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PubMed1990

The isolated perfused heart according to Langendorff technique--function--application.

1. Definition. The isolated perfused heart according to Langendorff is a preparation which is easily obtained from all warm-blooded animals. The heart is usually perfused at constant pressure, but frequently at constant flow, mostly with oxygenated saline solutions. The ventricles do not fill with the perfusate and therefore do not perform pressure-volume work. If, however, an intraventricular balloon is inserted, the ventricle can contract isovolumetrically. 2. Measuring parameters. Mechanical parameters of the working myocardium (contractile force, volume, ventricular diameter), mean coronary flow, bioelectrical parameters (EKG, monophasic injury potentials), and cardiac rhythm can be measured and recorded. 3. Function tests. The intact function of the working myocardium and the coronary vessels should be examined using various simple tests regarding the myocardium, the smooth musculature, and the endothelium of coronary vessels. 4. Possible applications. In the Langendorff-heart of normal or pretreated animals, inotropic, chronotropic, antiarrhythmic or vasoactive substances can be investigated in the steady state or by means of specific stress tests. In addition, the preparation is particularly suitable for biochemical studies of myocardial metabolism. 6. Advantages. Due to the technical ease with which a variety of parameters can be measured, a single heart can provide maximum information about the condition of the myocardium and the coronary vessels. Thus, it is not surprising to find that 90 years after its first description, the isolated perfused heart according to Langendorff continues to be utilized.

Animals↗
PubMed1988

The inhibition by chlorate of the sulphation of polyethyleneglycol in the isolated perfused guinea pig liver.

1. The sulphation of polyethyleneglycol 200 by the isolated perfused guinea pig liver is inhibited to about 60% by 10 mM ClO3- in the plasma of the perfusate when the concentration of SO4(2-) therein is 1.18 mM. 2. The inhibition is almost complete when the concentration of SO4(2-) is about 0.1 mM, a level which can be achieved by using a modified Ringer-bicarbonate solution, devoid of sulphate, to prepare the perfusate. 3. Chlorate, presumably through its action on ATP-sulphurylase, may therefore be a useful inhibitor of sulphation in the isolated perfused liver when the activity of the sulphurylase is rate-limiting. 4. The rate of bile production in the presence of chlorate is no different from that in its absence showing that, in the time scale of the perfusion, chlorate is not a general liver poison. 5. When the synthesis of PAPS is not rate-limiting, as in the sulphation of oestrone metabolites by rat liver, chlorate has no effect on the rate of sulphation.

Animals↗
PubMed1984

Regional isolation-perfusion: an experimental percutaneous approach tested and compared with arterial occlusion-infusion.

A percutaneous approach was developed for the performance of regional isolation-perfusion, a surgical chemotherapeutic procedure for the intraarterial treatment of neoplasms. This technique was compared with percutaneous transcatheter arterial occlusion-infusion concerning local and systemic drug levels. Floxuridine (FUDR) was administered into a femoral artery of adult mongrel dogs, first by arterial occlusion-infusion, and 4 weeks later by regional isolation-perfusion of the opposite hind limb. Local and systemic plasma samples and local muscle specimens were collected for determination of FUDR levels. Results indicated not only that regional isolation-perfusion could be accomplished percutaneously, using balloon catheters, but also that the technique produced significantly greater local tissue FUDR levels (P less than 0.05) than those achieved with arterial occlusion-infusion.

Angioplasty, Balloon↗
PubMed1977

Adaptive properties of the b-wave and the PIII in the perfused isolated carp retina.

1. Perfusion of isolated carp retina with a pure oxygen saturated standard solution used in this experiment permitted several continuous hours of ERG recordings showing a distinctive b-wave as well as the PIII isolated by sodium aspartate. 2. The dark-adapted threshold for the PIII required an absorption of 5 to 6 quanta per rod. The 'rod-cone break' in the increment threshold curve for the b-wave was induced at a background intensity of about 2.0 X 10(-2) muW/cm2. 3. Both the b-wave and the PIII showed rapid and complete recovery of sensitivity after exposure to dim adapting lights. After bright light adaptation, the sensitivities went through a short 'fast phase' followed by a prolonged 'slow phase' of recovery. The rate of recovery during the fast phase was significantly faster for the PIII than for the b-wave. Neither a lowered temperature (9 degrees C) nor the application of ouabain (10(-6) M) influenced the fast phase. This seems to prove that the visual pigment, photoproducts and the active transport hardly participate in its mechanism, if at all. 4. The prolonged slow phase that followed the fast phase was distinguished by the recovery of the rod activity, even in isolated retinas.

