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PubMedDate not supplied

Metabolism and excretion of 2,6-dinitro [14C]toluene in vivo and in isolated perfused rat livers.

The metabolism and excretion of the hepatocarcinogen 2,6-dinitro-toluene (2,6-DNT) was investigated in Fischer-344 rats in vivo and in isolated perfused livers. Urinary excretion accounted for half of the dose (10 mg/kg) 72 hr after administration of 14C-2,6-DNT. 2,6-Dinitrobenzoic acid, 2,6-dinitrobenzyl alcohol glucuronide (2,6-DNBAlcGluc), and 2-amino-6-nitrobenzoic acid accounted for 95% of the urinary 14C. Fecal excretion accounted for one-fifth of the dose in 72 hr. 2,6-DNBAlcGluc was the major metabolite found in the perfusate and bile of isolated perfused rat livers. Biliary excretion of 2,6-DNBAlcGluc by livers from male rats was 3.3- and 8.6-fold that of female rats on perfusion with 20 and 70 microM 14C-2,6-DNT, respectively. No sex-dependent differences in biliary flow rates were observed. Twice as much 14C was found to be covalently bound to hepatic macromolecules in male than female rat livers in vivo. Decreased biliary excretion of 2,6-DNBAlcGluc may account for the lesser amount of 14C found to be covalently bound in female rat livers. Observations with 2,6-DNT parallel those made with 2,4-DNT, suggesting that both isomers are metabolized by the liver, excreted in the bile, deconjugated and further metabolized by the intestinal microflora, and transported back to the liver for, perhaps, additional metabolism and covalent binding to an endogenous component of the liver.

Animals↗
PubMed1999

Different effects of dopamine and dopexamine on the isolated perfused rat kidney.

We have investigated the effect of dopamine and dopexamine on the isolated perfused rat kidney. After an equilibration period of 20 min and two control periods of 10 min, dopexamine 1.0, 2.5 or 4.0 micrograms kg-1 min-1 or dopamine 2.0 micrograms kg-1 min-1 were perfused for a further 40 min in random order. Renal blood flow, urine volume, glomerular filtration rate, absolute sodium excretion and fractional sodium reabsorption of the isolated perfused kidney were measured every 10 min during the experiment. Dopamine increased significantly urine production from mean 61.54 (SEM 4.7) to 117.2 (9.7) microliters min-1 g-1 and absolute sodium excretion from 0.4 (0.1) to 1.2 (0.1) mumol min-1 g-1, and decreased significantly fractional sodium reabsorption from 97.3 (0.5) to 90.7 (0.7)%. Renal blood flow and glomerular filtration rate were not altered. In contrast, dopexamine had no effect on the isolated kidney. These data suggest that the diuretic and natriuretic effects of dopexamine in humans may not result from a direct action on the kidney.

Adrenergic beta-Agonists↗
PubMed1984

Effects of chlorpromazine on the isolated perfused guinea pig heart.

Chlorpromazine altered the mechanical and electrical activity of the isolated perfused guinea pig heart. While its effects on coronary flow were variable, chlorpromazine increased resting diastolic isometric tension and decreased the isometric systolic tension developed by spontaneously beating hearts. Heart rate was also decreased. The drug depressed conduction through the His-Purkinje system and ventricular muscle to a greater extent than it did atrial conduction time and AV nodal conduction time. From our data, we concluded that the greatest depressant action of chlorpromazine on the electrical activity of the isolated perfused guinea pig heart occurred within the specialized ventricular conduction system and ventricular muscle.

Animals↗
PubMed2004

Global ischemic duration and reperfusion function in the isolated perfused rat heart.

