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PubMed1978

Physical properties of isolated perfused basement membranes from rabbit loop of Henle.

Isolated, perfused segments of late proximal straight tubule, descending thin limb of Henle, and ascending thick limb of Henle from the rabbit were studied before and after removal of the epithelium with sodium deoxycholate. The relationship between transmural hydrostatic pressure and outer tubule diameter was similar in paired intact tubules and basement membranes, indicating that basement membrane is the principal determinent of tubule distensibility. As calculated from teh measured perfusate flow at several different transmembrane hydrostatic pressures, the hydraulic conductivity of the basement membranes was 6-8 X 10(-3) cm3/cm2.min.cmH2O. With use of these LP values and the calculated oncotic pressure required experimentally to reduce transmembrane hydrostatic pressure transiently to zero, the apparent reflection coefficient of the basement membranes for serum albumin was estimated to be 0.05-0.16. It is concluded that basement membranes of the loop and of other previously studied segments of rabbit nephron provide very strong and elastic mechanical support to the epithelium while having minimal resistance to flow of water and of solutes as large as serum albumin.

Animals↗
PubMed1985

[Effect of a plant immunostimulant on phagocytosis of erythrocytes by the reticulohistiocytary system of isolated perfused rat liver].

By the help of the isolated, perfused rat liver, the influence of an immune stimulant of plant origin (Esberitox N; composition: herb. thujae occid. rec., rad. baptisiae tinct., rad. echinaceae ang. et purp.) on the activity of Kupffer cells was tested. It was shown that the phagocytosis of erythrocytes was improved significantly by the single extracts and the combination of this. The extract of thuja occidentalis had the most prominent effect on the first phase of phagocytosis, whereas the extract of echinacea purpurea dominantly influenced the phagocytosis dependent metabolism.

Adjuvants, Immunologic↗
PubMed1978

Regional chemotherapy by isolation-perfusion.

For 20 years, regional chemotherapy by isolation-perfusion has been employed for limb and selected pelvic lesions using high doses of drugs without systemic side effects. When used prophylactically, it is combined with local excision of the lesion and primary closure reducing the number of skin grafts and recurrence rate for local or intransit disease. Overall survival rate is better than for patients treated by surgery, and perfusion patients also do better with secondary therapy. For advanced melanoma patients with intransit metastasis, a 50% five-year survival may be less than expected. For patients with soft tissue sarcomas < 5 cm in diameter, the five-year survival is just under 80% and just over 40% for those > 5 cm. Complications may occur in 10% of patients treated by prophylactic perfusion, and the rate increases as the dosage and number of drugs are increased, up to a 37% complication rate for patients with advanced disease in a limb.

Antineoplastic Agents↗
PubMedDate not supplied

Comparative evaluation of the vasodilator effect of verapamil, nifedipine and diltiazem on isolated perfused coronary arteries of rabbit.

In experiments with isolated perfused rabbit heart, nifedipine (1, 2 and 4 micrograms) produced a dose-dependent increase in coronary outflow (P less than 0.01). On the other hand effects after verapamil and diltiazem were negligible in such doses, though in high doses (10, 20 and 40 micrograms) they produced a significant (P less than 0.01) increase in coronary outflow. In experiments where noradrenaline (0.1 micrograms/ml) was added in the perfusion fluid, nifedipine (1, 2 and 4 micrograms), as well as verapamil and diltiazem (10, 20 and 40 micrograms) produced a dose-dependent, significant increase in coronary outflow (P less than 0.01).

Animals↗
PubMed1983

The effects of amrinone on cardiac function, oxygen consumption and lactate production of an isolated, perfused, working guinea-pig heart.

