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PubMed1988

Kinetic analysis of the positive inotropic action (PIA) of ouabain in isolated perfused rabbit heart. Slow onset of PIA and slow binding to Na+, K+-adenosine triphosphatase.

The positive inotropic action (PIA) of ouabain was analyzed kinetically using isolated perfused rabbit heart. The input function of the ouabain concentration in the perfusate (Ci) into the heart was controlled by changing the volume of the reservoir and the rate of ouabain infusion into the reservoir fixed in front of the heart. The time courses of PIA were measured continuously with different infusion rates. The relationship between Ci and PIA clearly depended on the infusion rate in isolated perfused rabbit heart. The binding kinetics of ouabain to Na+, K+-adenosine triphosphatase (ATPase) in the cardiac homogenate showed two kinds of binding sites. The association rate constant (kappa 1), the dissociation rate constant (kappa-1) and the binding capacity of each site was estimated by the simultaneous fitting method. The occupation curve of the high affinity site corresponded well with the PIA measured in the isolated perfused heart at steady state. These results indicate that ouabain binding to the high affinity site is related to the PIA, and the slow binding process of ouabain to Na+, K+-ATPase may be one of the principal reasons for the infusion-rate dependence of ouabain PIA.

Animals↗
PubMed1984

A marked H1-receptor-mediated vasodilator effect of histamine in the isolated perfused rat heart.

Infusion of histamine into the coronary circulation of the isolated perfused rat heart produced a marked and concentration-dependent fall in perfusion pressure. A similar effect was obtained with 2-pyridylethylamine, a histamine H1-receptor agonist. Impromidine, a potent H2-receptor agonist, however, was found to be ineffective. Mepyramine but not cimetidine competitively inhibited the fall in perfusion pressure induced by histamine and 2-pyridylethylamine. Propranolol, a non-selective beta-adrenoceptor blocker, failed to abolish the coronary vasodilator effect of both histamine and 2-pyridylethylamine. From these results it was concluded that although the rat is known to be insensitive to histamine, this amine has a marked H1-mediated vasodilator effect in the isolated perfused coronary vasculature of this species.

Animals↗
PubMed1983

Effect of uridine supply on glycogen resynthesis after ischaemia in the isolated perfused rat heart.

Isolated rat hearts were subjected to 30 min low flow ischaemia (0.5 ml X min-1). During reperfusion, uridine (5 X 10(-5) mol X litre-1) was added to the perfusion medium for 30 min. The concentrations of creatine phosphate, adenine nucleotides, uridylic nucleotides and glycogen were determined at the end of the experiments. The purpose of this work was to study the effects of uridine supply on the concentration of energetic compounds during reperfusion recovery. Low flow ischaemia induced a breakdown of creatine phosphate, adenosine triphosphate, and total adenine nucleotides by 53%, 23% and 15% respectively. The creatine phosphate content was restored during reperfusion without uridine, but the adenine nucleotides remained unchanged. The uridylic nucleotides and the glycogen were also degraded during ischaemia by 56% and 53% for uridine triphosphate and glycogen respectively. Reperfusion without uridine induced a partial resynthetisation of uridylic nucleotides but glycogen stores were not significantly restored. When tested in oxygenated hearts, uridine supply induced a fall in creatine phosphate concentration and an enhancement of uridine triphosphate level but it had no effect on adenosine triphosphate, uridine diphosphate glucose or glycogen concentrations. If supplied during reperfusion, the nucleoside induced the complete restoration of myocardial ATP, total adenine nucleotide content, an increase in the uridylic nucleotide concentration and the resynthetisation of glycogen to supra-normal value.

Adenine Nucleotides↗
PubMedDate not supplied

HSP25 in isolated perfused rat hearts: localization and response to hyperthermia.

