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PubMed1988

Effects of leukotrienes and the thromboxane A2 analogue U-46619 in isolated perfused rat liver. Metabolic, hemodynamic and ion-flux responses.

1) Addition of leukotriene C4 to isolated perfused rat liver led to a stimulation of hepatic glucose output, a slight decrease of 14CO2 production from [1-14C] glutamate, an increase of portal pressure and an inhibition of hepatic oxygen uptake. Withdrawal of leukotriene C4 caused a transient further stimulation of hepatic glucose output. 2) These effects were accompanied by a slow net Ca2+ release from the liver, which was not completed within 8 min. Following leukotriene withdrawal there was a further Ca2+ release for about 1 min superimposing a slow reuptake of Ca2+ of about 10 min duration. 3) Leukotriene C4 induced a characteristic biphasic K+ release from the liver. Withdrawal of the leukotriene resulted in a further net K+ release for about 4 min, being followed by a K+ reuptake over more than 10 min. 4) Effects comparable to those induced with leukotriene C4 (20nM) were obtained with leukotriene D4 (20nM), were as leukotriene B4 and E4 (20nM each) were much less effective. 5) The thromboxane A2 analogue U-46619 produced ionic, metabolic and hemodynamic responses similar to leukotriene C4; however, when given at concentration yielding a comparable glucose release, the thromboxane analogue was much more vasoactive than leukotriene C4. The thromboxane A2 receptor antagonist BM-13.177 (20 microM) blocked the metabolic, hemodynamic and ion flux responses to U-46619 almost completely, but had no effect on the response to leukotriene C4. 6) Each, leukotrienes, U-46619 and UTP led to an inhibition of hepatic oxygen uptake. The extent of inhibition of oxygen uptake induced by these compounds was not exclusively explained by their effects on hepatic circulation: a 30% inhibition of oxygen uptake by leukotriene C4, U-46619 or UTP was accompanied by increases of the portal pressure of 4.9 +/- 0.4 (481 +/- 39 Pa) (n = 7), 16.0 +/- 1.9 (1570 +/- 186 Pa) (n = 7) or 11.4 +/- 0.4 (1118 +/- 39 Pa) (n = 13) cm H2O, respectively. 7) The data show that leukotrienes and possibly also thromboxanes are potent regulators of hepatic metabolism and hemodynamics, probably acting by a Ca2+ mobilizing mechanism and involving different receptor systems. The response of perfused liver to these compounds is qualitatively similar to that obtained with extracellular UTP, but different to that with prostaglandins, extracellular ATP or phenylephrine. The data further support the view that eicosanoids are important modulators of hepatic metabolism and point to a complex regulatory interaction between hepatic parenchymal and non-parenchymal cells.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

Inhibitory influence of amino acids on secretagogues induced exocrine secretion in isolated perfused rat pancreas.

Influence of amino acids upon pancreatic exocrine secretion has been investigated in the isolated perfused pancreas of rats. Arg produced significant and dose-related inhibition of pancreatic juice flow, protein output and amylase output evoked by CCK-PZ (1.25 pM). The secretory response evoked by CCK-PZ was inhibited by other amino acids (Ala, Asp, Asn, Gly, Ile, Leu, Lys, Met, Phe, Pro, Thr, Trp, Val, in each 20 mM). A similar inhibitory pattern was observed using 10 mixed amino acids of 2 mM each (Pro, Phe, Thr, Met, Lys, Asp, Leu, Trp, Val, Gly). Gly at a concentration of 20 mM produced significant inhibition of exocrine secretion evoked by ACh (50 nM) or GRP (36 pM). The inhibitory response induced by amino acids could not be repeated by using exogenous insulin (1 microM) and glucagon (280 nM). The inhibitory response was also not changed by increased extracellular Ca (5 or 10 mM). However, Gly (20 mM) produced inhibition of exocrine secretion evoked by Ca reintroduction into a pancreas which was pretreated with A 23187. It was suggested that the inhibitory effects of some amino acids on exocrine secretion are mainly caused by suppression of Ca influx in a stimulus-secretion coupling process.

Acetylcholine↗
PubMed1975

Effect of phenformin on gluconeogenesis from lactate and intracellular pH in the isolated perfused guinea pig liver.

