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PubMed1989

Direct hemodynamic effect of insulin in the isolated perfused kidney.

The hemodynamic effect of insulin was examined in isolated perfused kidneys. Experiments were designed to study the effect of the hormone on basal hemodynamics and in the presence of angiotensin II (ANG II). Physiological insulin concentrations caused both renal vasodilation and increased glomerular filtration rate (GFR) during basal perfusion periods and attenuated the vasoconstrictor action of ANG II while limiting the ANG II-induced reduction of GFR. Insulin also increased fractional sodium reabsorption and diminished the natriuretic effect of ANG II. The addition of insulin to perfusions in which ANG II was infused from the start caused renal vasodilation, although supraphysiological concentrations were required. Kidneys perfused with hyperoncotic albumin to prevent filtration similarly demonstrated a vasodilatory effect of insulin that did not require glomerular filtration. Inhibition of prostaglandin (PG) synthesis with indomethacin prevented the vasodilatory effects of insulin. These data support the hypothesis that insulin causes renal vasodilation by a PG-dependent process.

Angiotensin II↗
PubMed1990

Glucose absorption by isolated perfused rat proximal straight tubules.

Glucose absorption was investigated in isolated perfused proximal straight tubules from rats by use of a newly developed ultramicrofluorometric assay. This assay takes advantage of the increase in fluorescence associated with the reduction of NAD to NADH while glucose is degraded to 6-phosphogluconate. When tubules were perfused at 6.70 +/- 0.42 nl.mm-1.min-1, the mean rate of glucose absorption was 11.0 +/- 1.0 pmol.mm-1.min-1, and the mean rate of fluid absorption was 0.61 +/- 0.06 nl.mm-1.min-1. Glucose transport is generally due to Na-glucose cotransport in the proximal nephron. In the rat proximal straight tubule, glucose absorption also appeared to be primarily due to Na-glucose cotransport, since 10(-4) M phlorizin inhibited absorption by 100%, as did inhibition of Na(+)-K(+)-ATPase by K removal. To determine the maximum rate of transport, tubules were perfused at rates greater than 20 nl.mm-1.min-1 with a solution containing 5.5 mM glucose. The maximum rate of glucose absorption was approximately 20 pmol.mm-1.min-1 under these conditions. The concentration of glucose that supports 50% of the maximum rate of absorption, Km, was 0.6 mM. When tubules were perfused at flow rates of less than or equal to 2 nl.mm-1.min-1, the luminal glucose concentration reached a limiting value of 0.47 mM with 5.5 mM glucose in the bath. The glucose permeability was 3.1 X 10(-6) cm/s.

Absorption↗
PubMed1981

Carnitine optical isomers' action on the epinephrine stress induced in the isolated perfused rabbit heart.

A cardiac stress was performed in the isolated perfused rabbit heart by means of four injections of 0.5 micrograms epinephrine in the coronary vessels. The endogenous (-)carnitine/acetyl(-)carnitine ratio was also determined. The two exogenous optical isomers of carnitine possess a different pharmacological behavior on the epinephrine-induced stress. Exogenous (-)carnitine reduces the epinephrine stimulating effect whereas exogenous (+)carnitine increases it, including coronary flow. Furthermore, the endogenous (-)carnitine restores this ratio to the normal value, whereas exogenous (+)carnitine does not. It is concluded that carnitine might represent an important natural way for organism safeguard in the epinephrine stress as occurs in various emotional states. In this respect the importance of exogenous (-)carnitine as a therapeutic means remains to be investigated.

Animals↗
PubMed1976

Modification by prostaglandins E1 and E2, indomethacin, and arachidonic acid of the vasoconstrictor responses of the isolated perfused rabbit and rat mesenteric arteries to adrenergic stimuli.

In isolated perfused rabbit mesenteric arteries, prostaglandin (PG) E1 and E2, 1-5NG/ML, did not alter the basal perfusion pressure, but reduced the vasoconstrictor responses to sympathetic nerve stimulation; the responses to injected norepinephrine were reduced by PGE1 and variably affected by PGE2. In contrast, in rat mesenteric arteries PGE1 and PGE2, 1-5 ng/ml, potentiated the vasoconstrictor responses to nerve stimulation and to injected norepinephrine. In rabbit mesenteric arteries, the inhibitor of PG synthesis, indomethacin, augmented the responses to sympathetic nerve stimulation and to injected norepinephrine, whereas in rat mesenteric arteries indomethacin inhibited the responses to both adrenergic stimuli. Arachidonic acid, a PG precursor, reduced the vasoconstrictor responses to sympathetic nerve stimulation and to injected norepinephrine in rabbit, whereas in rat, potentiation of the responses to adrenergic stimuli occurred. Since these effects of arachidonic acid were abolished by the simultaneous infusion of indomethacin, they appear to be mediated through conversion of arachidonic acid to PG. We conclude that prostaglandins modulate adrenergic transmission in mesenteric arteries and this effect is species dependent.