Post-ischemic myocardial dysfunction has been observed in a variety of clinical situations including cardiac arrest. Potentially survivable cardiac arrest following short-term global myocardial ischemia may be of insufficient duration to cause irreversible myocyte injury, but still results in contractile and bioenergetic dysfunction. The purpose of this study was to characterize the ischemic transition from reversible to irreversible injury in the isolated perfused rat heart. Isolated, buffer perfused, male Sprague-Dawley rat hearts underwent normothermic ischemia of 15, 20, 25 or 30 min with or without 30 min of reperfusion and were freeze clamped in liquid nitrogen for bioenergetic analysis of LV tissue. Post-ischemic LV function and measurements of bioenergetic recovery were made between groups and with non-ischemic controls. Baseline LV function was similar in all groups. Post-ischemic contractile function was markedly depressed in the 25 and 30 min ischemia groups with persistent depression of high-energy phosphates, total adenine nucleotide pool, myocardial oxygen consumption, elevated CK release and evidence of significant mitochondrial edema in the 30 min group. In contrast with longer ischemic periods, the reduction in LV contractile function after 15 and 20 min of ischemia was mild, with more complete bioenergetic recovery, minimal CK release, and normal appearing mitochondrial. This data suggests a period of transition from reversible to irreversible injury occurring at approximately 20 min of normothermic global ischemia in the isolated perfused rat heart.

Adenosine Triphosphate↗
PubMed1979

Metabolism and excretion of benzo(a)pyrene 4,5-oxide by the isolated perfused rat liver.

Benzo(a)pyrene 4,5-oxide was metabolized in the isolated perfused rat liver by epoxide hydrase and glutathione S-transferases to the corresponding dihydrodiol and to thioether conjugates (derivatives of glutathione), respectively. Epoxide hydrase was more important relative to the glutathione S-transferases in the biotransformation of this oxide by the intact organ than was indicated by the results from earlier studies with subcellular fractions. The dihydrodiol was rapidly released into the circulation or conjugated with glucuronic acid; sulfuric acid esters were not found. All conjugated metabolites were rapidly excreted in the bile but some were also released into the circulation. The enzymatic systems responsible for the metabolism and excretion of benzo(a)pyrene 4,5-oxide remained viable in the isolated perfused liver for at least 60 min. The toxicological significance of the release of polycyclic aromatic hydrocarbon metabolites from the liver into the vascular circulation and the possible significance of UDP:glucuronyltransferase activity in preventing chemically induced carcinogenesis are discussed.

Animals↗
PubMed1991

High-resolution 1H NMR imaging of regional ischemia in the isolated perfused rabbit heart at 4.7 T.

High-resolution 1H NMR images of the isolated perfused rabbit heart were recorded before and after the induction of regional ischemia while the heart was arrested. On T2-weighted images the ischemic region appeared darker than the surrounding tissue and a 28% reduction in T2 was measured from the images. Infusion of an NMR contrast agent demonstrated that the hypointense region on the T2-weighted image was from the ischemic region, which was further confirmed by histological analysis of the heart. It is proposed that the decreased T2 in the ischemic region may be a consequence of changes in water compartmentalization. It is possible that these changes may be used to follow the evolution of tissue injury during ischemia, and therefore provide information regarding the transition between reversible to irreversible injury in the isolated perfused heart.

Animals↗
PubMed1985

Effect of hypoxia and pregnancy on antipyrine metabolism in isolated perfused rat livers.

The effect of hypoxia on antipyrine metabolism was studied in isolated perfused livers from pregnant (19-21 days gestation) and nonpregnant female Wistar rats. Hypoxia was induced by altering the blood content and/or flow rate of the recirculating perfusion medium. Inflow and outflow pO2 values, in themselves, were not valid indicators of oxygen delivery and consumption when the liver was perfused with a blood containing medium. At a given oxygen delivery rate, oxygen consumption per gram of liver was the same in nonpregnant and pregnant rat livers. The absolute clearance of antipyrine (milliliters per hour) was significantly greater in livers from pregnant compared to nonpregnant rats, whereas antipyrine clearance, corrected for liver weight (milliliters per hour gram of liver), was significantly lower in pregnant rat livers. Antipyrine clearance (milliliters per hour) was linearly related to oxygen consumption (milliliters per minute or micromoles per minute per gram of liver) in both the nonpregnant and pregnant rat livers. As oxygen consumption decreased, livers from pregnant rats maintained a greater ability to clear antipyrine than livers from nonpregnant rats. This study emphasizes the importance of maintaining adequate oxygen delivery to isolated perfused livers during drug metabolism studies to ensure constant oxygen consumption. Otherwise, alterations in the flow rate or hematocrit of the perfusion medium may directly alter the elimination rate of the substrate.