Gluconeogenesis from lactate and hepatic cell pH (pHi) were measured in the isolated perfused livers of starved guinea pigs in the presence and absence of phenformin (phenethylbiguanide). The observed decrease in lactate consumption and glucose output in the presence of phenformin was associated with a fall in pHi. The fall in glucose output observed was considerably greater than accountable for by the decrease in lactate consumption. A possible mechanism for the pathogenesis of clinical lactic acidosis due to phenformin therapy is suggested.

Acidosis↗
PubMed1991

The isolated perfused porcine skin flap as an in vitro model for percutaneous absorption and cutaneous toxicology.

The isolated perfused porcine skin flap (IPPSF) is a new perfused skin model which allows in vitro cutaneous pharmacology and toxicology studies to be conducted in a viable skin preparation which has a normal anatomical structure and a functional microcirculation. The purpose of this review is to (1) outline the background of this field which indicated the need for this type of model; (2) outline the surgical procedures needed to create and harvest viable preparations; (3) overview the criteria (biochemical, physiological, and histological) used to assess viability during an experiment; (4) present results of percutaneous absorption, cutaneous metabolism, transdermal delivery (passive and active), and skin distribution experiments conducted to date; (5) present the strategy developed to quantitate percutaneous absorption and cutaneous drug distribution using compartmental and physiological-based pharmacokinetic models; (6) assess the correlation of IPPSF data to in vivo results; (7) define the biochemical, physiological and histological (LM, TEM, enzyme histochemistry) response of the IPPSF to topically applied cutaneous vesicants; (8) overview where this type of in vitro model fits into the overall framework of cutaneous toxicology and pharmacology research; and (9) outline possible paths for future development. This review should provide the reader with an appreciation of some unique problems in this field which require an in vitro model that is closely integrated in structure and function to the in vivo setting.

Animals↗
PubMed1992

[Studies on biotransformation of etheofazine in isolated perfused rat liver].

The biotransformation of etheofazine (EDMTP), a new anticancer drug, was studied by using isolated perfused rat liver. Two main metabolites were separated from the perfusate by HPLC and TLC and their chemical structures were determined by MS, 1H-NMR and IR. EDMTP-I is the parent compound. EDMTP-II is 7-ethyl-8-aminotheophylline. EDMTP-II was also separated and identified from the blood of mice after iv of 10 mg/kg. Species difference of biotransformation of EDMTP between rat and mouse seems to be not significant in this study.

Animals↗
PubMed1992

The isolated perfused rat liver as an experimental model.

Intrinsic liver function may be specifically studied using the isolated perfused liver system. In this report, the metabolic characteristics of the perfused rat liver are described in response to lactate (5 mM) and ammonia (10 mM) loading. These conditions are analogous to the increased substrate availability that accompanies some acute disease states such as trauma. Glucose production (490 +/- 85 nm/gm liver/min) was constant during a 90-minute perfusion whereas albumin secretion exhibited a biphasic kinetic profile in the absence of exogenous amino acids. Liver oxygen consumption (VO2) was responsive to substrate loading as evidenced by a 20 to 60 per cent initial increase in VO2. The authors conclude that a large portion of hepatic VO2 may normally be directed toward substrate clearance. Additionally, although hepatic secretory protein synthesis persists despite the limitation of nutrient amino acid supply, the kinetics of secretion are complex.

Albumins↗
PubMedDate not supplied

Elimination of the antiviral drug 5-ethyl-2'-deoxyuridine by the isolated perfused rat liver.

