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PubMedDate not supplied

Influence of airborne particulate on the metabolism of benzo[a]pyrene in the isolated perfused lung.

Benzo[a]pyrene (BaP), a ubiquitous potent carcinogen, has been associated with the increased incidence of human bronchiogenic carcinoma in occupational and urban settings. A detailed knowledge of the rate and pattern of metabolite formation and factors affecting their formation is essential for understanding the mechanism of action of BaP in the lung. An isolated perfused New Zealand rabbit lung preparation was used to investigate the effects of a crude airborne particulate mixture on the metabolism of BaP. [14C]BaP with and without crude air particulate (CAP) was administered intratracheally to an isolated perfused lung (IPL) preparation after intratracheal pretreatment of the whole animal with CAP and/or BaP, or intraperitoneal pretreatment of the whole animal with BaP. BaP and its metabolites were extracted from perfusing blood at 6 time points up to 180 min after administration of [14C]BaP to the IPL. BaP and its metabolites were also extracted from lung tissue, washout fluid, aveolar macrophages, and trachea bronchi at the end of the perfusion at 180 min. Patterns of BaP metabolites were determined by chromatographic techniques and liquid scintillation counting. Particulate pretreatment of the whole animal or administration of the particulate to the IPL altered BaP metabolism by the perfusing lung. Particulate pretreatment of the whole animal resulted in increases in the total rates of appearance of metabolites of BaP in the blood (ng/g lung . h), while particulate administration to the IPL resulted in decreases in the total rate of appearance of metabolites of BaP in the blood and negated the effects of pretreatments. Coadministration of particulate with BaP to the IPL with and without particulate pretreatment of the whole animal, or BaP administration to the IPL preceded by particulate pretreatment of the whole animal, enhanced dihydrodiol formation and depressed formation of water-soluble materials. This is important because dihydrodiol formation is considered part of the active pathway of BaP carcinogenicity. These data suggest that pulmonary particulate exposure in the presence of BaP results in the initial increased production of dihydrodiols of BaP that may be further metabolized to compounds believed to be the ultimate carcinogenic form(s) of BaP.

Air Pollutants↗
PubMed2003

Effects of cardiac contusion in isolated perfused rat hearts.

Myocardial contusion is frequently suspected after blunt chest trauma, but the exact mechanisms of resulting cardiac dysfunction and the time course for enzymatic alterations have not yet been fully understood. Therefore, we investigated pathophysiological aspects of myocardial contusion in a controlled animal model. Male Wistar rat hearts were studied in an isolated perfusion model and were divided into two groups: control (n = 4) and heart contusion (n = 6) groups. The cardiac contusion was produced by a single blow with a weighted pendulum (m = 44 g, height = 20 cm). Functional implications of the contusion were examined in an "isolated perfused heart" model. Troponin 1 concentrations were determined in the perfusate. Cardiac contusion resulted in an increase of coronary perfusion pressure (CPP) of 9 mmHg (P < 0.05, 20 min postcontusion versus baseline and control), followed by a significant increase of left ventricular end-diastolic pressure (LVEDP) of 6 mmHg (P < 0.05, 20 min postcontusion versus baseline and control). Heart contusion was followed by an early increase of troponin 1 (+0.82 ng/mL). The troponin 1 concentration decreased again and, after 20 min, baseline levels were reached. The control group showed no such changes. In this model, high troponin 1 levels after cardiac contusion suggest direct damage to the myocardium. First functional response was shown by the alteration of the coronary perfusion, followed by impaired diastolic function, which persisted even after lowering of the troponin 1 levels.

Animals↗
PubMed1997

A 13C NMR study of 2-(13)C-chloroacetaldehyde, a metabolite of ifosfamide and cyclophosphamide, in the isolated perfused rabbit heart model. Initial observations on its cardiotoxicity and cardiac metabolism.