Compared with isolated heart muscle and Langendorff preparations, the isolated, working heart preparation allows a more complete analysis of cardiac function and metabolism. We have studied the effects of amrinone 20 micrograms/ml and 200 micrograms/ml on the isolated perfused working guinea-pig heart. We have measured: heart rate (HR), mean systolic aortic pressure (SP), aortic flow (AF), coronary flow (CF), total cardiac output (CO), and calculated the stroke volume (SV) and the rate of external work (W). The rates of oxygen consumption (VO2) and lactate production (Lact) were also measured and the external efficiency (Eff) calculated. Hearts were allowed to fail spontaneously after work for 90 min. Amrinone was then added at the required concentration to the perfusion medium. Amrinone 20 micrograms/ml, increased AF, CF, CO, SV, W and VO2. HR was slightly but significantly increased. Lact and Eff were not altered. Amrinone 200 micrograms/ml substantially increased CF and VO2, but it increased slightly and not significantly AF, CO, SV and W, suggesting the predominance of the coronary vasodilating effect of amrinone at higher doses. Lact and Eff remained unchanged. The positive chronotropic effect was of the same magnitude than that observed with the lower dose. No arrhythmias occurred with either concentration. These results would suggest that amrinone is a positive inotropic drug with vasodilating properties at higher doses, and weak positive chronotropic effect. It stimulates aerobic but not anaerobic metabolism of the heart.

Aminopyridines↗
PubMed1995

Fetal hepatic propranolol metabolism. Studies in the isolated perfused fetal sheep liver.

We have used an isolated perfused fetal sheep liver preparation to study the fetal hepatic metabolism of propranolol in vitro in the intact organ. Eight livers were perfused in situ via the umbilical vein in an oxygenated recirculating system at 300 ml/min. Radiolabeled 15-microns microspheres were used to quantify the hepatic ductus venosus shunt. Propranolol (4 mg) was dosed into the reservoir as a single bolus and perfusate and bile sampled over 150 min. Propranolol, 4-hydroxy propranolol (4OHP), 5-hydroxy propranolol (5OHP), desisopropylpropranolol (DIP), naphthoxylactic acid (NLA), and alpha-naphthoxyacetic acid (NAA) were assayed by HPLC, before and after deconjugation by enzyme hydrolysis. Mean age was 125 +/- 10 days, and mean liver weight was 66.1 +/- 18.8 g. Oxygen consumption (1.10 +/- 1.03 mumol/g/min), bile flow (0.51 +/- 0.18 microliters/g/min), and perfusion pressure (8.7 +/- 3.3 mm Hg) were stable. Ductus venosus shunt was 41.6 +/- 17.4% of umbilical vein flow. Propranolol clearance was 26.2 +/- 13.4 ml/min, and shunt-corrected extraction of propranolol was 0.26 +/- 0.13. The relative amounts of metabolites in perfusate after 150 min were: 4OHP (25.1%), 5OHP (5.08%) (ring-oxidation products), DIP (6.57%), and NLA (4.33%) (side-chain oxidation products). No alpha NAA (a product of N-dealkylation of NLA) was detected. Except for NLA, metabolites were present predominantly as conjugates. Biliary excretion of unchanged drug and metabolites accounted for a further 1.33% of the propranolol dose. These data indicate that, although the hepatic clearance and extraction of propranolol are low, the fetal sheep liver can metabolize propranolol by both ring- and side-chain oxidation reactions and can conjugate these metabolites.

Animals↗
PubMedDate not supplied

Effect of changes in vascular tone on the haemodynamic characteristics of the portal vascular bed of the isolated perfused rat liver.

