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PubMed2002

[Effects of ET-1 on isolated perfused rat liver and vascular rings at two stages of cirrhosis].

OBJECTIVE: To investigate the effects of ET-1 on isolated perfused rat liver and vascular rings at early and late stages of cirrhosis. METHODS: Liver cirrhosis was induced by an intraperitoneal injection of 50% CCl(4) (0.3 ml/100 g, twice a week). In the 9th and 14th weekend after injecting CCl(4), the isolated perfused liver and vascular rings were performed to evaluate effects of four concentrations of ET-1 on early and late stages of cirrhosis. RESULTS: The Ppv of L-HC group at baseline was higher than that of E-HC group, both were higher than that of the controls. However, there showed no differences on Phv in these groups. With the concentration of ET-1 increasing, PVP was elevated accordingly in E-HC and L-HC group. L-HC group showed higher PVP compared with E-HC group, both were higher than the controls. While in isolated vascular rings, with the deteriorating of cirrhosis, the cumulative response curves showed right-shift. 0.1 nmol/L ET-1 showed mild relaxation on vascular rings in L-HC group. CONCLUSION: ET-1 can increase the PVP, especially with the deterioration of cirrhosis, there showed higher reaction compared with normal controls. The vascular rings showed low response on the contrary. So ET-1 plays an important role in the pathogenesis of portal hypertension. In view of its different roles on liver and vascular rings at early and late stages, administration of different selective antagonist of ET receptor at different stages of cirrhosis should be well considered.

Animals↗
PubMed1976

Uptake, metabolism and efflux of methadone in "single pass" isolated perfused rabbit lungs.

The uptake, metabolism and persistence of racemic, d- and l-methadone were studied in the isolated perfused rabbit lung. The removal of the drug from the perfusate was resolved into two uptake processes (I1 and I2Y. The unidirectional flux of methadone from the perfusate into the lung was linear with respect to perfusate concentration, suggesting an uptake mechanism involving diffusion and/or binding. The uptake of d- and l-methadone was identical. In the absence of methadone in the perfusate, methadone that previously had accumulated in the lung effluxed at three rates (T1/2 = 0.37, 1.65 and 8.9 minutes) suggesting that accumulated methadone was stored in at least three pools (E1, E2, and E3) In addition, a pool with a half-life in excess of 5 hours (noneffuxable pool) was detected; this noneffluxable pool was shown not to be the result of irreversible covalent binding. Methadone was biotransformed to a small extent by the isolated perfused lung to mono- and di-N-demethylated metabolites. Although unchanged methadone and its N-demethylated metabolites were consistently found in the lung at the end of efflux, the mono-N-demethylated metabolite was not always detectable in the perfusate. Nevertheless, the decrease in the rate of efflux of the metabolites with respect to time was identical to that of unchanged methadone.

Animals↗
PubMed1987

Degradation of serum amyloid A by isolated perfused rat liver.

Degradation of serum amyloid A (SAA) was studied in the isolated perfused rat liver. Radioiodinated SAA was reconstituted with high density lipoproteins (HDL) and administered to rats. Plasma was taken 1 h later, and the HDL were isolated for use as tracer. HDL-bound 125I-SAA was cleared from the plasma of intact animals at a rate similar to SAA in native human HDL. Catabolism of SAA and HDL apoproteins was studied in parallel in the perfused liver. In a 3-h perfusion, 21% of SAA was degraded in contrast to 13% of apoC-III, 7% of apoA-I, and 6% of apoA-II. SAA1 (47% in 3 h) was degraded more rapidly than SAA5 (37%) although their in vivo clearance rates were similar. Degradation of SAA was inhibited when lipoproteins were added to the perfusate. At a protein concentration of 0.15 mg/ml, low density lipoproteins inhibited 47%, HDL 62%, and SAA-rich HDL 75%. Lipid-free normal HDL (0.3 mg/ml perfusate) did not appreciably affect SAA degradation; however, delipidated SAA-rich HDL (0.3 mg of protein/ml; 0.02 mg of SAA/ml) inhibited SAA degradation by 40%. Isolated perfused mouse liver proved more effective than rat liver in degrading SAA (5.3% versus 2.8%/g of liver/h). Degradation appeared to be mediated by cell-associated enzymes since perfusate, which had been recirculated through the liver for 3 h, accounted for less than 15% of the total degradation. Partial (38%) hepatectomy did not significantly reduce apoA-I clearance but reduced that of SAA by 16%, providing additional evidence for hepatic SAA catabolism. We conclude from these studies that SAA is catabolized independently of other HDL proteins, that association with lipoproteins retards SAA clearance, and that SAA catabolism is, in part, a specific process.