Recent investigations concentrate on the correlation between the myocardial expression of the inducible 70-kDa heat shock protein (HSP70i) by different stress conditions and its possible protective effects. Only few studies have focused on the involvement of small heat shock proteins in this process. We analyzed the location of the small heat shock protein HSP25 in isolated cardiomyocytes as well as its location and induction in isolated perfused hearts of rats. By immunofluorescence microscopy HSP25 was found to colocalize with actin in the I-band of myofibrils in cardiomyocytes of isolated perfused hearts as well as in isolated neonatal and adult cardiomyocytes. Hyperthermic perfusion of isolated hearts for 45 min resulted in modulation of different parameters of heart function and in induction of HSP25 is constitutively expressed even in normothermic perfused (44-46 degrees C) were lethal with respect to the contractile function of the hearts. Compared to control hearts perfused at 37 degrees C, significant increases during hyperthermic perfusion at 42 degrees C and 43 degrees C were obtained for heart rate, contraction velocity and relaxation velocity. In response to hyperthermia at 43 degrees C and after subsequent normothermic perfusion for 135 min at 37 degrees C, left to control values immediately after the period of heat treatment. HSP25 is constitutively expressed even in normothermic perfused hearts as shown by Western blotting. Hyperthermia increased the content of HSP25 only in the left ventricular tissue. In contrast, HSP70i was strongly induced in all analyzed parts of the myocardium (left ventricle, right ventricle, septum). Our findings suggest a differential regulation of HSP25 and HSP70i expression in response to hyperthermia in isolated perfused hearts. The constitutively expressed HSP25 seems to be located adjacent to the myofibrils which implies a specific role of this protein even under unstressed conditions for the contractile function of the myocardium.

Animals↗
PubMed2004

Glucagon-like peptide-1 secretion is influenced by perfusate glucose concentration and by a feedback mechanism involving somatostatin in isolated perfused porcine ileum.

Glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells in response to ingestion of meals. The mechanisms regulating its secretion are not clear, but local somatostatin (SS) restrains GLP-1 secretion. We investigated feedback and substrate regulation of GLP-1 and SS secretion, using isolated perfused porcine ileum (n=17). Effluents were measured for GLP-1 and SS. Perfusion pressure and motility were recorded. Investigated parameters included spontaneous fluctuations, changes in perfusate glucose concentrations (3.5, 5, 11 mM) and addition of insulin (1 nM). We also investigated the effect of proglucagon products, glucagon (10 nM), GLP-1 and GLP-2 (0.1, 1, and 10 nM) on GLP-1 and SS secretion, as well as on glucagon-like peptide-2 (GLP-2), peptide YY (PYY) and GIP secretion, all possible product of L-cells or neighbour cells. Perfusate glucose concentration dose-dependently stimulated GLP-1 secretion (p=0.011). Insulin had no effect. Glucagon weakly stimulated GIP secretion. GLP-1 stimulated SS secretion and motor activity, but inhibited GLP-2, GIP and PYY secretion and perfusion pressure. GLP-2 weakly stimulated SS secretion. We conclude (a) that GLP-1 secretion is influenced by perfusate glucose concentration and (b) that L-cell secretion is feedback regulated by GLP-1 itself, probably via paracrine SS activity.

Animals↗
PubMed2000

Factors responsible for acetylcholine-induced dilatation in the isolated perfused rat kidney.

Mechanism of acetylcholine (ACh)-induced dilatation was investigated in isolated perfused rat kidney. Under a constant flow of 8-10 ml/min, ACh (0.001-3 microg/0.1 ml) caused a dose-dependent decrease in perfusion pressure raised by submaximum concentration of phenylephrine (PE). ACh-induced dilatations were inhibited by atropine (10(-6) mol/l), hexamethonium (10(-4) mol/l), indomethacin (10(-5) mol/l), methylene blue (10(-5) mol/l), N(G)-nitro-L-arginine (L-NOARG, 10(-4) mol/l), tetrodotoxin (TTX, 10(-6) mol/l), capsaicin (10(-6) mol/l), and glibenclamide (10(-5) mol/l). These results suggest that in the isolated perfused rat kidney, endothelium-derived hyperpolarizing factor (EDHF), nitric oxide (NO), and tachykinin neuromediators may play a role in ACh-induced dilatation via stimulation of guanylate cyclase and opening of ATP-sensitive potassium channels.

Acetylcholine↗
PubMedDate not supplied

A carrier-protein receptor is not a prerequisite for avid hepatic elimination of highly bound compounds: a study of propranolol elimination by the isolated perfused rat liver.

The highly efficient hepatic extraction of propranolol by the isolated perfused rat liver does not diminish when albumin binding is increased from 30 to 75%. One possible explanation of this insensitivity of propranolol uptake to changes in albumin binding is the mediation of uptake of bound ligand by an albumin receptor on the hepatocyte as postulated for oleate, taurocholic acid and rose bengal. To test this hypothesis, the hepatic extraction of propranolol was studied in the isolated perfused rat liver using alpha 1-acid glycoprotein, which lacks a hepatocyte receptor, as the carrier protein in the perfusate rather than albumin. Livers were perfused with a medium containing propranolol (4 microM) and varying concentrations of alpha 1-acid glycoprotein (0 to 25 microM). Hepatic extraction of propranolol was very high (0.990 +/- 0.006; mean +/- S.D.) and did not alter significantly despite an increase in bound fraction from 0.2 to 0.8, thus closely paralleling the findings when albumin is the carrier protein. This result indicates that bound propranolol is efficiently cleared by the liver, presumably by a "free intermediate" mechanism, in the absence of a specific carrier-protein receptor on the hepatocyte. This study does not, therefore, support the albumin receptor hypothesis.