The metabolism of 2-(13)C-chloroacetaldehyde at doses of 1.5, 2, 3 and 4 mg/kg b.w. and that of 2-(13)C-chloroacetaldehyde at a dose of 5.9 mg/kg b.w. were studied in the isolated perfused rabbit heart model using carbon-13 nuclear magnetic resonance. We have shown that, whereas chloroacetaldehyde is cardiotoxic at doses above 2 mg/kg b.w., this toxic effect is not accompanied by an increase in intramyocardial citrate levels. Chloroacetate, its main metabolite, is not cardiotoxic. The metabolism of chloroacetaldehyde is complex and leads, in addition to chloroethanol, glycolic acid, conjugates of glutathione with chloroacetate or chloroethanol (and/or their metabolites, S-(2-carboxymethyl) cysteine, N-acetyl-S-(2-carboxymethyl) cysteine, S-(2-hydroxymethyl)cysteine) and thiodiglycolic acid. Low amounts of chloroacetate are metabolized by isolated perfused rabbit hearts into glycolic acid and glutathione conjugate (and/or its metabolites, S-(2-carboxymethyl) cysteine, N-acetyl-S-(2-carboxymethyl)cysteine). The present results suggest the need to evaluate further the role that chloroacetaldehyde may play in the cardiotoxic effects of ifosfamide and cyclophosphamide.

Acetaldehyde↗
PubMed1985

Effects of 4,4'-diisothiocyano-2,2'-stilbene disulphonic acid and amiloride on salivary secretion by isolated, perfused rat submandibular glands.

Isolated submandibular glands of adult rats were perfused through the arterial system with oxygenated, HCO3-containing or HCO3-free physiological salt solutions. Secretion of saliva was then induced with acetylcholine (10(-6) M) in the absence or presence of the ion-transport inhibitors 4,4'-diisothiocyano-2,2'-stilbene disulphonic acid (DIDS), furosemide or amiloride. In HCO3-containing perfusates, 10(-4) M DIDS enhanced the initial secretory response (maximum rate of flow increased 18 per cent), but reduced the overall volume of saliva secreted in a 60-min period by 47 per cent. Furosemide (10(-3) M) alone reduced the volume of saliva by 73 per cent and, in combination with 10(-4) M DIDS, by 82 per cent. Amiloride (10(-3) M) caused a 68 per cent reduction in salivary volumes. Replacement of perfusate HCO3 with HEPES did not affect acetylcholine-induced secretion but enhanced the effects of the transport inhibitors, so that total volume of secretion was reduced 94 per cent by furosemide, 55 per cent by DIDS and 80 per cent by amiloride. In HCO3-containing perfusates, DIDS caused a 30-50 per cent increase in salivary Na+ and residual anion (Na + K - Cl) concentrations but amiloride induced a marked increase in salivary Na+ and Cl- concentrations and a decrease in salivary K+ concentrations. Furosemide caused a marked decrease in salivary Cl- concentrations and a marked increase in residual anions. These effects were similar but of smaller magnitude in HCO3-free, HEPES-containing perfusates.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1994

Hepatic uptake and excretion of [14C]sodium taurocholate by the isolated perfused fetal sheep liver.

We have developed an in situ isolated perfused fetal sheep liver preparation to study fetal hepatic function free from the confounding influences of the mother and other fetal organs, and we have used the preparation to study the fetal hepatic clearance and biliary excretion of sodium taurocholate (TC). The viability and stability of this model were established by monitoring perfusion pressure, oxygen consumption, perfusate enzymes and electrolytes, the perfusate concentration ratio of lactate to pyruvate, bile flow, and liver histology. Perfusate delivery was 300 mL/min with a mean value of 3.94 mL/min/g liver (range: 2.46-6.72 mL/min/g liver). Gadolinium radiolabeled 15 microns microspheres were used to quantify the ductus venosus shunt through the liver and to determine relative flow rates between right and left hepatic lobes. TC was added to the reservoir either as a [14C]TC tracer bolus dose (2 microCi, N = 5) followed by a constant infusion of unlabeled TC, or as an initial bolus of [14]TC (54 mumol) followed by a [14C]TC constant infusion (30 mumol/hr, specific activity 30 microCi/mmol; N = 3). Perfusate samples were taken from the reservoir every 15 min and bile was collected in 30 min aliquots. Perfusion pressure (7.9 +/ 0.30 mmHg), perfusate potassium and oxygen consumption (0.9 +/- 0.07 mumol/min/g liver) were constant throughout, and the perfusate lactate/pyruvate concentration ratio was low (< 20). Liver histology showed no hypoxic changes. Bile flow fell slightly over the 150 min experiment time from 0.6 to 0.5 muL/min/g liver. These data indicate preparation viability and stability. The extent of the ductus venosus shunt was 16-66% (mean 35 +/- 6%) of umbilical vein flow, which correlated inversely with fetal gestational age (r = 0.94, P < 0.001). Relative flow to right and left lobes of liver was 1:1.4. In bolus dose experiments, TC t1/2 was 81.6 +/- 26 min, clearance (Cl) was 35.0 +/- 22.6 mL/min, shunt corrected extraction (E*) was 0.29 +/- 0.17 and biliary clearance (ClB) was 35.5 +/- 19.5 mL/min. In constant infusion experiments the corresponding results were Cl: 34.7 +/- 18.2, E*: 0.23 +/- 0.16, and ClB 32.7 +/- 17.7. The cumulative biliary excretion of [14C]TC in bolus dose experiments was 86.5 +/- 8.7% of the dose, and in constant infusion experiments, concentration of TC in bile was on average over 800 times that in plasma.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

A technique for isolation perfusion of the canine liver with survival.