Animals↗
PubMed1983

Effects of circulating renin substrate on renal function in isolated perfused rat kidney.

The effects of two different amounts of pure rat angiotensinogen were investigated in a closed circuit isolated perfused rat kidney. In response to angiotensinogen, circulating levels of angiotensin I (AI) and angiotensin II (AII) immunoreactive materials were found to increase in a time and dose-dependent manner. Vasoconstrictor and renin inhibitory effects were observed in parallel with the increase in AII. Glomerular filtration rate decreased after administration of angiotensinogen to a greater extent than renal flow and filtration fraction. The characterization by high performance liquid chromatography of peptides generated showed the liberation of AI, des-Asp1AI, AII and des-Asp1AII (AIII). These findings demonstrate that administration of angiotensinogen in an isolated perfused kidney model generates AI and that renal converting enzyme and aminopeptidases are able to convert AI to AII, AI to des-Asp1AI, and des-Asp1AI and/or AII to AIII. Changes in circulating level of angiotensinogen influence the activity of the renin-angiotensin system and, therefore, renal function.

Angiotensin I↗
PubMed1982

An isolated perfused dog lung preparation for the study of cyclic GMP metabolism: effects of sodium nitroprusside and oxygen.

The intact, isolated perfused dog lung was evaluated as a model for studies directed at defining the role of oxidative modulation of lung cyclic GMP metabolism in pulmonary function. Sodium nitroprusside added to the perfusion blood increased the cyclic GMP content of lung over 4-fold in a dose-dependent manner. Although sodium nitroprusside administration caused changes in lung vascular resistance, these occurred independently of the changes in cyclic GMP. Ventilation of lungs with a high oxygen gas mixture containing 95% O2. 5% CO2 acutely increased the cyclic GMP content of lungs after 15 min from 1.3 +/- 0.06 (mean +/- SE) to 3.4 +/- 0.12 pmol cyclic GMP/mg protein. Cyclic GMP levels returned toward control during continued ventilation with the high oxygen concentration. The oxygen-induced elevation of lung cyclic GMP content was not accompanied by changes in lung vascular resistance. The results indicate that the isolated perfused lung may be useful in studies of cyclic GMP, tissue oxidation and pulmonary function.

Animals↗
PubMed2004

Mechanism of CGRP-induced vasodilation in the rat isolated perfused kidney.

We investigated the intracellular mechanisms involved in calcitonin gene-related peptide (CGRP)-induced vasodilation in rat isolated perfused kidney. CGRP-1 receptor antagonist, CGRP-8-37, abolished the responses. Endothelial denudation by Triton X-100 or nitric oxide (NO) synthase inhibition by NG-nitro-L-arginine attenuated the maximum dilation by about 63 and 55%, respectively. Protein kinase A inhibitor, KT-5720, caused an about 72% inhibition in CGRP-induced maximum dilation. Soluble guanylate cyclase inhibitor, ODQ, and ATP-sensitive potassium channel blocker, glibenclamide, inhibited the CGRP-induced maximum responses by 75 and 55%, respectively. Cyclooxygenase inhibitor, indomethacin, had no effect. Our data suggest that CGRP-1 receptors, endothelium, NO synthase, protein kinase A, soluble guanylate cyclase, and ATP-sensitive potassium channels, but not the cyclooxygenase pathway, may play a role in CGRP-induced vasodilation in rat isolated perfused kidney.