Albumins↗
PubMedDate not supplied

Subcellular origin of the surface fluorescence of reduced nicotinamide nucleotides in the isolated perfused rat heart.

Surface fluorometric measurements and indicator metabolite determinations in the isolated perfused rat heart showed that the NADH + NADPH fluorescence of the intact tissue originates largely from the mitochondria. The redox potential of the lactate dehydrogenase system calculated from the endogenous lactate/pyruvate ratios was closely similar to that of the glycerol-3-phosphate dehydrogenase system calculated from the concentrations of glycerol-3-phosphate and dihydroxyacetone phosphate in the tissue. Thus, in contrast to the liver, the cytosolic redox state of the NADH/NAD+ system in isolated perfused heart oxidizing external glucose or fatty acid is not amenable to optical monitoring, but can be assessed from the state of the lactate dehydrogenase or glycerol-3-phosphate dehydrogenase systems.

Animals↗
PubMed1987

Renal handling of cadmium and cadmium-metallothionein: studies on the isolated perfused rat kidney.

The isolated kidney perfusion model was used to study the uptake of Cd and metallothionein (MT)-complexed Cd. Cd2+ at concentrations above 40 nM strongly depressed the glomerular filtration rate (GFR), whereas MT-complexed Cd (Cd-MT) at concentrations of 0.8-920 nM had no effect on the GFR. In contrast to Cd2+, Cd-MT was readily reabsorbed by the kidney and uptake saturation for Cd-MT occurred at 240 nM. The maximal transport rate for Cd-MT calculated in this study was 18 pmoles Cd-MT . g-1 . min-1. The accumulation of Cd in the kidney was more efficient in the experiment using Cd-MT, in which case the Cd kidney contents were about 2-4 times higher than compared to CdCl2.

Animals↗
PubMed1996

Hepatic clearance and retention of aluminium: studies in the isolated perfused rat liver.

Aluminium (Al) exposure can result in Al accumulation in the liver and this metal can be toxic to the hepatic tissue at high concentrations. In the present study the model of the isolated perfused rat liver was used to investigate the hepatic handling of Al. Livers from male Wistar rats were perfused in a recirculating system for 240 min. The liver function remained unchanged at perfusate concentrations of Al ranging from 4.9 to 1530.0 micrograms/l. At higher Al levels of 6535.3-16694.9 micrograms/l signs of toxicity towards isolated perfused livers were observed as indicated by an increased release of the enzymes AST and ALT into the perfusate, a pronounced reduction of bile flow rate and a 50% suppression of oxygen consumption. The hepatic Al clearance was low and decreased with increasing concentrations of Al in the perfusate from 4.3 +/- 0.6 microliters/min per g liver at a nominal Al concentration of 9.1 micrograms/l in control perfusate to 0.04 +/- 0.02 microliter/min per g liver at the highest concentration group. There was almost a linear dose dependent retention of Al in the liver with 4.9-635.7 micrograms Al/l perfusate while at higher concentrations Al levels in this organ increased disproportionally. It is concluded that by using the isolated perfused rat changes of liver functions occur only at very high Al concentrations in the perfusate and that only negligible amounts of Al are eliminated by the liver.

Alanine Transaminase↗
PubMed1993

The disposition of nifurtimox in the rat isolated perfused liver: effect of dose size.

The disposition of nifurtimox was studied in the rat isolated perfused liver using a recirculating system. The drug was administered as a bolus (5.0, 15.0 or 30.0 micrograms mL-1), and its disappearance was monitored by analysing perfusate samples. In all experiments perfusate disappearance was monoexponential, and no significant difference was found between the three doses for the elimination constant (0.016, 0.011 and 0.012 min-1, respectively), half-life (46.6, 65.8 and 66.8 min, respectively), extraction rate (0.128, 0.091 and 0.099, respectively) and distribution volume (41.1, 47.3 and 30.7 mL g-1, respectively). At 30 micrograms mL-1 the hepatic clearance was lower than the other concentrations of nifurtimox (0.66, 0.51 and 0.34 mL min-1 g-1, respectively). Relatively little parent drug was recovered from the liver at the end of the perfusions. In summary, nifurtimox is cleared slowly from the rat isolated perfused liver, is poorly extracted by hepatocyte cells and is completely metabolized from 2 to 4 h after perfusion.