The elimination of the antiviral drug 5-ethyl-2'-deoxyuridine (EdUrd) by the isolated perfused rat liver was investigated. EdUrd (3.9-39 mumol) was injected into the perfusion reservoir and serial samples were collected for HPLC determination of EdUrd and its metabolites 5-ethyluracil (EUra) and 5-(1-hydroxyethyl)uracil (HEUra). At each dosage level, semilogarithmic plots of concentration vs. time showed apparent first order disappearance of EdUrd. However, with increasing dose, there was a progressive increase in EdUrd half-life from 18.9 to 36.4 min and decrease in total clearance from 5.5 to 2.5 ml/min, indicating dose-dependent elimination. Dose dependence was confirmed by the lack of superposition of logarithm concentration/dose vs. time plots obtained with different doses. After EdUrd administration, the concentration of EUra reached a peak value in about 1 hr, and then gradually decreased. The concentration of HEUra, which was initially much lower than that of EUra, increased throughout the experiment and appeared to approach a plateau at 2-3 hr. Biliary excretion of each ethylpyrimidine was negligible. 6-Benzyl-2-thiouracil, a thymidine phosphorylase inhibitor, slowed the disappearance of EdUrd and decreased the peak concentrations of EUra and HEUra. Cimetidine, a cytochrome P-450 inhibitor, had little effect on the rate of EdUrd disappearance, but caused a large increase in the peak EUra concentration and decrease in HeUra concentration. 3-Methylcholanthrene, a cytochrome P-450 inducer, increased the formation of HEUra but had little effect on the rate of EdUrd disappearance. The results indicate that the hepatic elimination of EdUrd is dose-dependent and involves an initial cleavage to EUra, which is then oxidized to HEUra.

Animals↗
PubMed1989

Octanoate transport in the isolated, perfused rat liver.

The multiple indicator dilution technique was used to investigate octanoate transport in the isolated, perfused rat liver. The form of the octanoate outflow profiles depends on albumin concentration. The steady-state intracellular octanoate concentration and the rate of uptake increase when the albumin concentration is decreased. At physiological albumin concentrations, the intracellular concentration of octanoate is only 7% of the extracellular concentration. Exchange between the intra- and extracellular space, however, is very rapid, irrespective of the albumin concentration and consequently exchange is not rate limiting for metabolism.

Albumins↗
PubMedDate not supplied

The disposition of primaquine in the isolated perfused rat liver. Effect of dose size.

The disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation was investigated after the administration of 0.5-, 1.5-, and 5.0-mg doses of the drug. The pharmacokinetics of primaquine in this experimental model were dependent on dose size. Increasing the dose from 0.5 to 5.0 mg produced a significant reduction in clearance from 11.6 +/- 2.5 to 2.9 +/- 1.0 ml X min-1. This decrease was accompanied by a disproportionate increase in the value of AUC from 25.4 +/- 5.9 to 1128.6 +/- 575.7 micrograms X min X ml-1, elimination half-life from 33.2 +/- 10.7 to 413.0 +/- 239.3 min, and volume of distribution from 547.7 +/- 153.1 to 1489.0 +/- 249.0 ml. Furthermore, primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected in perfusate after the 0.5-mg dose, it was the principal perfusate metabolite after the 5.0-mg dose. Primaquine was subject to extensive biliary excretion at all doses; the total amount of 14C radioactivity excreted in the bile decreased from 60 to 30% as the dose of primaquine was increased from 0.5 to 5.0 mg. The metabolite composition of radioactivity excreted in the bile was also examined. Total recovery of the administered radioactivity from bile, perfusate, and liver was essentially complete at all doses. The perfusate concentrations at the conclusion of each experiment (i.e. 5 hr) did not differ among dosage groups. By contrast, increased dose size produced a reduction in the amount of 14C radioactivity recovered in bile which was associated with increased levels of 14C in the liver.

Animals↗
PubMed1986

Differential biological effects of calcitonin and parathyroid hormone on isolated perfused bone.

These studies examine the release of 3',5'-cyclic adenosine monophosphate (cyclic AMP) from isolated perfused canine bones in response to synthetic bovine parathyroid hormone (syn b-PTH 1-34) and human calcitonin (hCT). Bones for perfusion were obtained from three groups of dogs: control (n = 11); thyroparathyroidectomized (n = 7), and mithramycin-treated thyroparathyroidectomized animals (n = 5). The results indicate that PTH causes a greater release of cyclic AMP from adult bones than CT; the addition of the two hormones simultaneously results in a synergistic rather than an additive effect; mithramycin inhibits the cyclic AMP response to calcitonin; and thyroparathyroidectomy decreases the cyclic AMP release in response to CT stimulation, suggesting that the cells (osteoclast-like) that respond to CT have an impaired response in the absence of PTH; acute TPTX does not affect the response of the cell populations of adult bones to PTH.