A technique of isolation perfusion of the canine liver was developed as a model for treating cancer limited to the liver. Preservation of hepatic functional integrity was dependent on maintenance of near physiologic conditions for the perfusion. Flow to the liver, 1 ml/min/g, was provided by gravity to the portal vein at two thirds total flow, and by pump to the hepatic artery at one third total flow. Utilizing the technique described, six dogs died 4-12 hr after a 1-hr perfusion. The dogs received Ringer's lactate solution IV and had a rising blood lactate to greater than 9 mM and a rising lactate/pyruvate ratio. After changing IV fluids to nonlactate containing solutions, 4/6 dogs survived a 1-hr perfusion at 37 degrees. Blood lactate concentrations remained below 6 mM (alpha less than 0.05) during perfusion, and the lactate/pyruvate ratios remained in a physiologic range on comparison to the nonsurvivors (alpha less than 0.05). Mild elevations occurred in the SGOT and SGPT with the peak on the first postoperative day of 93 +/- 54 and 79 +/- 56, respectively, but returned to normal within 4-7 days. Perfusate chemistries lactate, pyruvate, glucose, total alpha-amino acids, ketone bodies, SGOT, and SGPT demonstrated that hepatic functional integrity was maintained during the 1-hr perfusion. Hepatic function as assessed was no different between survivors and nonsurvivors. Hypoglycemia (glucose less than 2 mM) contributed to the two deaths. Tolerance of the dog to the temporary anhepatic state may be the limiting factor to prolonged perfusions.

Alanine Transaminase↗
PubMed1989

The effect of temperature on isolated perfused hearts of heterothermic marsupials.

1. The thermal response of isolated perfused hearts of four dasyurid marsupials was determined and compared with that of two rodents. 2. Heart beat rate was strongly temperature dependent in all species. 3. The temperature of cardiac arrest in the species investigated in the present study and of others collected from the literature occurred at a mean of about 13 degrees C in homeotherms, 7 degrees C in daily heterotherms, and 1 degrees C in hibernators. 4. For both marsupials and placentals the temperature of cardiac arrest in hibernators and daily heterotherms correlated with the minimum body temperature during torpor.

Analysis of Variance↗
PubMed1988

13C-NMR analysis of alanine metabolism by isolated perfused livers from C3HeB/FeJ mice infected with African trypanosomes.

1. Isolated perfused livers from mice infected with Trypanosoma brucei rhodesiense formed substantially more [3-13C]-lactate from [3-13C]-alanine than livers from uninfected mice. Quantities formed by infected livers increased as infection progressed. 2. Infected livers produced more 13C-labeled glutamate and glutamine, with label scrambled between C-2 and C-3. Scrambling also produced [2,3-13C]-aspartate, [2-13C]-alanine and [2-13C]-lactate. Delayed appearance of label in C-4 of glutamate/glutamine in infected livers reflects significant endogenous stores of unlabeled acetyl CoA. 3. Although differences do exist in catabolism of [3-13C]-alanine by perfused livers from infected and control mice, trypanosomiasis does not cause permanent breakdown or blockage of hepatic alanine metabolism.

Alanine↗
PubMed1995

The effect of C5a and U46619 on the isolated, perfused human placental lobule: development of a method for the online estimation of tissue fluid accumulation.

A method for the automatic and simultaneous determination of perfusion pressure and fluid accumulation in the isolated, perfused human placental lobule is described. We demonstrated that the inflammatory mediator, C5a, a C5a agonist analogue peptide, and the thromboxane mimetic U46619 caused increased fetal perfusion pressure and increased tissue weight when administered via the fetal arterial circulation. Occlusion of the fetal venous effluent tubing caused significantly greater increases in tissue weight than the pharmacological agents. Detectable increases in tissue weight occurred within 47 +/- 3 sec (n = 21) following pressure increases caused by the pharmacological agents. In each case, the increase in tissue weight was accompanied by an increased permeability of the materno-fetal barrier, shown by the transfer of Evans blue albumin from the fetal circulation to the maternal compartment.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1982

pH-dependency of iodothyronine metabolism in isolated perfused rat liver.