Animals↗
PubMed1983

Glomerular filtration in the isolated perfused kidney. I. Sieving of macromolecules.

The permeability of the glomerular capillary wall to neutral macromolecules was studied in isolated perfused rat kidneys. Pluronic F108 (BASF, Wyandotte, MI, USA), a polyoxyethylene-polyoxypropylene block copolymer of mol weight approximately 14,000, was used as plasma expander. Pore theory was applied to the fractional clearances of Pluronic F108 and dextran (mol weight 19,400) molecules measured both as a function of glomerular filtration rate. Using the pore model of Verniory et al. [30] the effective pore radius (60.9 A) and the ratio of total pore area and pore length (4.0 cm/nephron) were estimated, and a hydraulic permeability coefficient KF (0.036 nl/s . mm Hg) was calculated. There was no significant difference between the fractional clearance of Pluronic F108 obtained with different Pluronic F108 concentrations over the range 15-35 g/l, hence with largely differing osmotic pressures. It was concluded that the sieving properties of the glomerular membrane of the isolated perfused rat kidney are not detectably different from those in the intact rat, at least in the case of uncharged macromolecules.

Animals↗
PubMedDate not supplied

The isolated perfused bovine udder as a model of dermal eicosanoid release.

The aim of this study was to examine whether the isolated perfused bovine udder could be used as a suitable in vitro inflammation model. A common in vivo inflammation model is arachidonic acid-induced inflammation in mouse ears. As an in vitro substitute for this model, arachidonic acid was administered topically to the skin of an isolated perfused bovine udder and the subsequent changes in eicosanoid synthesis were examined. As with the mouse-ear model, there was a significant increase in eicosanoid synthesis (prostaglandins E(2) and F(2 alpha) and leukotrienes B(4) and C(4)/D(4)/E(4)) following topical irritation. This effect lasted for 3 hours. In addition, the changes in prostaglandin E(2) synthesis in the skin following irritation with arachidonic acid were measured by the microdialysis technique. In conclusion, the in vitro model described seems suitable for studies of pharmacological effects on eicosanoid synthesis.

Administration, Topical↗
PubMed1986

31P NMR spectroscopy of isolated perfused lungs.

31P NMR spectra of isolated blood-perfused pig lungs were obtained by degassing the lungs in vivo to remove field inhomogeneities caused by air-tissue interfaces. The spectra show the presence of ATP, phosphodiester, inorganic phosphate, and phosphomonoester, but no phosphocreatine. All the metabolites remained stable for more than 4 h when the lungs were perfused with oxygenated blood. Blood gas tensions, glucose concentration, pH, and temperature were controlled throughout the experiment. During anoxia or ischemia, ATP and intracellular pH declined and Pi increased but returned to control levels during subsequent normoxia or reperfusion. These results demonstrate the applicability of NMR spectroscopy to isolated perfused lungs, enabling studies of metabolic processes in normal and pathologic lungs, as well as establishment of optimal conditions for lung preservation for transplantation.

Animals↗
PubMed1983

Effect of parathyroid hormone on Na+-dependent phosphate transport and cAMP-dependent 32P phosphorylation in brush border vesicles from isolated perfused canine kidneys.