Animals↗
PubMed1977

Studies on the effects of C. coli endotoxin on canalicular bile formation in the isolated perfused rat liver.

The impairment of biliary excretory function induced by E. coli endotoxin in the isolated perfused rat liver was studied by investigating its effects on canalicular bile formation. In experiments where no bile salt was infused, endotoxin administration resulted in significant decreases in bile salt-independent bile flow (BSIF) and sulfobromophthalein (BSP) excretion. It also caused dose-dependent decreases in the transport maximum of BSP but did not alter the ability of the liver to concentrate BSP in the bile. At 2 mg./100 ml. it decreased the hepatic removal rate but increased the hepatic storage of the dye. Measurement of 14 C-erythritol clearance and bile salt secretion also revealed that endotoxin significantly reduced the BSIF fraction of bile. The results indicated that the primary effects of endotoxin were on BSIF and BSP excretion.

Animals↗
PubMed1985

Release of plasminogen activator from isolated perfused dog heart.

The release and the local activity of plasminogen activator (PA) were studied in isolated perfused dog hearts, without or with intimal injury induced by means of a balloon catheter inserted into the left anterior descending coronary artery (LAD). Thrombin but not DFP-thrombin induced a dose-dependent PA release in doses of 8 to 32 units. ADP 20 or 200 mumol but not ergonovine 20 or 200 micrograms induced a weak PA release. The local PA activity was much lower in the LAD at 1 or 4 weeks after this injury than in the intact LAD. However, the release of PA from the hearts after intimal injury was similar to findings in the intact hearts. We conclude from this study that thrombin plays an important role in regulating the coagulation-fibrinolysis system in endothelial cells and that changes in the properties of the endothelial cells may lead to initiation and enhancement of atherosclerosis.

Adenosine Diphosphate↗
PubMed1973

Use of the isolated perfused rat lung in studies on lung lipid metabolism.

A procedure for the use of the isolated perfused rat lung in studies on metabolic regulation has been developed. The procedure, reasonably uncomplicated, yet physiological, maintains the lung so that edema is not observed. The phospholipid content remains normal, and incorporation of [1-(14)C]-palmitate, [2-(14)C]acetate, and [U-(14)C]glucose is linear with time for a minimum of 2 hr. The incorporation of [1-(14)C]-palmitate and [2-(14)C]acetate into the total lung phospholipid fraction and into the phosphatidylcholine and phospatidylethanolamine fractions has been studied. Increasing the concentration of palmitate in the medium from 0.14 to 0.51 mm increased by 60% the incorporation of [1-(14)C]palmitate into the total lung phospholipid fraction at 2 hr. When the palmitate concentration of the medium was 0.14 mm, addition of 0.11 and 0.79 mm oleate to the medium decreased [1-(14)C]palmitate incorporation into the total lung phospholipid fraction at 2 hr by 37 and 49%, respectively. The results suggest that the incorporation of exogenous fatty acids, present in the medium perfusing the lung, into lung phospholipids may depend upon the fatty acid composition of the medium. Known specific acyltransferase activities may be responsible for the ordered incorporation of available fatty acids into lung phospholipids.

Acetates↗
PubMedDate not supplied

The effect of pregnancy and estradiol-17 beta treatment on the biliary transport maximum of dibromosulfophthalein, and the glucuronide conjugates of 5-phenyl-5-p-hydroxyphenyl[14C]hydantoin and [14C]morphine in the isolated perfused rat liver.

The biliary transport maximum (Tm) of three organic axions was determined in the isolated perfused livers of untreated female (control), estradiol-17 beta (E2)-treated female (1 mg/kg/day, s.c. for 14 days), and pregnant (19-21 days of gestation) rats. Dibromosulfophthalein (DBSP), 5-phenyl-5-p-hydroxyphenyl[14C]hydantoin (HPPH) and [14C]morphine were infused continuously into the perfusate for a total dose of 41.2, 18, or 40.5 mumol, respectively. The concentration of [14C]HPPH and [14C]morphine declined in the perfusate, whereas the concentrations of [14C]HPPH glucuronide and [14C]morphine glucuronide increased during the 90-min experiment, indicating that the rate of formation of the glucuronide exceeded its rate of excretion in bile. E2 treatment decreased the Tm (nmol/min/g liver) for [14C]HPPH glucuronide and [14C]morphine glucuronide but not for DBSP, whereas pregnancy decreased the Tm for all three organic anions. Pregnancy, and to a lesser extent E2 treatment, increased liver weight. When expressed per whole liver, the Tm was not altered by pregnancy for any of three organic anions. E2 treatment increased the Tm for DBSP, had no effect on the Tm for HPPH glucuronide and decreased the Tm for [14C]morphine glucuronide. These data suggest the presence of multiple carriers for organic anions which are differentially affected by estrogen treatment and pregnancy.