Animals↗
PubMed1979

Gel filtration pattern of immunoreactive glucagon secreted by the isolated, perfused, porcine pancreas.

The isolated pancreatic glands from six pigs were perfused in a single pass system and then stimulated with arginine. Samples of the early response perfusate were subjected to gel filtration. Glucagon was determined radioimmunologically in the column effluents using four different antisera with various capacities to recognize other molecular forms of pancreatic type glucagon immunoreactivities. One antiserum crossreacted with purified gut type glucagon. More than 93% of the assayed glucagon in the effluent was eluted within the distribution of pancreatic glucagon when chromatographed under identical conditions. In fifteen experiments there was no detectable immunoreactivity corresponding to the void volume, whereas in the remaining seven experiments less than 7% was eluted at this position. The immunoreactivity in the void volume was detected variably by the four antibodies. No immunoreactivity was detected between the void volume and the elution position of pancreatic glucagon. It is concluded that the arginine stimulated porcine pancreas almost exclusively secretes one molecular species of glucagon, which probably is the 29-amino acid peptide.

Animals↗
PubMed1986

Disposition of a soluble chromate in the isolated perfused rat liver.

The uptake of potassium dichromate in the isolated perfused rat liver was almost complete after one hour of perfusion. No significant sex differences in chromium distribution were observed. At the end of the experiments (one hour), about 60% of the applied Cr(VI) dose (312 micrograms Cr/liver) was located in the cytosol, 14% was in the mitochondria, 9% in the microsomal pellet and 2% was associated with the nuclei. Gel chromatography of the cytosol showed that most of the chromium was in fractions with an apparent molecular weight of 6000 Da and absorption maxima at 410 nm and 548 nm. Similar optical properties and molecular weight are characteristic of GSH-Cr complexes formed by reaction of Cr(VI) with GSH in vitro.

Animals↗
PubMed1976

Disappearance of gastrin heptadecapeptide in the isolated perfused pig liver.

To elucidate the role of the liver in gastrin metabolism three liver perfusions and two control experiments were performed; 2,5, 5 and 250 microgram of porcine nonsulphated gastrin-17 were injected into a perfusate of pig blood circulated through an isolated perfused liver. A significant decrease of gastrin concentration was observed during liver perfusions, concentration being halved in 35 minutes with all doses. It is suggested that this decrease is due to hepatic degradation and that the liver may play an important role in metabolism of gastrin-17.

Animals↗
PubMed1987

[The isolated perfused hindlimb of the rat. Method and use].

Diaphragm and isolated perfused hindquarter of rat are among the most thoroughly studied skeletal muscle preparations. Preparation and perfusion techniques are described. The preparation is characterized with respect to tissue and muscle fiber type composition as well as functional metabolic parameters. Some applications are demonstrated.

Amino Acids↗
PubMed1976

Effects of thyroxine pretreatment and calcium on the isolated perfused rat heart.

Phosphorylase a activity was the same in isolated perfused hearts from euthyroid and thyroxine-pretreated rats. Perfusion with 3.6 mM Ca2+ caused an increase in phosphorylase a in hearts from euthyroid as well as those from thyroxine-pretreated animals, but the Ca2+-induced stimulation of phosphorylase activity was similar in both groups over the time course studied. Greater conversion of phosphorylase b to a occurred with 7.2 mM than with 3.6 mM Ca2+ in both groups, but once again thyroxine pretreatment did not significantly influence the conversion of phosphorylase b to a. Isometric systolic tension increased in response to 3.6 mM and 7.2 mM Ca2+ in hearts from normal and thyrotoxic rats, but thyroxine pretreatment did not appreciably alter the nature of this response. While spontaneous heart rate was higher in hearts from thyroxine-pretreated rats, perfusion with 3.6 mM or 7.2 mM Ca2+ had no significant effect on heart rate in hearts from euthyroid or thyrotoxic rats.

Animals↗
PubMedDate not supplied

Does Z-protein have a role in transport of bilirubin and bromosulfophthalein by isolated perfused rat liver?