Animals↗
PubMedDate not supplied

Effect of endomorphin on somatostatin secretion in the isolated perfused rat stomach.

UNLABELLED: Recently the two peptides endomorphin-1 and -2 were isolated from bovine brain, which are postulated to be endogenous agonists for mu-opiate receptors in the CNS. Since exogenous and endogenous opioids have been shown to influence gastric functions, it was of interest to examine the effects of endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2), EM-1) and -2 (Tyr-Pro-Phe-Phe-NH(2), EM-2) in the isolated perfused rat stomach. RESULTS: EM-1 10(-8) M and 10(-6) M inhibited somatostatin (SLI) levels from a mean of 79 +/- 2.7 pg/min and 73 +/- 2.7 pg/min to 52 +/- 4.0 pg/min (n = 5, n.s.) and 27 +/- 3.0 pg/min (n = 5, P < 0.05), respectively. To characterize the effect on stimulated SLI-secretion, it was prestimulated for 30 min with gastric inhibitory polypeptide (GIP, 10(-9) M). EM-1 decreased prestimulated SLI-secretion in a concentration-dependent manner from a mean of 469 +/- 64.9 pg/min during the immediately preceding 15 minutes to 184 +/- 12.1 pg/min (67 +/- 4.0 %) at 10(-7) M and from a mean of 1146 +/- 269.6 pg/min to 111 +/- 14.1 pg/min (94 +/- 2.2 %) at 10(-6) M (each n = 6, each P < 0.05). In addition EM-2 was also examined at a concentration of 10(-6) M, which inhibited prestimulated SLI-secretion from a mean of 514 +/- 14.9 pg/min to a nadir of 204 +/- 44.7 pg/min (42 +/- 5 %, n = 6, P < 0.05). Application of the specific mu-opiate receptor antagonist CTOP in doses of 10(-7) to 10(-5) M significantly attenuated the inhibitory effect of EM-1 10(-7) M from 67 +/- 4.0 % to 34 +/- 4.7 % (10(-7) M), 33 +/- 3.0 % (10(-6) M) or 30 +/- 8.6 % (10(-5) M), respectively. This residual inhibition, however, was still significantly different from the preceding perfusion period. On the other hand, naloxone 10(-6) M completely abolished the inhibitory effect of EM-1 10(-7) M. Similarly, the inhibitory effect of 10(-6) M EM-1 was also significantly reduced by CTOP from 94 +/- 2.2 % to 60 +/- 10.9 % (10(-7) M), 61 +/- 5.5 % (10(-6) M) or 51 +/- 12.5 % (10(-5) M), respectively, and the residual effect was significantly different from the preceding perfusion period as well. At this higher dose of EM-1 (10(-6) M) naloxone 10(-6) M reduced the effect to 35 +/- 8.2 %, but there was still a significant difference of SLI levels compared to the preceding stimulation period (P < 0.05). Naloxone 10(-6) M reduced the inhibitory effect of EM-2 10(-6) M from 42 +/- 5.0 % to 20 +/- 5.0 % (P < 0.05), which was still significantly different compared to the preceding stimulation period. EM-1 at the doses of 10(-12) M, 10(-10) M, 10(-8) M and 10(-6) M had no significant effect neither on basal gastrin, bombesin (BLI) and vasoactive intestinal polypeptide (VIP) release nor during concomitant infusion of GIP. CONCLUSIONS: EM-1 and -2 inhibit basal and prestimulated SLI secretion in the isolated perfused rat stomach, which is in part attenuated by the mu-receptor antagonist CTOP. The greater inhibitory effect of naloxone, which can be demonstrated at least during the lower dose of EM-1, indicates that other opiate receptors contribute as well. The failure of naloxone to completely antagonize the effect of the higher concentration of EM-1 or EM-2 could be due to insufficient dosage or might indicate the involvement of non-opiate receptor mechanisms.

Analgesics, Opioid↗
PubMed1990

Activated eosinophils increase vascular permeability and resistance in isolated perfused rat lungs.