Adaptation, Ocular↗
PubMed1981

The role of intrarenal pH in regulation of ammoniagenesis: [31P]NMR studies of the isolated perfused rat kidney.

1. [31P]NMR spectra were obtained from a functioning isolated perfused rat kidney with the aim of determining intrarenal pH in acute acidosis. 2. Signals from intracellular inorganic phosphate could be observed in the absence of phosphate in the perfusion medium. Under these conditions renal ATP and inorganic phosphate content fell by 30% but total adenine nucleotide and phosphorylation potential ATP/ADP x Pi were unchanged compared with kidneys perfused with phosphate-containing medium. In addition, G.F.R., Na+ reabsorption and ammonia formation from glutamine remained normal. Ammonia production increased 93%, urine pH fell to 5.8 +/- 0.1 and kidney 2-oxoglutarate content fell by 80% upon acidification of the perfusion medium from pH 7.4 to pH 6.9, findings identical with those obtained in controls (Ross & Tannen, 1979). 3. [31P]NMR spectra of the isolated perfused rat kidney showed a pattern of adenine nucleotides and a small concentration of phosphocreatine, Intra-renal pH was measured from the resonance position of intracellular inorganic phosphate and in perfusions with pH 7.4 buffer was 7.19 +/- 0.10 (n = 11). 4. Acidification of the perfusion medium to pH 7.0 resulted in 0.3 pH unit fall in intrarenal pH. This fall in total intrarenal pH is insufficient to explain the fall in 2-oxoglutarate concentration observed if the glutamate-dehydrogenase-equilibrium model is invoked. 5. The line-width of the NMR signal is compatible either with heterogeneity of intra-renal pH or the existence of a pH gradient between cytosol and mitochondria, or both.

Acidosis↗
PubMed1987

Effects of adenosine triphosphate depletion in the isolated perfused rat kidney.

Glycerol or fructose (40 mM) was added to the control perfusate and renal function was observed in the isolated perfused rat kidney during nonischemic perfusions or perfusions following 30 min of clamp ischemia. Addition of glycerol or fructose resulted in lowering adenosine triphosphate (ATP) levels to 62 and 35%, respectively, of levels achieved with control perfusate under nonischemic conditions (p less than 0.01). Total adenine nucleotides (TAN) were also lowered to 67% with glycerol and 61% with fructose of control values under nonischemic conditions (p less than 0.05). However, physiologic parameters of renal plasma flow and inulin clearance were essentially unaffected by either glycerol or fructose. Following ischemia, glycerol and fructose reduced ATP levels to 51 and 37% and TAN levels to 67 and 65%, respectively, of values seen with control perfusate. However, recovery of renal plasma flow and inulin clearance were uneffected by the addition of either glycerol or fructose. Thus, a 33-65% reduction in renal tissue ATP by glycerol or fructose does not appear to have a deleterious effect on organ function in the basal state or during recovery from an ischemic insult in the isolated perfused rat kidney.

Adenine Nucleotides↗
PubMed1987

Effect of trimethoprim, paracetamol and cimetidine on trimetrexate metabolism by rat perfused isolated livers.

Trimetrexate (TMTX), a non-classical antifolate, is currently in clinical trial as an antineoplastic drug. In the rat perfused isolated liver, it undergoes extensive metabolism to two metabolites, M1 and M2, which are excreted primarily in the bile. The metabolites result from demethylation, and M1 is also glucuronidated. We examined the effects of three commonly used drugs on the elimination of 1 mg of TMTX by the rat perfused isolated liver (perfusate volume was 100 mL). Co-administration of either 1 or 5 mg cimetidine, a well-known inhibitor of microsomal oxidation, caused an increase in TMTX terminal elimination half-life (69 and 100% at 1 and 5 mg, respectively) and a decrease in clearance (40 and 46% at 1 and 5 mg, respectively). Paracetamol (acetaminophen) was chosen for a possible interaction with TMTX because its major metabolic pathway is glucuronidation. Five mg paracetamol resulted in no change in TMTX pharmacokinetics, but M1 concentrations were increased by 72% in bile, and M2 was not present in perfusate. The third drug tested was trimethoprim, which has some structural similarities to TMTX; however, no effects were noted on the levels of TMTX, M1 or M2 after 1 mg trimethoprim. These results indicate that TMTX elimination can be inhibited by cimetidine, probably due to competition for microsomal enzymes, and that paracetamol may alter the metabolite profiles; trimethoprim had no effect on TMTX disposition under the conditions employed.