Bilirubin and other organic anions are transported in serum avidly bound to albumin from which they are extracted and transferred into the hepatocyte where they bind to cytosolic proteins. Two abundant organic anion binding proteins, ligandin and Z-protein, were previously purified from liver cytosol and characterized. Other studies in isolated perfused rat liver revealed that selectively increased cytosolic ligandin concentration, following phenobarbital treatment or thyroidectomy, directly correlated with net bilirubin uptake which resulted from reduced bilirubin efflux. To clarify the role of Z-protein in hepatic organic anion transport, we have now determined the kinetics of bilirubin and bromosulfophthalein (BSP) uptake in isolated perfused liver of normal rats and compared results to rats in which Z-protein, but not ligandin, was selectively increased following treatment with clofibrate (ethylchlorophenoxy-isobutyrate). These studies revealed that despite a 147% induction of Z-protein in treated animals, there was no effect on influx or efflux of tracer doses of bilirubin or BSP. Addition of albumin to the protein-free 10% fluorocarbon perfusate reduced influx of 3H-bilirubin (p less than 0.03) and tended to reduce influx of BSP. In this situation, there was still no influence of Z-protein concentration on efflux. These studies indicate that Z-protein does not appear to play a role in the hepatic uptake of bilirubin and BSP.

Animals↗
PubMed1999

Inhibition of paclitaxel elimination in the isolated perfused rat liver by Cremophor EL.

PURPOSE: Cremophor can alter the pharmacokinetics of cytotoxic drugs, including doxorubicin and etoposide. In view of its presence in the formulation of paclitaxel, the aim of this study was to investigate the influence of Cremophor on the hepatobiliary elimination of paclitaxel. METHODS: In a recirculating isolated perfused rat-liver system the elimination of 1.7 mg paclitaxel given as a bolus into the perfusate reservoir was monitored in perfusate and bile in controls and after the administration of either 80 or 800 microl Cremophor. The higher dose of Cremophor yields clinically relevant perfusate concentrations. Paclitaxel was measured in perfusate, bile, and liver tissue by high-performance liquid chromatography. RESULTS: Cremophor caused a dose-dependent inhibition of the elimination of paclitaxel, with a statistically significant mean value +/-SD, n=3; (P < 0.05 versus controls Bonferroni t-test) 9-fold increase in AUC (2227+/-106 versus 245+/-40 microg ml(-1) min), 9-fold decrease in total clearance (0.8+/-0.1 versus 7.0+/-1.1 ml/min), and 5-fold increase in elimination half-life (92+/-14 versus 18+/-4 min) being observed after a dose of 800 microl Cremophor. With the addition of Cremophor the amount of paclitaxel remaining after 3 h increased in perfusate from none to 20%, increased in liver tissue from 4% to 18%, and remained constant in bile at 11-13%. In the control group, 86% of the paclitaxel dose was recovered in bile as five putative metabolites, which were measured in paclitaxel equivalents, with the major metabolite. M3 co-eluting with 3'-p-hydroxypaclitaxel. This decreased to 45% of the dose on the addition of Cremophor, and the ratio of M3 to paclitaxel in bile decreased. CONCLUSIONS: Cremophor inhibits the hepatic elimination of paclitaxel in the isolated perfused rat liver, primarily by preventing the drug from reaching sites of metabolism and excretion. The presence of Cremophor in the paclitaxel formulation may therefore contribute to the nonlinear pharmacokinetics and pharmacodynamics of paclitaxel.

Animals↗
PubMed2003

Role of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts.

AIM: It has recently been shown that nitric oxide synthase in the presence of suboptimal levels of tetrahydrobiopterin (BH(4)), an essential cofactor of nitric oxide synthase, may favor increased production of oxygen free radicals. This study was designed to define the role of BH(4) in myocardial ischemia-reperfusion injury. METHODS: Isolated perfused rat hearts were subjected to 37 degrees C ischemia and reperfusion. Hearts were received with BH(4) or vehicle for 5 min just before ischemia and during the first 5 min of the reperfusion period. The effects of BH(4) on left ventricular function, myocardial contents of lipid peroxidation and high energy phosphates, and levels of lactate dehydrogenase and nitrite plus nitrate in perfusate before ischemia and after reperfusion were estimated. Moreover, the effect of BH(4) given with 2,4-diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of BH(4) production, intraperitoneally 24 h before the experiments were estimated. RESULTS: BH(4) improved contractile and metabolic abnormalities in reperfused hearts. Furthermore, BH(4) significantly alleviated ischemic contracture during ischemia, and restored diminished perfusate levels of nitrite plus nitrate after reperfusion. On the other hand, DAHP-treatment aggravated ischemia-reperfusion induced functional and metabolic abnormalities. Administration of BH(4) improved DAHP-induced functional and metabolic abnormalities. CONCLUSION: Results demonstrated that BH(4) lessens ischemia-reperfusion injury in isolated perfused rat hearts. Conversely, deficiency of BH(4) seems to accelerate endothelial dysfunction and myocardial ischemia-reperfusion injury. Present data may be compatible with the hypothesis that nitric oxide synthase in the presence of insufficiency of BH(4) serve as the cause of oxidative injury.