The effects of eosinophils activated with phorbol myristate acetate (PMA) on isolated perfused rat lungs were examined. Eosinophils were obtained from lungs of rats infected with Toxocara canis by bronchoalveolar lavage, incubated with PMA, and administered to an isolated perfused rat lung preparation. Vascular endothelial permeability was assessed by measuring the capillary filtration coefficient (Kf,c) in the perfused lungs. In lungs receiving either no eosinophils (control) or nonactivated eosinophils, there were no changes in pulmonary hemodynamics or Kf,c. However, in lungs receiving 2 x 10(6) eosinophils activated with PMA, there was a transient 4.8-fold increase in pulmonary vascular resistance that peaked at 30 min, primarily due to the constriction of small arteries and veins. After the initial pressor response, Kf,c was increased to 7.5 times control at 130 min and resulted in marked lung edema, increased wet-dry weight ratios, and edema on histologic examination. Pulmonary arterial pressure and Kf,c responses were dose related for eosinophil numbers between 1 x 10(6) and 4 x 10(6) cells. Peak airway pressure (Paw) during constant tidal volume ventilation also increased in lungs receiving activated eosinophils compared to the control and nonactivated eosinophil groups. These findings indicate that activated eosinophils are potent effector cells and can cause pulmonary vasoconstriction, bronchoconstriction, and vascular endothelial injury without widespread plugging of capillaries by aggregated eosinophils.

Animals↗
PubMed1997

Hepatic distribution and clearance of antisense oligonucleotides in the isolated perfused rat liver.

PURPOSE: This study was conducted to investigate the impact of backbone modifications on the hepatobiliary disposition of oligonucleotides. METHODS: The disposition of backbone-modified antisense oligonucleotides [phosphorothioate (PS) and methylphosphonate (MP)] of the same base-length and sequence (5'-TAC-GCC-AAC-AGC-TCC-3'), complementary to the codon 12 activating mutation of Ki-ras, was investigated in the isolated perfused rat liver. Livers were perfused for 2 hr: perfusate and bile concentrations were analyzed by HPLC. Hepatocellular distribution was examined by measuring the amount of radiolabeled PS oligonucleotide associated with hepatocytes and Kupffer cells. Protein binding of the PS and MP oligonucleotides was determined in rat serum by ultrafiltration. RESULTS: MP oligonucleotide perfusate concentrations remained constant during the 2-hour perfusion. In contrast, PS oligonucleotide was eliminated slowly by the isolated perfused liver [CI = 1.05 +/- 0.21 mL/min; extraction ratio = 0.06 +/- 0.01]. Uptake of PS oligonucleotide by Kupffer cells appeared to exceed uptake by hepatocytes, based on standard cell separation techniques as well as confocal microscopy. The degree of protein binding in rat serum was greater for the PS oligonucleotide (79.9 +/- 2.2%) than for the MP oligonucleotide (53.0 +/- 4.7%). CONCLUSIONS: Backbone modifications significantly-influence the hepatic clearance of oligonucleotides. Uncharged MP oligonucleotides are not extracted by the isolated perfused rat liver, whereas the charged PS oligonucleotide is processed more readily.

Animals↗
PubMed1991

Pharmacokinetics and toxicity of isolated perfusion of lung with doxorubicin.

The treatment of pulmonary metastases from soft tissue sarcomas with chemotherapy has an overall response rate of less than 30%, and the majority of these responses are short lived. It is postulated that increased drug delivery to the pulmonary metastases may improve the outcome of these patients. An isolated perfusion system would have the ability of delivering increased levels of drug to target tissue without the systemic toxic effect of the drug. The purpose of this study was to establish the pharmacokinetics of doxorubicin delivery, lung toxicity, and the ideal dose for clinical application in an in vivo isolated perfusion model. Our results suggest that normothermic isolated perfusion of the lung with doxorubicin using a dose level up to 6 micrograms/ml in the perfusate can be accomplished without histologic lung injury, systemic toxicity, or adverse clinical outcome. Perfusate concentration of greater than 7 micrograms/ml caused significant histologic injury and adverse clinical outcome without systemic toxicity. The technique may be utilized in selective settings to improve treatment in mesenchymal tumors metastatic to the lung.