The effect of altered vascular tone on the haemodynamic characteristics of the intrahepatic portal vascular bed was studied in the isolated perfused rat liver preparation. The relationship between portal venous inflow (Q) and portal perfusion pressure (P) was determined in the presence of a maximally effective concentration of a vasoconstrictor agent (noradrenaline, NAmax, 3 x 10(-5)mol/L), an intermediate concentration (NAmed, 1 x 10(-6)mol/L) or a vasodilator agent (papaverine, PAP, 6 x 10(-4)mol/L). At flow rates greater than 20 mL/min, the pressure-flow relationship could be regarded as linear (P < 0.001), with mean values for the extrapolated intercept with the pressure axis (Po) of 6.8 +/- 0.9 mmHg for NAmax, 4.5 +/- 0.5 mmHg for NAmed, and 1.65 +/- 0.05 mmHg for PAP-treated preparations. Over the full flow range (0-70 mL/min), in both NA- and PAP-treated preparations, portal vascular conductance (G = Q/P) was related directly to perfusion pressure. Thus, G = C.P, where C is a constant (mean values for NAmax, NAmed, and PAP-treated preparations were 0.0090 +/- 0.0020, 0.023 +/- 0.005, and 0.26 +/- 0.02 mL/min per g per mmHg2, respectively). It is concluded that both C and Po may be useful indices of tone in the isolated perfused rat liver, and that analysis of hepatic portal haemodynamics in this manner may have considerable practical value in studies of the action of vasoactive agents.

Animals↗
PubMed1987

Isolated perfused rat kidney and liver combined. A new experimental model.

Interaction between hepatic and renal metabolism is found in many endocrine systems. We therefore developed a new experimental model, combining the isolated perfused rat kidney and rat liver. Krebs-Henseleit buffer with bovine serum albumin 67 g X l-1 and amino acids was recirculated to both organs through two rolling pumps, four 8 microns Millipore filters and two specially designed membrane lungs. The kidney was cannulated by a modification of the technique described by Nishiitsutsuji-Uwo 1967 and the liver was cannulated by a modification of the technique described by Hems 1966. Kidney function: Perfusion pressure 12.4 +/- 1.1 kPa (93 +/- 8 mmHg), flow 28 +/- 6 ml X min-1 X g-1, FRNa 94.0 +/- 2.9%, GFR 491 +/- 191 microliters X min-1 X g-1, urine production 48 +/- 34 microliters X min-1 X g-1, FEK 60 +/- 36%. Liver function: Flow 25 ml X min-1 (fixed), portal vein pressure 12 +/- 3 cm H2O, bile flow 0.18 +/- 0.13 ml X h-1, oxygen consumption 2.0 +/- 0.2 mumol X min-1 X g-1. Only minor differences were found between single perfusions (N = 25) and combined perfusions (N = 6). We conclude that it is possible to combine the isolated perfused rat kidney and rat liver without impairment of the function of either.

Animals↗
PubMed1987

Effect of inflammation and proadifen on the disposition of antipyrine, lignocaine and propranolol in rat isolated perfused liver.

The effect of inflammation, induced in rats by injection of turpentine oil, on drug disposition has been evaluated in rat isolated perfused livers. The drugs studied were a low extraction drug, antipyrine, and two high extraction drugs, lignocaine and propranolol. Turpentine significantly increased the half-life of antipyrine and of propranolol, but not that of lignocaine. Proadifen (SKF 525A) significantly increased the half-life of all three drugs. Turpentine decreased the clearance of antipyrine significantly by about 50% and that of propranolol non-significantly by about 20%, but did not affect the clearance of lignocaine. Proadifen significantly decreased the clearance of all three drugs, but this was most pronounced for antipyrine. In both turpentine- and proadifen-treated rats a significant increase in volume of distribution of propranolol was observed. The results show that, as with proadifen, turpentine-induced inflammation affects the hepatic clearance of antipyrine in the rat isolated perfused liver. With both high extraction drugs, the effect of inflammation on their clearance was low or absent, in contrast to the effect of proadifen. This suggests that a possible effect of inflammation on intrinsic clearance is not large enough to influence the hepatic clearance of the high extraction drugs.

Animals↗
PubMed1993

Effects of K+ channel openers on ischemic dysfunction and metabolic disturbance in isolated perfused rat heart.