Animals↗
PubMed2003

Drug absorption from the isolated perfused rat lung--correlations with drug physicochemical properties and epithelial permeability.

The pulmonary absorption of nine low-molecular-weight (225-430 Da) drugs (atenolol, budesonide, enalaprilat, enalapril, formoterol, losartan, metoprolol, propranolol and terbutaline) and one high-molecular-weight membrane permeability marker compound (FITC-dextran 10000 Da) was investigated using the isolated, perfused and ventilated rat lung (IPL). The relationships between pulmonary transport characteristics, epithelial permeability of Caco-2 cell monolayers and drug physicochemical properties were evaluated using multivariate data analysis. Finally, an in vitro-in vivo correlation was made using in vivo rat lung absorption data. The absorption half-life of the investigated drugs ranged from 2 to 59 min, and the extent of absorption from 21 to 94% in 2 h in the isolated perfused rat lung model. The apparent first-order absorption rate constant in IPL (ka(lung)) was found to correlate to the apparent permeability (P(app)) of Caco-2 cell monolayers (r = 0.87), cLog D(7.4) (r = 0.70), cLog P, and to the molecular polar surface area (%PSA) (r = -0.79) of the drugs. A Partial Least Squares (PLS)-model for prediction of the absorption rate (log ka(lung)) from the descriptors log P(app), %PSA and cLogD(7.4) was found (Q2 = 0.74, R2 = 0.78). Furthermore, a strong in vitro-in vivo correlation (r = 0.98) was found for the in vitro (IPL) drug absorption half-life and the pulmonary absorption half-life obtained in rats in vivo, based on a sub-set of five compounds.

Absorption↗
PubMedDate not supplied

Biotransformation of 7-ethoxycoumarin in isolated perfused rainbow trout liver.

A reliable technique for rainbow trout liver perfusion has been developed for studies on xenobiotic biotransformation. Normal function of the perfused liver was indicated throughout the perfusion experiment by 1) a proper oxygen consumption, 2) a low leakage of intracellular enzymes, 3) a stable pH value in the effluent, and 4) a stable release of metabolites into the effluent perfusate and bile for at least 2 hr after maximal rate of metabolism was attained. The main metabolite of 7-ethoxycoumarin in effluent perfusate was identified as 7-hydroxycoumarin glucuronide. Only trace amounts were identified as sulfates. When fish were pretreated with Clophen A50 or beta-naphthoflavone, the amount of metabolites released into the effluent perfusate increased 3.4- and 6.4-fold, respectively, when compared to control livers. Furthermore, in livers from Clophen A50- or beta-naphthoflavone-treated fish, only 80 and 67%, respectively, of excreted products were conjugated. Influence of temperature on 7-ethoxycoumarin metabolism was studied in perfused liver and isolated liver microsomes. Results indicate that the Q10 for the metabolism of 7-ethoxycoumarin in perfused liver deviates from that found in isolated microsomes. The amount of metabolites excreted into the bile consisted of about 25% of the amount found in effluent perfusate. The only metabolite detected in bile from perfused liver from control as well as treated fish was 7-hydroxycoumarin glucuronide.

Animals↗
PubMedDate not supplied

Acute renal failure following hyperthermic isolation perfusion of the left leg.

This is the case report of a 37-year-old female who underwent primary excision of a malignant melanoma on the left foot as well as an inguinal lymphnode dissection in May 1983. In January 1984 a satellitosis on the same foot was treated with an isolation perfusion which had to be repeated in December of the same year due to secondary satellitosis. For the first perfusion, Alkeran 80 mg was used with a temperature of up to 41.4 degrees C, whereas Cis-Platinum 20 mg/l and Eldesine 0.3 mg/l were used for the second perfusion, with a maximum temperature in the tumor area of 39.0 degrees C. On the first postoperative day, significant edema of the left leg accompanied by severe pain was noticed. This was followed by an increase of the serum creatinine to 2.2 mg % two days later. Despite the immediate inducement of a forced diuresis, renal function deteriorated during the following days with serum creatinine going up to 4.8 % and CK to 14800 U/L. After a forced diuresis of two weeks' duration, the laboratory parameters slowly went back to normal. As a consequence of this complication we analyzed the influence of hyperthermic isolation perfusion on five patients with regard to muscular damage and its influence on renal failure. During perfusion we observed myoglobinemia which subsided within 36 hours. This slope was paralleled by CK values. A discrete myoglobinuria which was observed in two patients disappeared within 36 hours after perfusion. No rise of creatinine could be found. The changes described above were not influenced by cytostatic medication (Alkeran versus Cis-Platinum and Eldesine). In addition, none of the cases showed a leakage of over 16%. The case of acute renal failure was apparently caused by increased rhabdomyolysis as a consequence of the second hyperthermic perfusion.