Animals↗
PubMed2002

The metabolism and liver toxicity of N,N-dimethylformamide in the isolated perfused rat liver.

N,N-dimethylformamide (DMF) is metabolized by the microsomal cytochrome p-450 into mainly N-hydroxymethyl- N-methylformamide (HMMF), which further breaks down to N-methyformamide (NMF). However, the detailed mechanism of its toxicity remains unclear. We investigated the metabolism and the toxicity of DMF using the isolated perfused liver model. DMF was added to the recirculating perfusate of the isolated perfused rat liver at concentrations of 0, 10 and 25 mM. Samples were collected from the inferior vena cava at 0, 30, 45, 60, 75, and 90 minutes following addition of the DMF. The metabolites of DMF were analyzed using Gas-chromatography (GC). The changes in the rate of oxygen consumption by the DMF were monitored during perfusion. The enzyme activities (aspartic aminotransferase:AST, alanine aminotransferase:ALT, and lactic dehydrogenase:LDH)) in the perfusate were monitored to see if DMF caused hepatotoxicity. As the perfusion progressed, the DMF concentration in the perfusate decreased, but the level of NMF increased to a maximum of 1.16 mM. The rate of oxygen consumption increased at DMF concentrations of 10 mM and 25 mM. However, when a known inhibitor of cytochrome p-450, SKF 525A (300 micro M), was used to pretreat the perfusate prior to the addition of the DMF, the rate of oxygen consumption was significantly inhibited, indicating the cytochrome p-450 system was responsible for the conversion of DMF to NMF. On addition of the DMF, the activities of the enzymes AST, ALT and LDH were significantly increased a time and dose dependent manner. However, following pretreatment with SKF 525A, their releases were inhibited.

Animals↗
PubMed1985

Vitamin D3 uptake by the isolated perfused rat liver from lipoprotein fractions is separate from cholesterol and triglyceride uptake.

Using the isolated perfused rat liver we examined the uptake of [14C] or [3H] vitamin D3 and [14C] triglycerides or [3H] cholesterol by the liver of normal rats, from different lipoprotein fractions, as measured by disappearance from the perfusate. When incorporated into chylomicrons only 43% of the vitamin D3 remained in the perfusate at 60 min (i.e. 57% uptake) as compared to 68% of the triglycerides (i.e. 32% uptake). When added on very low density lipoproteins (VLDL) at 60 min 37 +/- 3% (n = 6) of the vitamin D3, 38 +/- 2% of the cholesterol (n = 3) (P NS), and 83 +/- 4% of the triglycerides (n = 3) remained in the perfusate (P less than 0.0005 for cholesterol:triglycerides and vitamin D3:triglycerides). For high density lipoprotein fraction (HDL) isolated perfused livers were studied with and without albumin present in the perfusate. Without albumin 19 +/- 8% (n = 3) of the vitamin D3 and 43 +/- 8% (n = 3) of the cholesterol remained in the perfusate at 60 min. The results with albumin present were 40 +/- 1% (n = 5) of the vitamin D3 and 63 +/- 4% (n = 5) of the cholesterol at 60 min (P less than 0.0005). The cholesterol:cholesterol ester ratio of the VLDL fraction was 8.8:1 and of the HDL fraction 1:1.4. There was no metabolism of vitamin D3 during the 1 h perfusion. These results suggest that vitamin D3 is in equilibrium with the lipoprotein surface, and the hepatic uptake of vitamin D is a surface phenomenon independent of lipoprotein metabolism.

Animals↗
PubMed2001

Near-infrared and nuclear magnetic resonance spectroscopic assessment of tissue energetics in an isolated, perfused canine hind limb model of dysoxia.