The effects of two structurally different K+ channel openers, KRN2391 and cromakalim, on cardiac mechanisms during ischemia and reperfusion were studied in isolated perfused rat hearts. Isolated buffer-perfused rat hearts pretreated with KRN2391, cromakalim and vehicle were subjected to 25 min of ischemia followed by 30 min of reperfusion. Before ischemia, KRN2391 (1-10 microM) and cromakalim (1-10 microM) increased coronary flow, but did not modify cardiac function or biochemical parameters (adenine nucleotides, energy charge potential: ECP, lactate). During ischemia, KRN2391 (3, 10 microM) and cromakalim (10 microM) significantly accelerated the reduction in cardiac function and attenuated the decreased levels of ATP and ECP, but did not change the lactate content. After 30 min of reperfusion, pretreatment with KRN2391 and cromakalim resulted in a significant improvement in cardiac function, ischemic contracture and biochemical parameters. Thus, both KRN2391 and cromakalim have beneficial effects on biochemical parameters during ischemia and reperfusion, effects which may be related to cardiodepression during ischemia.

Animals↗
PubMed1976

Distribution of extravascular fluid volumes in isolated perfused lungs measured with H215O.

The distributions per unit volume of extravascular water (EVLW), blood volume, and blood flow were measured in isolated perfused vertical dog lungs. A steady-state tracer technique was employed using oxygen-15, carbon-11, and nitrogen-13 isotopes and external scintillation counting of the 511-KeV annihilation radiation common to all three radionuclides. EVLW, and blood volume and flow increased from apex to base in all preparations, but the gradient of increasing flow exceeded that for blood and EVLW volumes. The regional distributions of EVLW and blood volume were almost identical. With increasing edema, lower-zone EVLW increased slightly relative to that in the upper zone. There was no change in the distribution of blood volume or flow until gross edema (100% wt gain) occurred when lower zone values were reduced. In four lungs the distribution of EVLW was compared with wet-to-dry ratios from lung biopsies taken immediately afterwards. Whereas the isotopically measured EVLW increased from apex to base, the wet-to-dry weight ratios remained essentially uniform. We concluded that isotopic methods measure only an "exchangeable" water pool whose volume is dependent on regional blood flow and capillary recruitment. Second, the isolated perfused lung can accommodate up to 60% wt gain without much change in the regional distribution of EVLW, volume, or flow.

Animals↗
PubMed1979

Functional and metabolic features of an isolated perfused guinea pig heart performing pressure-volume work.

Cardiac performance and some parameters of glycolytic and oxidative metabolism were analyzed in isolated perfused guinea pig hearts performing pressure-volume work. Perfusion medium was an oxygenated Krebs-Henseleit bicarbonate buffer (pH 7.4) which contained glucose and physiological concentrations of pyruvate and insulin. The pressure-flow relationship in the coronary vascular bed indicated autoregulation of coronary flow. Left ventricular function was influenced by aortic pressure (Pa) and venous filling pressure (Pv) in accordance with the Frank-Starling principle, i.e. stroke work increased as a function of Pa or Pv to a certain maximum and then decreased. Myocardial oxygen consumption (MVO2), on the other hand, was linearly correlated with Pa and Pv, respectively, over the entire pressure range. Efficiency of the left ventricle, therefore, increased to an optimum (16%) and decreased at higher pressures. Myocardial contents of glycogen, ATP and creatine phosphate were not markedly influenced by a change in Pa or Pv. L-Noradrenaline (0.08 micrometer, NA) stimulated stroke work and MVO2 at a all Pv tested; efficiencies reached physiologic values (21%) at high volume loads. The increased MVO2 was associated with an acceleration of pyruvate decarboxylation and lactate release up to 10- and 15-fold, respectively, at elevated but physiological NA concentrations (0.2 micrometer). Our results demonstrate that the isolated perfused working guinea pig heart compares favourably with the non-failing Starling heart-lung preparation and hearts in situ, as far as coronary function, left ventricular performance and oxidative metabolism are concerned.

Animals↗
PubMed1995

Benzoic acid glycine conjugation in the isolated perfused rat kidney.