Acetaminophen↗
PubMed1996

Conjugation of para-nitrophenol by isolated perfused fetal sheep liver.

Using our recently described, isolated perfused fetal sheep liver model, we have studied the metabolism and disposition of para-nitrophenol (PNP) in intact fetal liver. Fetal sheep (mean gestational age, 137 +/- 7 days; range, 127-145 days; n = 8) were delivered under anesthesia near term, and the livers were isolated and perfused in situ, via the umbilical vein, in an oxygenated 1-liter recirculating system, at pH 7.40 at 37 degrees C. The perfusate delivery rate was 4.39 +/- 1.46 ml/g liver/min. Either a 14-micromol (n = 4), 72-micromol (n = 3), or 144-micromol (n = 5) bolus dose of PNP was added to the reservoir. Samples were taken from the reservoir every 5-10 min, and all bile was collected at 15-30-min intervals. Elimination of PNP from perfusate demonstrated Michaelis-Menten kinetics, and the calculated pharmacokinetic parameters for PNP elimination were KM = 13.0 +/- 9.66 microM, Vmax = 32.1 +/- 22.4 nmol/min/g liver, and intrinsic clearance = 3.39 +/- 2.54 ml/min/g liver. At the end of the 120-min perfusion period, PNP could be accounted for entirely as PNP-sulfate (PNP-S) and PNP-glucuronide (PNP-G). The perfusate ratio of PNP-S to PNP-G at 120 min was 2.21 +/- 0.88 at the 14-micromol dose, 0.86 +/- 0.56 at the 72-micromol dose, and 0.31 +/- 0.17 at the 144-micromol dose, because of saturation of sulfate production with increasing dose. PNP-S and PNP-G were eliminated into bile in small amounts (<3% of dose), and the PNP-S/PNP-G ratio in bile was 1. We conclude that near-term fetal sheep liver can metabolize PNP to PNP-G and PNP-S with efficiencies that may be comparable to those of adults, that, as in adults, sulfation is of low capacity, relative to glucuronidation, and that, unlike adults, fetuses have little capacity to transport the PNP-G formed in the hepatocytes into bile.

Animals↗
PubMed1995

Functional and ultrastructural features of ethanol/bile salts interaction in the isolated perfused rat liver.

We investigated whether bile salts (BS) with different hydrophobic-hydrophilic properties interact with ethanol on bile secretion, enzyme (aspartate transaminase [AST], lactate dehydrogenase [LDH]) release in the perfusate, liver ultrastructure, and vesicular exocytosis in the isolated perfused rat liver. Ethanol (0.1 or 1%) promoted a rapid decrease of bile flow and BS secretion in livers perfused with taurocholate (TCA), the physiologic BS in the rat (-28% decrease of baseline values with 0.1% and -34% with 1% ethanol). The inhibitory effect of ethanol on bile flow and BS secretion was significantly (P < .02) attenuated by perfusing liver with the hydrophilic BS, tauroursodeoxycholate (TUDCA), and it was exacerbated (P < .02) by perfusion with the hydrophobic BS, taurodeoxycholate (TDCA). The release of AST and LDH in the perfusate was unaffected by 0.1% ethanol, but increased threefold to fivefold by 1% ethanol in TCA-perfused livers. This cytolitic effect of ethanol was not observed in TUDCA-perfused livers, but it was enhanced (P < .03) by perfusion with TDCA. No ultrastructural abnormalities were found in either TCA- or TUDCA-perfused livers, with or without 1% ethanol. Only minimal changes were found in livers perfused with TDCA alone, but, in the presence of TDCA, 1% ethanol induces marked mitochondrial damage. The biliary excretion of the fluid phase marker horseradish peroxidase was inhibited by ethanol, an effect reversed by TUDCA (P < .02) and exacerbated by TDCA (P < .04). In conclusion, this study demonstrates that hydrophilic BS such as TUDCA counteract the inhibitory effect of ethanol on bile secretion and vesicular exocytosis as well as the ethanol-induced cytolitic effect in the isolated perfused rat liver. In the presence of hydrophobic BS such as TDCA, the exposure to ethanol promotes a marked inhibition of bile secretion and vesicular exocytosis as well as prominent mitochondrial damage.