Concentrative uptake of 32Pi induced by the dissipation of a Na+ gradient (overshoot) was demonstrated in brush border membrane vesicles obtained from isolated perfused canine kidneys. Na+-dependent 32Pi transport was decreased in brush border vesicles from isolated kidneys perfused with parathyroid hormone (PTH) for 2 h compared to uptake measured in vesicles from kidneys perfused without PTH. Cyclic AMP-dependent 32P phosphorylation of a 62,000 Mr protein band was demonstrable on autoradiograms of sodium dodecyl sulfate-polyacrylamide gels of membrane suspensions from kidneys perfused +/- PTH. Evidence that perfusion with PTH resulted in cAMP-dependent phosphorylation in isolated kidneys from parathyroidectomized dogs (decreased cAMP-dependent 32P phosphorylation of the 62,000-Mr band in brush border vesicles) was obtained after 2-h perfusion with PTH. Decreased 32P phosphorylation was not observed if membranes were allowed to dephosphorylate prior to 32P phosphorylation in vitro. We conclude that brush border vesicles from isolated perfused canine kidneys can be used to study the action of PTH on Na+-Pi cotransport in brush border membranes and on cAMP-dependent phosphorylation of the membrane. It is strongly suggested that PTH effects changes in Na+-dependent 32Pi transport in isolated brush border vesicles and changes in 32P phosphorylation of vesicles via a direct action on the renal cortical cell rather than as a consequence of extrarenal actions of the hormone.

Animals↗
PubMed1989

Effect of plasma protein binding on kinetics of PN 200-110 in the isolated perfused rat heart.

The myocardial accumulation and elimination pharmacokinetics of PN 200-110 (PN) were investigated in the single pass isolated perfused rat heart by two methods. A direct method, radioactivity measurement in myocardial tissue after various perfusion times, and an indirect method, concentration determination in coronary effluent, by fractionary collection of samples, during infusion and elimination periods. Both methods showed that the myocardium could be considered as a one-compartment model with regard to PN pharmacokinetics. The perfusion with a modified Krebs-Ringer (MKR) solution containing 1 nM of (+/-)PN 200-110 and [3H]-(+)PN 200-110 as radioactive tracer, led to an accumulation of about 61.4 fmol.mg-1 myocardial tissue at steady-state. The effect of protein binding on the uptake and pharmacokinetic parameters of PN has been investigated in this isolated perfused heart (IPH) model. binding of PN decreased as a function of increasing bovine serum albumin (BSA) levels in the perfusion solution. As a matter of fact, the mean steady state myocardial concentration of PN was decreased by 42.9, 56.2, 76.5, 83.9 and 95.5% for respectively, 1, 2.5, 6, 10 and 40 g.l-1 of BSA. In the same way, the free fraction, the apparent volume of distribution (Vd) and the distribution and elimination half-lives were decreased. On the contrary, the elimination rate constant was increased.

Animals↗
PubMed2005

Hepatobiliary disposition of liposomal amphotericin B in the isolated perfused rat liver.

The hepatic distribution, biliary excretion, and mass balance of liposomal amphotericin B (L-AmB) were investigated in recirculated isolated perfused rat liver. The results were compared with those from the conventional AmB formulation, amphotericin B deoxycholate (D-AmB). L-AmB was introduced as a bolus into the perfusate reservoir, at doses of 1000, 4000, and 8000 mug, to achieve therapeutically relevant concentrations. AmB concentrations in perfusate, ultrafiltrate, bile, and liver homogenate over 120 min were measured using a validated high-performance liquid chromatography assay. AmB hepatic disposition in isolated perfused rat liver after L-AmB bolus was characterized by a higher recovery in perfusate (81.7 +/- 9.4%, n = 13) and a significant decrease in hepatic distribution (5.9 +/- 2.4% at low dose, 2.4 +/- 0.9% at medium dose, and 1.9 +/- 0.7% at high dose) compared with D-AmB (32.2 +/- 4.5% in perfusate, 52.1 +/- 8.2% in liver at the dose of 198 microg). Tissue-to-perfusate partition coefficient of L-AmB calculated at 120 min decreased dramatically with the dose and was approximately 100-fold less than that achieved with D-AmB at the high dose (0.17 +/- 0.11 in L-AmB versus 15.82 +/- 6.43 in D-AmB). AmB displayed negligible biliary excretion, representing <0.1% of the dose administered with L-AmB. Hepatic uptake clearance of L-AmB (CL(H,uptake)) decreased with the increase in perfusate area under the curve at each dose. The relationship between perfusate area under the curve and CL(H,uptake) was described by a parallel hepatic uptake clearance model. In conclusion, liposomal encapsulation significantly alters the hepatobiliary disposition of AmB; the ability of liposomes to sequester AmB and the dose-dependent hepatic uptake clearance may account for dose-form-dependent differences in AmB pharmacokinetics.