Animals↗
PubMed1983

Neuropeptide Y (NPY) reduces myocardial perfusion and inhibits the force of contraction of the isolated perfused rabbit heart.

Isolated rabbit hearts, perfused under constant pressure (Langendorff technique) were used to study the effect of neuropeptide Y (NPY) on heart rate, force of heart contraction and rate of myocardial perfusion. No significant net change in heart rate was noted. A dose-dependent negative inotropic effect was consistently demonstrated which was characterised by slow onset and was often preceded by a transient positive inotropic response. Addition of small doses of NPY resulted in a prompt reduction in flow of the perfusate through the coronary vasculature. Since NPY is present locally in cardiac nerves, these effects may have physiological importance.

Acetylcholine↗
PubMed1997

The effects of perfusion conditions on melphalan distribution in the isolated perfused rat hindlimb bearing a human melanoma xenograft.

An isolated rat hindlimb perfusion model carrying xenografts of the human melanoma cell line MM96 was used to study the effects of perfusion conditions on melphalan distribution. Krebs-Henseleit buffer and Hartmann's solution containing 4.7% bovine serum albumin (BSA) or 2.8% dextran 40 were used as perfusates. Melphalan concentrations in perfusate, tumour nodules and normal tissues were measured using high-performance liquid chromatography (HPLC). Increasing the perfusion flow rates (from 4 to 8 ml min(-1)) resulted in higher tissue blood flow (determined with 51Cr-labelled microspheres) and melphalan uptake by tumour and normal tissues. The distribution of melphalan within tumour nodules and normal tissues was similar for both Krebs-Henseleit buffer and Hartmann's solution; however, tissue concentrations of melphalan were significantly higher for a perfusate containing 2.8% dextran 40 than for one containing 4.7% BSA. The melphalan concentration in the tumour was one-third of that found in the skin if the perfusate contained 4.7% BSA. In conclusion, this study has shown that a high perfusion flow enhances the delivery of melphalan into implanted tumour nodules and normal tissues, and a perfusate with low melphalan binding (no albumin) is preferred for maximum uptake of drug by the tumour.

Animals↗
PubMed1984

Glutathione conjugation by isolated lung cells and the isolated, perfused lung. Effect of extracellular glutathione.

Cells isolated from rat lung by protease digestion were found to catalyze the reduced glutathione (GSH) conjugation of 1-chloro-2,4-dinitrobenzene. The rate of conjugation was stimulated severalfold in the presence of GSH, indicating uptake and utilization of extracellular GSH by the lung cells. The stimulation was dependent on the GSH concentration and not due to a spontaneous nonenzymatic reaction or to extracellular GSH-transferase activity. Conjugation of 1-chloro-2,4-dinitrobenzene was also measured using isolated perfused rat lung. The conjugation, which was linear for a longer time than with the isolated cells, was also stimulated in the presence of GSH in the perfusion medium. The results indicate the ability of rat lung to utilize extracellular GSH.

Animals↗
PubMed1999

Biotin enhances glucose-stimulated insulin secretion in the isolated perfused pancreas of the rat.

The effects of biotin on insulin secretion in pair-fed control rats and biotin-deficient rats were investigated using the method of isolated pancreas perfusion. Isolated pancreas perfusion was performed using 20 mM glucose, 10 mM arginine, and 20 mM glucose plus various concentrations of biotin (20 mM glucose + biotin solution) as stimulants of insulin secretion. The insulin response to 20 mM glucose in biotin-deficient rats was approximately 22% of that seen in control rats. The level of the insulin response to 10 mM arginine was also significantly lower in biotin-deficient rats than in control rats. These results indicate that insulin release from the pancreas was disturbed in biotin-deficient rats. The insulin responses to 20 mM glucose + 1 mM biotin in biotin-deficient and control rats increased to 165% and 185%, respectively, of that to 20 mM glucose. These biotin-induced increases in glucose-stimulated insulin release were evident within the first few minutes of the infusion. An enhancement of the arginine-induced insulin response in control rats was not found when arginine and biotin was administered. These results suggest that biotin may play an important role in the mechanism by which glucose stimulates insulin secretion from the beta cells of the pancreatic islets.