Acute Kidney Injury↗
PubMed1989

Direct nephrotoxicity of Russell's viper venom demonstrated in the isolated perfused rat kidney.

Envenoming by Russell's Viper (Vipera russelli) is an important cause of acute renal failure. The mechanism of renal damage is unresolved. It is difficult to obtain evidence of a direct nephrotoxic action because of the coincidental disturbance to the systemic circulation. We studied the action of Russell's Viper venom on the function of the isolated perfused rat kidney. Direct nephrotoxic action was indicated by a dose dependent decrease in inulin clearance and an increase in fractional excretion of sodium seen at venom concentrations down to 50 ng/ml, a concentration likely to be achieved in the human circulation after envenoming. The isolated perfused kidney was also used to assess the efficiency of antivenom and for a comparison with snake venoms from the Thai cobra (Naja kauothia) and the Nigerian Saw-Scaled Viper (Echis ocellatus).

Animals↗
PubMed1992

Estradiol potentiates the vasopressor response of the isolated perfused rat lung to the thromboxane mimic U-46619.

The high incidence of primary pulmonary hypertension in young women suggests a role of female sex hormones in the pathogenesis of this disease. Thromboxane A2 is a potent pulmonary vasoconstrictor, and a possible mediator of pulmonary hypertension. We studied the pulmonary vascular expression of thromboxane in isolated perfused lungs from sexually mature male and female rats, as well as the modulation of this expression by estrogen. Our data show that lungs from female rats exhibited a significantly (P less than .05) greater pressor response to the thromboxane mimic U46619, but not to angiotensin II, than those from their male cohorts. The difference in the response to U46619, however, was abolished by indomethacin (10 microM). Addition of 10 nM concentrations of estradiol 17-beta or diethylstilbestrol to the perfusate significantly potentiated (55 and 63%, respectively) the pressor response to U46619. Similarly, perfusion with diethylstilbestrol enhanced the pressor response to angiotensin II (70%). Estradiol 17-alpha or testosterone, however, were ineffective at similar concentrations. Ovariectomy, on the other hand, depressed, whereas chronic administration of estradiol 17-beta enhanced the pressor response to the thromboxane mimic, but had no effect on the response to angiotensin II. These data show a gender difference in pulmonary vascular expression of thromboxane in isolated perfused rat lungs, possibly modulated by estradiol. Thus, changes in estradiol levels may play a role in the development of primary pulmonary hypertension in young women.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2005

Iron chelators do not reduce cold-induced cell injury in the isolated perfused rat kidney model.

BACKGROUND: In vitro, cold-induced injury is an important contributor to renal tubular cell damage. It is mediated by iron-dependent formation of reactive oxygen species and can be prevented by iron chelation. We studied whether iron chelators can prevent cold-induced damage in the isolated perfused rat kidney (IPK) model both after cold perfusion (CP) and after cold storage (CS). We hypothesized that in the CP model iron-dependent cold-induced injury is more pronounced, since oxygen is constantly provided. METHODS: The IPK was either flushed with University of Wisconsin (UW) solution and stored for 4, 18 or 24 h at 4 degrees C or perfused during 4 h at 4 degrees C with UW for machine perfusion. The iron chelators 2,2'-dipyridyl or desferal, or the negative control 4,4'-dipyridyl were added during the cold perfusion. Kidney function was measured during 2 h reperfusion at 37.5 degrees C and compared to a control group (without cold preservation). RESULTS: Compared to control perfusion, kidney function was decreased in all experimental protocols. glomerular filtration rate and FR(H2O) were significantly decreased, while FE(gluc) and FE(Na) were higher after 4 h CS and CP. After 4 h CP, also renal vascular resistance was increased. Addition of 2,2'-dipyridyl did not improve kidney function after either CS or CP. Prolonged periods of CS worsened kidney function. The addition of 2,2'-dipyridyl or desferal did not improve kidney function after longer periods of CS. CONCLUSIONS: Addition of an iron chelator to the preservation solution UW did not improve kidney function after both CS and CP. Iron chelation is not able to prevent cold-induced damage in the isolated perfused rat kidney.

Animals↗