Animals↗
PubMed1989

The vulnerability of the thin descending limbs of Henle's loop in the isolated perfused rat kidney.

In the isolated rat kidney perfused without erythrocytes, the medullary thick ascending limb shows extensive injury. Damage to the thin limbs of Henle's loop has been mentioned only briefly. Thin limbs were examined in the isolated perfused kidney under a variety of conditions that alter oxygenation and active transport in the medulla and are known to affect injury to the medullary thick ascending limb. The thin descending limbs of short loops were preserved in all experimental groups, but those of the long loop showed necrosis that was restricted to the proximal portion, where the epithelium is more complex. In oxygenated kidneys, necrosis involved 41% +/- 5% (mean +/- SE) of the medullary thick ascending limbs and 10% +/- 3% of the proximal portion of long loops of thin descending limbs. Under hypoxic conditions, necrosis involved 90% +/- 3% of the medullary thick ascending limbs and 70% +/- 5% of the proximal portion of long loops of thin descending limbs (P less than 0.0001 compared with oxygenated kidneys). Ouabain and absence of filtration completely prevented necrosis of both nephron segments. Thus, the proximal portions of long loops of thin descending limbs, in resemblance to medullary thick ascending limbs, are especially susceptible to transport-dependent hypoxic injury.

Animals↗
PubMed1977

In vitro release of gastrin from isolated perfused antrum.

Gastrin is released from isolated perfused rat antra in a regular fashion by a variety of stimuli, including acetylcholine, glycine, and calcium. Two peaks are seen with the physiologic stimulus, acetylcholine, suggesting perhaps two different antral gastrin populations.

Acetylcholine↗
PubMed1990

Protection by exogenous glutathione against hypoxic and cyanide-induced damage to isolated perfused rat livers.

In experiments with isolated perfused livers from fasted rats, addition of 2 mmol/l glutathione (GSH) to the perfusion medium protected against hepatic damage induced by cyanide or hypoxia and reoxygenation as evidenced by leakage of lactate dehydrogenase and hepatic calcium accumulation. In control experiments as well as in experiments with cyanide or hypoxia and reoxygenation, exogenous glutathione resulted in an augmentation of cellular glutathione content, indicating either direct uptake of GSH or stimulation of its intracellular synthesis. The protective effects of glutathione against hypoxic and cyanide-induced hepatotoxicity substantiate the role of oxidative stress in both types of injury.

Animals↗
PubMed1978

The effects of methysergide on the constrictor response to serotonin on the isolated, perfused rabbit ear artery.

On the isolated, perfused rabbit ear artery methysergide 10(-9) mol.1(-1) only potentiated the constrictor response to serotonin while at a concentration of 2.5 x 10(-8) mol.1(-1) it only blocked the response. At an intermediate concentration (2.5 x 10(-9) mol.1(-1)) it produced initial potentiation followed by subsequent blockade. In contrast, at all three concentrations it only potentiated the constrictor response to noradrenaline. The results thus show that methysergide can exert a dual effect on the constrictor response to serotonin with the actual effect produced being dependent not only on the concentration of methysergide used but also on the period of time the artery is exposed to methysergide.

Animals↗
PubMed1966

The fate of acetyl groups derived from glucose in the isolated perfused goat udder.

1. In the isolated perfused goat mammary gland, both glucose and acetate contribute 20-30% of carbon to citrate via acetyl-CoA. 2. Carbon dioxide does not contribute significantly to the formation of acetyl-CoA. 3. ATP citrate lyase, which, in rats, yields acetyl-CoA for fatty acid synthesis, is absent from or very low in high-speed supernatant fraction of ruminant tissue. 4. It is reasonable to infer that intramitochondrial acetyl-CoA, to which both glucose and acetate contribute, is separated from extramitochondrial acetyl-CoA to which glucose does not contribute and which is used for fatty acid synthesis.

Acetates↗
PubMed1972

The role of glucose in the survival and 'recovery' of the anoxic isolated perfused rat heart.