Journal Article↗
PubMed1981

The arterio-venous difference for immunoreactive parathyroid hormone and the production of adenosine 3,'5'-monophosphate by isolated perfused bone: studies with analogs of parathyroid hormone.

Recent studies suggest that the uptake of immunoreactive parathyroid hormone (iPTH) displays different characteristics in liver, kidney, and bone. Using the isolated perfused canine bone, we have characterized the uptake of two synthetic analogs of PTH, bovine PTH-(3-34) [bPTH-3(3-34)] and [Nle8,Nle18,Tyr34]bPTH-(3-34) amide, which had previously been shown to inhibit PTH-stimulated adenylate cyclase activity in renal membranes. During the infusion of synthetic bPTH-(1-34) (3 ng/ml), extraction of iPTH by isolated perfused bone averaged 37 +/- 1%, and cAMP production rose from 6.2 +/- 2.0 to 21 +/- 3 pmol/min. Extraction of bPTH-(3-34) was similar (35 +/- 2%), but cAMP levels did not increase over baseline with PTH concentrations as high as 100 ng/ml. Simultaneous infusion of bPTH-(1-34) and bPTH-(3-34) at molar ratios of 1:2 led to a 50% inhibition of PTH-stimulated cAMP increases. The extraction by bone of the more potent in vitro inhibitor of renal cortical adenylate cyclase [Nle8,Nle18,Tyr34]bPTH-(3-34) NH2 (3 ng/ml) averaged 39 +/- 2%. In contrast, cAMP production rose from a baseline of 5.6 +/- 0.5 to 12.5 +/- 2.0 pmol/min, demonstrating agonist activity for the analog. These studies show that [Nle3,Nle18,Tyr34]bPTH-(3-34) NH2 has agonist properties in isolated perfused bone, and unsubstituted bPTh-(3-34) inhibits PTH-stimulated cAMP release by perfused bone.

Animals↗
PubMed1986

Comparison of vascular responses of isolated, perfused simian and canine coronary arteries to adrenergic agonists.

The vascular responses of the isolated, perfused simian left circumflex coronary arteries to adrenergic agonists were compared to those of canine coronary arteries in isolated, perfused preparations. Norepinephrine and epinephrine produced only vasoconstriction in monkey arteries in contrast to vasoconstrictor, vasodilator and biphasic responses of canine coronary arteries. Isoproterenol induced a dose-dependent vasodilatation. Salbutamol, a selective beta 2-agonist, produced either a slight vasodilatation or no response. Phenylephrine, a selective alpha 1-agonist, usually caused a marked vasoconstriction in a dose-related manner in both preparations. Xylazine and clonidine, selective alpha 2-agonists, caused a slight vasoconstriction in low doses, but these two agonists relaxed both preparations in high doses. These observations suggest that adrenoceptor subtypes may be mainly alpha-1 and beta-1 in the large coronary arteries of monkeys and dogs and that the alpha-adrenoceptor is predominant in simian large coronary arteries.

Adrenergic Agonists↗
PubMed1994

Prognostic factors for tumor response and limb recurrence-free interval in patients with advanced melanoma of the limbs treated with regional isolated perfusion with melphalan.

BACKGROUND: At this time little is known about prognostic factors for tumor response and subsequent limb recurrence-free interval in patients suffering from advanced melanoma of the limbs who were treated with regional isolated perfusion. METHODS: A retrospective analysis was done, with a logistic regression model and a Cox proportional hazard analysis, looking at possible patient-, tumor-, and treatment-related prognostic factors in all 120 patients with advanced melanoma of the limbs who were treated with regional isolated perfusion with melphalan in the period 1978 to 1990 at our institutions. RESULTS: Complete remission was achieved in 65 patients (54%) with a median duration of 9+ months (range, 1 to 97+ months), and partial remission was seen in 30 patients (25%). Prognostic factors for complete remission were multiple versus single perfusion schedule, the absence of regional node involvement, and leg versus other tumor sites. The 3-year limb recurrence-free interval was 38%. Factors associated with this interval were one as opposed to more than one lesion, complete remission after perfusion, and female sex. Patients exhibiting complete remission after perfusion had a better overall 3-year survival rate than had patients without complete remission (60% vs 35%; p = 0.0012). CONCLUSIONS: In the present study prognostic factors for tumor response and limb recurrence-free interval could be determined. A multiple perfusion schedule may be more effective in providing complete remission in patients undergoing regional isolated perfusion than single perfusions are.

Adult↗