The fate of varying input concentrations (0.002-372 microM) of benzoic acid was examined in the single-pass isolated perfused rat kidney preparation under constant flow rate (8 ml min-1.organ-1). With an increasing concentration of benzoate, the steady-state renal extraction ratio decreased from 0.24 to 0.1. Little unchanged drug was found in the urine; the urinary clearance of benzoate was low (0.018 ml-1 min-1.g-1) and concentration-independent, yielding a rather constant fractional excretion of approximately 0.2. Metabolic clearance, due primarily to conjugation with glycine to form hippuric acid, constituted the majority of total renal clearance, and this decreased with concentration. These divergent trends for the metabolic and urinary clearance with concentration suggest that benzoate net influx across the basolateral membrane has not been saturated. Upon fitting of the hippurate formation rates vs. the plasma unbound logarithmic average concentrations of benzoate, overall kinetic constants (KM = 5.3 microM and Vmax = 195 nmol min-1.g-1) that likely reflect glycine conjugation were obtained. The formed hippurate either returned to the venous circulation or was excreted into urine without further biotransformation; the apparent renal extraction ratio (excretion rate/formation rate of hippurate) was quite high (approximately 0.48). Avid glycine conjugation and hippurate excretion thus occurred with administration of benzoic acid to the isolated perfused rat kidney.

Absorption↗
PubMed1987

Neutrophil-derived oxygen metabolites stimulate thromboxane release, pulmonary artery pressure increases, and weight gains in isolated perfused rat lungs.

Addition of normal human neutrophils and the neutrophil stimulant, phorbol myristate acetate (PMA), caused perfusate thromboxane (TXB2) elevations, pulmonary artery pressure (PAP) increases, and lung weight gains in isolated perfused rat lungs. Addition of PMA and neutrophils that do not generate O2 metabolites from a patient with chronic granulomatous disease (CGD) - or addition of PMA and normal neutrophils with the purported O2 metabolite scavenger, dimethylthiourea (DMTU) - also caused PAP increases but did not cause perfusate TXB2 elevations or lung weight gains in isolated lungs. In parallel, mixtures of normal neutrophils and PMA made hydrogen peroxide (H2O2) concentrations in vitro which exceeded concentrations found in mixtures containing PMA and CGD neutrophils or mixtures containing PMA, normal neutrophils, and DMTU. TXB2 levels were not detectable in mixtures containing normal neutrophils and PMA in vitro. Our results indicate that neutrophil-derived O2 metabolites contribute to perfusate TXB2 elevations and lung weight gains but not PAP increases in isolated perfused rat lungs.

Animals↗
PubMed1976

Metabolism of a benzothiazine compound (SQ 11,579) by the intact rat, isolated perfused rat liver, and rat-liver microsomes.

1. The metabolic dispositions of a benzothiazine compound (SQ 11,579) by the intact rat, isolated perfused rat liver, and rat-liver microsomes have been investigated, and the results compared. 2. The drug was well absorbed after oral administration to rats and was widely distributed in all tissues, which, with the exception of brain, had higher concentrations of the drug, its metabolites, or both, than did plasma. 3. Metabolism by rat-liver microsomes included N-oxidation, N-demethylation, S-oxidation and aryl hydroxylation. Metabolites hydroxylated in the aromatic ring were excreted only in bile, both by the isolated perfused rat livers and by anaesthetized bile-duct-cannulated rats. 4. Liver perfusion of the benzothiazine or its monodesmethyl analogue (V) resulted in temporary cessation of the flow of perfusate through the organ. The benzothiazine sulphoxide (IV) had only a slight effect on the flow of liver perfusate, but IV followed by I caused the flow of perfusate to cease.

Administration, Oral↗
PubMed2000

Method for measuring luminal efflux of fluorescent organic compounds in isolated, perfused renal tubules.