1. Isolated livers from fed male rats were perfused for 2 h with T4 (L-thyroxine), T3 (L-3,3',5-tri-iodothyronine) or rT3 (L-3,3',5'-tri-iodothyronine) at different pH values (7.1--7.6) in a fully synthetic medium, whereby normal metabolic functions were maintained without addition of rat blood constituents or albumin. 2. T3 output into the medium and net T3 production reached a maximum at a pH of the medium of 7.2 and significantly decreased with alteration of the pH when livers were perfused with T4 as a substrate. 3. However, the net T4 and T3 uptake by the liver, as well as the hepatic T4 and T3 content after perfusion, were not dependent on the pH of the perfusion when livers were offered T4 or T3 as substrates respectively. 4. Determination of intracellular pH by the analysis of the distribution of the weak acid dimethyloxazolidinedione allows the conclusion that the pH optimum of iodothyronine 5'-deiodinase in the intact perfused liver corresponds to the maximum determined in vitro for the membrane-bound enzyme localized in the endoplasmic reticulum. 5. The rapid 5'-deiodination of rT3 to 3,3'-T2 (L-3,3'-di-iodothyronine), the fast disappearance of 3,3'-T2, and the fact that no net rT3 production from T4 could be detected, supports the hypothesis that in rat liver iodothyronine 5'-deiodinase activity seems to predominate over iodothyronine 5-deiodinase activity. 6. Thus the rat liver can be considered in normal physiological situations as an organ forming T3 from T4 and deiodinating rT3 originating from extrahepatic tissues, whereby the cellular iodothyronine 5'-deiodination rate is controlled by the intracellular pH.

Animals↗
PubMed1993

Augmented portal flow in the isolated perfused cirrhotic rat liver: a haemodynamic and morphological study.

1. Isolated perfused cirrhotic rat livers were used to study the effects of an increase in portal perfusion pressure and portal flow on the microcirculation and viability of the hepatocytes. Cirrhosis was induced by CCl4, and Krebs-Ringer bicarbonate buffer solution was used as the perfusate. Portal perfusion pressures were increased incrementally between 25 and 45 cm H2O. The viability of the livers was assessed and histological studies were performed under light and electron microscopy. 2. An increase in portal perfusion pressure induced an increase in hepatic flow in all the experiments (P < 0.05). Hepatic flow was 2.52 ml min-1g-1 of liver (SD 0.67; n = 5) at basal pressure compared with 4.19 ml min-1g-1 of liver (SD 0.93; n = 5) and 5.91 ml min-1g-1 of liver (SD 0.63; n = 5) when pressures were raised to 25 and 45 cmH2O, respectively. Portal perfusion pressure and hepatic flow were correlated (r = 0.908; P < 0.001; n = 30). 3. Production of the enzyme alanine aminotransferase (EC 2.6.1.2) increased significantly from 5.69i.u. ml-1min g-1 of liver (SD 3.62; n = 5) to 23.53i.u. ml-1min g-1 of liver (SD 16.7; n = 5) when the perfusion pressure was raised from baseline to 30 cmH2O. In all the cases the porto-caval gradient of enzyme production was within the normal range. No correlation existed between the release of enzyme and portal perfusion pressures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1980

Transcapillary exchange and distribution of carbon-11 labelled ethanol in the isolated perfused rat liver.

The distribution kinetics of ethanol in the isolated perfused rat liver at various flow rates and ethanol concentrations were studied by the indicator diffusion technique using 11C-labelled ethanol. A double tracer solution with 99mTc-labelled red blood cells as the vascular reference and 11C-ethanol as the test substance was injected into the catheter connected to the portal vein. Time-activity curves were monitored by a NaI(Tl) scintillation detector above the outflow catheter. The following values were obtained: 0.95 +/- 0.01 for the maximal extraction (Emax), 3.0 +/- 0.1 x flow (r = 0.98) for the capillary permeability surface area product (PScap), 18.7 +/- 2.5% for the vascular volume (V1) and 56.2 +/- 9.0% for the ethanol distribution volume (V2). The volumes were calculated from the products of mean transit time (MTT) and flow (f), and PScap was calculated from the equation PScap = -f x ln(1-Emax). The results show that the ethanol distribution in the liver is flow limited since Emax was constant at various flow rates (0.67-2.55 ml/g x min-1). The distribution volumes obtained agree well with the values for liver vascular volume and water distribution volume reported in the literature.