This controlled laboratory study examined the efficacy of near-infrared spectroscopy (NIRS) and 31P-nuclear magnetic resonance (NMR) spectroscopy in measuring regional tissue oxygenation in a isolated, perfused hind limb model of tissue dysoxia. Isolated hind limb perfusion was carried out in 20 mongrel dogs and oxygen delivery was varied by manipulating either hemoglobin concentration, oxygen saturation, or flow. Hind limbs from anesthetized mongrel dogs (n = 20) were separated and isolated perfusion performed. NIRS probes for recording relative O2 saturation of tissue hemoglobin (HbO2) and cytochrome a,a3 and NMR probes for measuring 31P-high energy phosphates were placed over the limb. Measurements of physiologic parameters, blood gases, lactate, NIRS values for HbO2 and cytochrome a,a3 redox state, and 31P-phosphate levels were recorded at set intervals throughout the experiment. Measures of tissue oxygen consumption (VO2) correlated with tissue oxygenation as measured by HbO2 and cytochrome a,a3 redox state (NIRS), as well as by 31P-high energy phosphate levels (NMR) throughout the experiment. Delivery-dependent tissue oxygenation was detected at a higher DO2 by NIRS than by VO2 or NMR. Tissue oxygenation as measured by NIRS and NMR shows excellent correlation with oxygen delivery in an isolated, perfused model of shock. NIRS may allow early detection of tissue dysoxia using rapid non-invasive techniques.

Animals↗
PubMed2001

[A new model of isolated perfused heart. Study of hypodermin A in hyperacute xenograft rejection].

AIMS OF THE STUDY: Isolated perfused heart (IPH) system and heart transplantation in the guinea-pig/rat combination represent a good model for the study of hyperacute xenograft rejection (HAR) in which the component plays a central role. Hypodermin A (HA), a protease cleaving the component, could be used to delay the HAR. METHODS: Creation of an original IPH working with rat serum (30 mL) and ex vivo study of HAR and I'HA. RESULTS: Study of HAR is possible with this IPH system. The mean guinea-pig heart survival after perfusion by normal rat serum was 38 +/- 7 min and was lower than survival observed after perfusion by guinea-pig serum (210 +/- 34 min) (p < 0.001), by decomplemented rat serum (177 +/- 45 min) (p < 0.001), and by rat serum with 20 micrograms/mL of HA (154 +/- 71 min) (p < 0.001). CONCLUSION: We developed an original system of isolated perfused heart allowing ex vivo study of HAR. HA delayed the occurrence of the HAR and confirmed the central role of the component in the HAR.

Acute Disease↗
PubMedDate not supplied

Urodilatin inhibits sodium reabsorption in the isolated perfused rat kidney.

The effect of human urodilatin (hURO) on kidney function has been examined in stable recirculating isolated perfused rat kidney. The concentration-dependent effects of urodilatin (URO) on isolated perfused rat kidney were analyzed at different perfusion pressures. The experiments show that at perfusion pressures of 100 or 130 mm Hg, 100 nmol/l hURO cause a significant increase of urine flow and a significant decrease of the fractional sodium reabsorption from 95.2 (SD 0.9, n = 5) to 85.6% (SD 0.9, n = 5) and 86.8 (SD 1.6, n = 5) to 77.6% (SD 3.2, n = 5), respectively. In contrast, at a perfusion pressure of 80 mm Hg sodium excretion was not increased by URO. The glomerular filtration rate was unchanged. Furthermore, the renal effects of hURO were compared with rat urodilatin (rURO) and the circulating form of rat cardiodilatin/atrial natriuretic peptide (rCDD/ANP 99-126). hURO, rURO, and rCDD/ANP produced a concentration-dependent increase in sodium excretion. However, differences in natriuretic efficiency are observed. rCDD/ANP causes a decrease in fractional sodium reabsorption from 93.6 (SD 2.6, n = 5) to 86.8% (SD 2.4, n = 5), similar to hURO. rURO shows a significantly higher natriuretic effect decreasing fractional sodium reabsorption from 92.0 (SD 0.7, n = 5) to 79.1% (SD 1.2, n = 5). From these results we conclude that the response of the isolated kidney to URO is critically dependent on the perfusion pressure and that URO exhibits tubular action on renal sodium excretion. The observed differences among the tested peptides on renal function may be due to species differences in the peptide sequence.

Absorption↗
PubMed1994

Tumor necrosis factor-alpha alters phospholipid content in the bronchoalveolar lavage-accessible space of isolated perfused rat lungs.

