-induced diabetic rats. A 100-microliter volume of FD-150 solution (10%, w/v) was injected as a rapid bolus dose into the inlet catheter of the isolated livers, and samples were collected from the outlet catheter in 2-sec intervals for 80 sec. Statistical moment theory was used to calculate the distribution and elimination parameters of the tracer based on the concentrations of FD-150 in the outflow. The values (mean +/- SD) of mean transit time, volume of distribution, and extraction ratio of FD-150 in the isolated livers from control rats were 16.3 +/- 2.00 sec, 0.298 +/- 0.054 ml/g liver, and 0.24, respectively. Similar values were obtained in diabetic livers, suggesting that streptozotocin-induced diabetes does not affect the hepatic disposition of FD-150.

Animals↗
PubMed2000

Conjugation of para-nitrophenol by the isolated perfused neonatal sheep liver.

We examined the metabolism of para-nitrophenol (PNP) in the isolated perfused neonatal sheep liver (n = 8, 0.25-11 days) and compared the findings with our previous data from the perfused near-term fetal sheep liver (Ring, J. A., et al. Drug Metab Dispos 1996, 24, 1378). A three-step dosage regimen was used (72, 144, and 288 micromol of PNP). At the end of each dosage phase, PNP had fallen below detectable levels, and 101 +/- 16% of the dose was accounted for as PNP conjugates. Elimination of PNP from perfusate varied with dose. Elimination was first order with the 72-micromol dose; with the 144-micromol dose, elimination was first order in four livers but Michaelis-Menten kinetics in the remaining four. With all the 288-micromol doses, elimination was Michaelis-Menten and gave the following biochemical parameters: K(m) = 255 +/- 138 microM (fetal = 14.7 microM, P < 0.01), V(max) = 515 +/- 285 nmol/min/g liver (fetal = 34.3 nmol/min/g liver, P < 0.01), and intrinsic hepatic clearance = 2.36 +/- 1.21 mL/min/g liver (fetal = 4.74 mL/min/g liver, P > 0. 05). The mean shunt-corrected hepatic extraction ratio of PNP was 0. 82 (range, 0.40-1.0) and strongly correlated with neonatal age (r = 0.90, P < 0.05). We conclude that PNP is highly extracted by the isolated perfused neonatal sheep liver at much higher efficiency than in the near-term fetal sheep, reflecting a maturation of conjugation that progresses further in the early neonatal period.

Animals↗