Animals↗
PubMed1985

Interstitial fluid pressure in the isolated perfused rabbit lung.

Interstitial fluid pressure was measured in nine isolated perfused rabbit lungs with the servonull micropipette method. Bevelled glass micropipettes, with tip diameter 2-6 micrometers (o.d.) were inserted 2-6 mm into the left lung. At alveolar pressures of 3 to 5 cm H2O we found mean interstitial fluid pressures of 1.0 (SD 1.0) and 1.6 (SD 1.0) cm H2O relative to pleural pressure in the upper (n = 19) and lower (n = 21) lobes respectively. The vertical distance between the measuring sites in the upper and lower lobes was about 3 cm. Net filtration caused by elevated left atrial pressure caused practically no change in interstitial fluid pressure. Increased alveolar pressure either increased or decreased interstitial fluid pressure. The measured pressures probably represent interstitial fluid pressure in alveolar junctions or in the interstitium around small pulmonary arteries or veins. We conclude that interstitial fluid pressure in these sites is between alveolar and pleural pressure, and that it is only moderately affected by changes in alveolar pressure. The interstitial compliance appears to be high and there seem to be little or no vertical gradients in interstitial fluid pressure within the lung.

Animals↗
PubMed1984

Tetraethylammonium transport by isolated perfused snake renal tubules.

Tetraethylammonium (TEA) transport was studied in isolated perfused snake (Thamnophis spp.) proximal renal tubules. Unidirectional lumen-to-bath (J1----bTEA) and bath-to-lumen (J1----bTEA) fluxes exhibited saturation kinetics, but Jb----1TEA also exhibited an apparent diffusive component and J1----bTEA did not. Jb----1TEA exceeded J1----bTEA at all concentrations studied, resulting in net TEA secretion. Transport into cells across both luminal and peritubular membranes was apparently against an electro-chemical gradient and was inhibited by cyanide. Km for J1----bTEA (5.9 microM) was about one-third Km for Jb----1TEA (19.9 microM), indicating greater affinity of the luminal transporter for TEA; but Vmax for Jb----1TEA (153 fmol X min-1 X mm-1) was about six times Vmax for J1----bTEA (27 fmol X min-1 X mm-1), indicating a greater capacity of the peritubular transporter for TEA, which could account for net TEA secretion. Jb----1TEA was inhibited by N-methylnicotinamide (NMN) in the bath, but J1----bTEA was inhibited initially and then apparently transstimulated by NMN in the lumen, indicating possible countertransport. J1----bTEA, but not Jb----1TEA, was significantly reduced by replacement of sodium with sucrose, indicating possible sodium dependency of the luminal transporter. All data indicate active (either primary or secondary) TEA transport at both luminal and peritubular membranes but net transepithelial transport in the bath-to-lumen direction.

Animals↗
PubMed1985

Bicarbonate transport by isolated perfused rat collecting ducts.

Previously, bicarbonate transport was measured in isolated perfused rabbit cortical collecting ducts (CCD) and outer medullary collecting ducts (OMCD). Rabbit CCD either absorbed or secreted bicarbonate in vitro, depending on whether the animals were treated with NH4Cl or NaHCO3, but the OMCD absorbed bicarbonate regardless of the treatment. The general significance of these findings (particularly the bicarbonate secretion) was questioned because rabbits are herbivores that normally excrete alkaline urine. Therefore, we have now studied rats, an omnivorous species, that normally excrete acid urine. The overall pattern of bicarbonate transport in rats was similar to that previously found in rabbits. CCD from rats given NaHCO3 initially secreted bicarbonate, but those from rats given NH4Cl absorbed bicarbonate. Rat OMCD all absorbed bicarbonate, regardless of the treatment. The significant differences between the results with rats and rabbits were 1) a marked shift in bicarbonate transport in control and bicarbonate-loaded rat (but not rabbit) CCD with time of perfusion in vitro from secretion toward absorption; this implies an additional regulatory mechanism in rats; and 2) rat OMCDs absorbing bicarbonate more than three times faster than rabbit OMCD. These results provide additional evidence that conditioned changes in cortical collecting duct bicarbonate transport, now observed in two different species, play a significant role in the control of net acid excretion.

Animals↗