Studies with the isolated perfused working rat heart were carried out to investigate factors that may enable the heart to recover after periods of anoxia. It was found that the presence of glucose in the perfusion fluid during anoxia was essential for complete post-anoxic recovery and the presence of a high concentration of K(+) increased not only the rate of recovery but also the final extent of recovery. In an attempt to clarify the roles played by glucose and K(+) in aiding the survival and recovery of the anoxic myocardium the concentrations of parameters associated with energy liberation and anaerobic glycolysis (ATP, ADP, AMP, P(i), creatine phosphate, glycogen and lactate) were measured in the presence and absence of glucose during the anoxic phase. Determinations of these parameters were carried out during the working aerobic control period, the anoxic period (K(+) arrest) and the recovery period. The results demonstrated that glucose acted as an energy source during anoxia and thus maintained myocardial concentrations of high-energy phosphates, particularly ATP. These studies have also shown a direct relationship between the ability of the heart to recover and the concentration of myocardial ATP at the time of reoxygenation.

Adenosine Diphosphate↗
PubMed1973

Xylitol metabolism in the isolated perfused rat liver.

1. Loading the isolated perfused liver from well-fed rats with xylitol (20mm) caused a depletion of adenine nucleotides and P(i) and an accumulation of alpha-glycerophosphate. The ATP content fell to 66% of the control value after 10min and to 32% after 80min. The ADP and AMP contents also fell. After 80min 63% of the total adenine nucleotides and 59% of the P(i) had been lost. 2. The alpha-glycerophosphate content rose from 0.13 to 4.74mumol/g at 10min and reached 8.02mumol/g at 40min. 3. Xylitol was rapidly metabolized, the main products being glucose, lactate and pyruvate. 4. The [lactate]/[pyruvate] ratio in the presence of xylitol rose to 30-40. 5. On perfusion of livers from starved animals the main product of xylitol metabolism was glucose and the mean ratio xylitol removed/glucose formed was 1.29 (corrected for endogenous glucose and lactate production). This is close to the predicted value of 1.2. 6. Evidence is presented indicating that the loss of adenine nucleotides caused by xylitol is not due to the increased ATP consumption but to the accumulation of alpha-glycerophosphate and depletion of P(i). 7. The loss of adenine nucleotides accounts for the hyperuricaemia which can occur after xylitol infusion in man. 8. The relevance of the findings to the clinical use of xylitol as an energy source is discussed.

Journal Article↗
PubMed1988

Distinction between major chloroquine-inhibitable and adrenergic-responsive pathways of protein degradation and their relation to tissue ATP content in the Langendorff isolated perfused rat heart.

In the Langendorff isolated perfused rat heart, 36% of total basal protein degradation was inhibited by the lysosomal inhibitor chloroquine (30 microM), after elimination of rapid turnover proteins during a 3 h preliminary degradation period. Prior inhibition of degradation with chloroquine was additive to the 30% inhibition caused by simultaneous infusion of 50-200 nM-isoprenaline. This additivity suggests that the adrenergic-controlled process is independent of the lysosomal degradative pathway. After discontinuation of drug infusions, the isoprenaline-inhibited degradation rate returned to the previous baseline; however, the chloroquine-inhibited degradation rate transiently exceeded the previous baseline. NaN3 (0.3 mM) caused a decrease of left-ventricular myocardial ATP content of approx. 60% at 14 min and extreme impairment of contractile function; however, the total lysosomal and non-lysosomal protein degradation was not changed at this time. Conversely, left-ventricular tissue ATP content was not changed during proteolytic inhibition by 10 nM-isoprenaline or 10 microM-chloroquine at 14 min. The results indicate that depletion of myocardial energy stores in this preparation is neither necessary nor sufficient to cause inhibition of the total of lysosomal and non-lysosomal protein degradation.

2,4-Dinitrophenol↗
PubMed1982

[A method for the investigation of cholegraphic contrast media. Experiments using isolated perfused rat livers (author's transl)].

Isolated perfused rat livers were used for investigating possible interactions between two simultaneously injected contrast media, and which technique, using parenteral application of cholegraphic media, is optimal. The results show that excretion of a parenteral contrast medium is reduced by giving an oral contrast medium at the same time. Simultaneous administration of two different contrast media therefore does not result in improved diagnostic information. The effect depends on the dose, and a sufficiently long interval should be observed between giving an oral and a parenteral contrast medium. A comparison of excretion values following injection of a bolus and prolonged infusion shows higher biliary contrast concentration and increased excretion after a single injection. Comparing only the period after the infusion, no difference was found between these two methods of administration. The single injection offers pharmacokinetic advantages, but an infusion is better tolerated and has fewer side effects. A rapid infusion of 10 to 15 minutes is therefore recommended as the optimal means of administration.

Animals↗