To examine directly in real time the efflux of organic compounds [e. g., organic anions (OAs) such as fluorescein (FL)] across the luminal membrane of isolated, perfused renal tubules during net secretion, we devised an approach utilizing a recently developed epifluorescence microscopy system for continuous monitoring of fluorescence in the collected perfusate. To illustrate this approach, we measured the luminal efflux rate of FL in mineral oil-covered, isolated, perfused S2 segments of rabbit renal proximal tubules. The washout profile of FL showed a deviation from linearity at time 0 when plotted on a semilog scale, indicating that the luminal efflux of FL was a saturable process. We were able for the first time to determine the kinetic parameters of luminal efflux [FL concentration at one-half maximal FL efflux (K(t)(lumen)) of approximately 560 microM and maximal rate of FL efflux across the luminal membrane (J(max)(lumen)) of approximately 635 fmol. min(-1). mm(-1)]. From the present study, we conclude that the transport step for OAs across the luminal membrane of OAs is a carrier-mediated process. This approach will work to measure luminal transport in real time for any secreted organic compound that is sufficiently fluorescent to be measured with commonly available, highly sensitive optical equipment.

Animals↗
PubMed1997

Diltiazem inhibits fatty acid oxidation in the isolated perfused rat liver.

The effects of diltiazem on fatty acid metabolism were measured in the isolated perfused rat liver and in isolated mitochondria. In the perfused rat liver diltiazem inhibited oxygen uptake and ketogenesis from endogenous substrates. Ketogenesis from exogenously supplied palmitate was also inhibited. The beta-hydroxybutyrate/acetoacetate ratio in the presence of palmitate alone was equal to 3.2. When the fatty acid and diltiazem were present simultaneously this ratio was decreased to 0.93, suggesting that, in spite of the inhibition of oxygen uptake, the respiratory chain was not rate limiting for the oxidation of the reducing equivalents coming from beta-oxidation. In experiments with isolated mitochondria, incubated in the presence of all intermediates of the Krebs cycle, pyruvate or glutamate, no significant inhibition of oxygen uptake by diltiazem was detected. Inhibition of oxygen uptake in isolated mitochondria was found only when palmitoyl CoA was the source of the reducing equivalents. It was concluded that a direct effect on beta-oxidation may be a major cause for the inhibition of oxygen uptake caused by diltiazem in the perfused liver.

Animals↗
PubMed1998

Comparative effects of englitazone and glyburide on gluconeogenesis and glycolysis in the isolated perfused rat liver.

Englitazone (CP 68,722, Pfizer) is a member of a family of drugs known as thiazolidinediones. One member of this family, troglitazone (Rezulin), is currently utilized in the treatment of Type 2 diabetes. Previous studies have focused on the ability of englitazone to increase insulin sensitivity in various tissues. However, little information is available regarding the direct effect of englitazone on hepatic glucose metabolism in the absence of insulin. Therefore, the following studies were conducted to comparatively evaluate the effect of englitazone and glyburide (a representative sulfonylurea) on gluconeogenesis and glycolysis from various substrates in the isolated perfused rat liver (IPRL). In isolated perfused rat livers of 24-hr fasted rats infused with lactate (2 mM), englitazone (6.25 to 50 microM) produced a concentration-dependent decrease (32-93%) in hepatic gluconeogenesis. When dihydroxyacetone (1 mM) and fructose (1 mM) were used as metabolic substrates, englitazone inhibited gluconeogenesis by 31 and 15%, respectively, while increasing glycolysis by 42 and 50%. Similar effects on gluconeogenesis and glycolysis were observed with glyburide, even though the effects with glyburide were more acutely evident, reversible, and of a greater magnitude. Such data suggest alterations in hepatic glucose production may contribute to the decrease in plasma glucose concentrations observed in individuals treated with englitazone and glyburide. These alterations may include effects on several regulatory enzymes (e.g. fructose-1,6-bisphosphatase, pyruvate kinase, and phosphoenolpyruvate carboxykinase), which warrant further investigation.

Animals↗