Algorithms↗
PubMed1991

Kinetics of melphalan leakage during hyperthermic isolation perfusion in melanoma of the limb.

The kinetics of melphalan leakage into the peripheral blood were studied in 21 patients undergoing hyperthermic isolation perfusion of the upper or lower limb as an adjuvant treatment in high-risk melanoma; in 5 patients cisplatin was added. The melphalan concentrations in the peripheral blood rose predominantly during the first 20 min of perfusion and levelled out to an apparent steady state of about 0.28 micrograms/ml in upper extremity perfusions, and 0.34 (without cisplatin) and 0.37 micrograms/ml (with cisplatin) in lower extremity perfusion. Erythrocytes labelled with technetium Tc 99m, which were added concomitantly with melphalan to the perfusion medium, appeared in the systemic circulation of the patients at an almost constant rate of 0.32% (lower and upper limb perfusions without cisplatin and 0.37% (with cisplatin) of total tracer/min. This perfusate flow rate indicated by labelled erythrocytes completely explained the leakage of melphalan from the perfusion circuit into the peripheral blood. Peak concentrations of melphalan in the peripheral blood were observed immediately after reconstitution of normal hemodynamic conditions once isolation perfusion had been terminated. This fraction of melphalan might originate from tissue-binding sites, but also from vascular compartments; therefore, a thorough washing-out procedure might minimize this effect.

Adult↗
PubMedDate not supplied

[Effect of anti-ischemic protection on biochemical indices of the isolated perfused liver].

alpha-Tocopherol and prednisolone exhibited the highest antiischemic activity, while lidocaine and sodium glutamate were less active after administration into isolated perfused rabbit liver tissue subjected to 60-min thermic ischemia. Chlorpromazine.HCl did not affect the biochemical patterns studied in isolated perfused liver tissue.

Alanine Transaminase↗
PubMed1999

Inhibition of Na+ channel or Na+/H+ exchanger attenuates the hydrogen peroxide-induced derangements in isolated perfused rat heart.

The effect of tetrodotoxin, a specific inhibitor of the Na+ channel, and 5-(N,N-dimethyl)-amiloride, a specific inhibitor of the Na+/H+ exchanger, on the mechanical and metabolic derangements induced by hydrogen peroxide (H2O2) was studied in the isolated perfused rat heart. The isolated rat heart was perfused aerobically at a constant flow rate and driven electrically. H2O2 (600 microM) decreased the left ventricular developed pressure and increased the left ventricular end-diastolic pressure (i.e. mechanical dysfunction), decreased the tissue levels of adenosine triphosphate and adenosine diphosphate (i.e. metabolic derangement), and increased the tissue level of malondialdehyde (i.e. lipid peroxidation). These mechanical and metabolic derangements induced by H2O2 were significantly attenuated by tetrodotoxin (3 microM) or 5-(N,N-dimethyl)-amiloride (15 microM). Neither tetrodotoxin nor 5-(N,N-dimethyl)-amiloride modified the tissue malondialdehyde level, which was increased by H2O2. In the normal (H2O2-untreated) heart, neither tetrodotoxin nor 5-(N,N-dimethyl)-amiloride affected the mechanical function and energy metabolism. These results suggested that inhibition of the Na+ channel or Na+/H+ exchanger was effective in attenuating the H2O2-induced mechanical dysfunction and metabolic derangements in the isolated perfused rat heart.

Amiloride↗
PubMed1975

High degree of conversion of angiotensin I to angiotensin II in the mesenteric circulation of the isolated perfused terminal ileum of the cat.