OBJECTIVES: To examine the effect of tumor necrosis factor-alpha (TNF-alpha) on pulmonary artery pressure and on total protein, phospholipid, lysophosphatidylcholine, phosphatidylcholine, phosphatidylinositol, and phosphatidylglycerol content in the bronchoalveolar lavage-accessible space of the isolated perfused rat lung, and to evaluate the role of the lung in the clearance of TNF-alpha from the perfusion medium in this model. DESIGN: Prospective, controlled trial. SETTING: Research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: The lungs from all subjects were isolated, perfused, and ventilated in the same manner. After a baseline sampling bronchoalveolar lavage, a reduction bronchoalveolar lavage was performed to establish a uniform amount of phospholipid in all lungs. This procedure was followed by the zero time sampling bronchoalveolar lavage, which verified the efficacy of the reduction lavage. After 5 mins, isoproterenol was added to the perfusion medium to promote surfactant secretion. Five minutes later, TNF-alpha (experimental group) and/or its carrier solution (control group) was added to the perfusion medium. Sampling bronchoalveolar lavages were repeated at 1 and 2 hrs after the zero time. Bronchoalveolar lavage samples were subsequently analyzed for protein and phospholipid content. After each sampling bronchoalveolar lavage, perfusion medium was obtained for immediate determinations of pH and the partial pressures of oxygen and carbon dioxide and the subsequent determination of TNF-alpha content. Pulmonary arterial pressures were continuously measured. MEASUREMENTS AND MAIN RESULTS: The pH and PCO2 in the perfusion medium remained in the physiologic range for all lungs, while the PO2 remained consistently increased. Mean pulmonary arterial pressures did not differ between groups. TNF-alpha levels were constant throughout the 2-hr period in the experimental group, and no TNF-alpha was detected in the perfusion medium of the control group. Amounts of total protein, total phospholipid, and lysophosphatidylcholine did not differ between the two groups. Although not statistically significant, phosphatidylglycerol was lower in the experimental group (p < .07). An increase in phosphatidylinositol content in the experimental group with a concomitant decrease in the control group between 60 and 120 mins was noted (p < .01). Amounts of phosphatidylcholine were found to be lower in the experimental group throughout the 2-hr period (p < .02). CONCLUSIONS: a) TNF-alpha alters the amounts of phosphatidylcholine, phosphatidylinositol, and possibly phosphatidylglycerol present in the lavage-accessible space of the isolated perfused rat lung. Possible mechanisms might include a direct effect of TNF-alpha on phospholipid secretion and/or reuptake, or an indirect effect via alteration of the type II pneumocytes' response to beta-adrenergic receptor stimulation. b) Increases in pulmonary arterial pressures seen in vivo with TNF-alpha administration are not due to a direct effect. Alterations in cardiac function or the interaction of other agents may be necessary to develop changes in pulmonary arterial pressure. c) This in vitro model does not demonstrate the rapid clearance of TNF-alpha from the circulation that is seen in vivo, suggesting that TNF-alpha metabolism does not occur primarily in the lung. Our findings support the hypothesis that TNF-alpha may alter surfactant composition, which may in turn contribute to the development of the adult respiratory distress syndrome.

Analysis of Variance↗
PubMed1980

Renal clearance of salicylic acid and salicyluric acid in the rat and in the isolated perfused rat kidney.

The renal clearance of salicylate (SA) and salicyluric acid (SU) was studied after i.v. bolus injection of 5 mg/kg of SA to ureter cannulated rats and after administration of 1 to 20 mg of SA or 2.5 to 10 mg of SU to the isolated perfused rat kidney. Previous studies in this laboratory have shown that SA and SU are metabolically interconverted in the isolated perfused rat kidney. The renal clearance of SU was greater than the glomerular filtration rate after either SA or SU administration. SA renal clearance was much less than the glomerular filtration rate when SA was administered but was greater than the glomerular filtration rate when it was formed from SU. The data support the hypothesis that administered SA is cleared differently than SA formed from SU in the isolated perfused rat kidney, presumably due to rate-limiting diffusion of SA into the cell.

Animals↗