Conversion of AI to AII has been studied in the mesenteric circulation of the isolated perfused cat terminal ileum. Infusion of AI through the mesenteric circulation induced a significantly potentiated response when the venous return was superfused over the rat colon and the rabbit aortic strip. Addition of converting-enzyme inhibitor, SQ 20881 to the perfusion medium competitively prevented the potentiation of AI on the assay organs without altering its direct effects. The percent conversion of AI to AII was found to be 68 in the mesenteric circulation. In contrast, infusion of AII through the mesenteric circulation has lost about 40% of its biological activity as measured on the same assay organs. SQ 20881 abolished the inactivation of AII in the mesenteric circulation. It is concluded that the mesenteric circulation of the isolated perfused cat terminal ileum is one of the major conversion areas of AI to AII. SQ 20881 prevented the conversion of AI to AII as well as abolishing the inhibition of AII passing through the mesenteric circulation.

Angiotensin II↗
PubMed1994

Intracellular Ca2+ transients in isolated perfused rat heart: measurement using the fluorescent indicator Fura-2/AM.

We have investigated the nature of Fura-2/AM loading into isolated perfused rat heart and the temporal and kinetic relationship between left ventricular [Ca2+]i dependent fluorescence and isovolumic pressure. The contribution of hydrolysed mitochondrial matrix Fura-2 fluorescence to that measured from the surface of the heart was estimated to be 43.9 +/- 5.5% by the addition of 100 microM Mn2+ to the perfusate. Maximum endothelial Fura-2 fluorescence ratio, estimated by the addition of 3 microM bradykinin to the perfusate, was found to constitute 33.6 +/- 2.7% of the maximum myocardial Fura-2 fluorescence ratio. Approximately 11.2% of the 340 nm surface fluorescence was insensitive to 20 mM Mn2+ in the presence of ionomycin (3 microM) and therefore indicates the degree of partial hydrolysis of Fura-2/AM. Thus, depending on the contribution of endothelial Fura-2 fluorescence at a physiological endothelial calcium concentration, cytosolic fluorescence may comprise between 11-45% of the total cellular fluorescence at 340 nm. Net tissue interference of the Fura-2 fluorescence ratio by NADH emission and myoglobin absorption remained unaltered, providing the oxygenation state of the tissue was unaltered throughout the experiment. The [Ca2+]i dependent fluorescence decay from peak systole was best fitted to a biexponential decay with fast and slow rate constants of 18.08 +/- 1.97 s-1 and 0.23 +/- 0.02 s-1, respectively. In addition, a phase shift was observed between temporal and kinetic measurements of the left ventricular isovolumic pressure and calcium dependent fluorescence traces during a contraction-relaxation cycle. We conclude that despite imperfect Fura-2/AM loading, the temporal and kinetic characteristics of intracellular [Ca2+] transients in normal isolated perfused rat heart are similar to those reported in more controlled preparations such as isolated myocytes and cardiac trabeculae.

Animals↗
PubMed1984

[Effect of series E and F prostaglandins on the reaction of the pentosephosphate pathway of carbohydrate metabolism in isolated perfused rat organs].

The effects of prostaglandins E2 and F2 alpha on oxidative and non-oxidative reactions of the pentose phosphate pathway of carbohydrate metabolism in isolated perfused liver and uterus of the rat were studied. The prostaglandins (0.5 X 10(-8) M) activate dehydrogenase but do not practically affect the activity of non-oxidative enzymes of the pentose phosphate pathway. Upon perfusion of isolated rat liver and uterus by the prostaglandins, the degree of dehydrogenase activation depends on the perfusion time and the nature of the prostaglandins. Under effects of prostaglandin E2, the maximal activity of liver glucose-6-phosphate dehydrogenase (280% above the normal level) was observed already after 15 min, that of 6-phosphogluconate dehydrogenase (104% above the normal level) after 30 min. In the uterus, the maximal activity of these enzymes was induced by prostaglandin F2 alpha, showing an increase in the whole course of perfusion and after 1 hour exceeded the normal value by 120 and 80% for glucose-6-phosphate and 6-phosphogluconate dehydrogenases, respectively.

Animals↗