Animals↗
PubMed1982

Synthesis of fibronectin by the isolated perfused rat liver.

The major site(s) of synthesis of plasma fibronectin is unknown. Using the isolated perfused rat liver and anti-rat fibronectin antiserum, we have measured net hepatic synthesis of fibronectin during 10-hr perfusion periods. We calculated the circulating plasma fibronectin pool of a 195-g rat with body surface area of 300 sq cm to be 3.3 mg: net hepatic synthesis of 3.75 +/- 1.0 mg/300 sq cm body surface area of the rat liver donor was seen in liver perfusions of 10 hr. When the hormones cortisol and insulin were added to the liver perfusate, net synthesis of 5.05 +/- 0.82 mg/300 sq cm was seen. Synthesis of two known acute phase reactant proteins, fibrinogen and alpha-2 acute phase globulin, was also substantially greater in the presence of cortisol and insulin. Plasma fibronectin levels measured in intact rats that had abscess produced by subcutaneous turpentine injection were 0.57 +/- 0;05 mg/ml compared to 0.38 +/- 0.02 mg/ml in normal control animals. Our studies indicate that hepatic synthesis contributes substantially to the plasma fibronectin pool and show that such synthesis is enhanced by the hormones cortisol and insulin. In the intact rat, inflammation was associated with elevated levels of plasma fibronectin.

Animals↗
PubMed1980

Prostaglandins and renin release studies in the isolated perfused rat kidney.

The efficacy of various prostaglandins to stimulate renin release was compared in the isolated perfused rat kidney. Renin release was stimulated in decreasing order of potency by PGE2, PGE2, PGF2 alpha and PGI2, whereas PGA2, PGD2 and 6-keto-PGF1 alpha were without effect. Renovascular resistance (RVR) was increased following infusion of PGE2, PGE1 and PGF2 alpha, whereas PGI2 did not change RVR. When PGF2 alpha or 3H-PGF2 alpha was infused, PGE2 could be identified in the venous effluent by high-performance liquid chromatography and combined gas chromatography/mass spectrometry.

Animals↗
PubMedDate not supplied

Renal tubular transport of cimetidine in the isolated perfused kidney of the rat.

The renal handling of cimetidine (pKa = 6.8) was studied in the isolated perfused rat kidney (IPK). Concentrations in the therapeutic range (< 10 micrograms/ml) had little adverse effects on the functional parameters of the IPK, and even a concentration of 250 micrograms/ml still had only minor effects. When initial perfusate concentrations were low (< 2.5 micrograms/ml), the ratio of renal clearance over filtered amount (CLR/GF) was approximately 3, indicating net tubular secretion. CLR/GF decreased at increasing perfusate concentrations, and above 25 micrograms/ml, there was progressive net reabsorption (CLR/GF < 1). CLR/GF was highly dependent on variations in urine flow and pH, which is indicative of substantial tubular reabsorption by nonionic diffusion. A kinetic model was used to describe the renal handling of cimetidine. This model incorporates the variables influencing the clearance of cimetidine, like urine flow, glomerular filtration rate, and urine pH. Cimetidine was subject to active tubular secretion following Michaelis-Menten kinetics and passive tubular reabsorption of the unionized fraction. The constant for reabsorption was 197 +/- 40 microliters/min, the Michaelis-Menten constant for tubular secretion was 0.2 +/- 0.1 microgram/ml, and the maximum transport capacity was 1.3 +/- 0.3 microgram/min. Cimetidine did not accumulate in IPK, with kidney to perfusate ratios of approximately 2. In conclusion, the renal handling of cimetidine in the IPK is concentration-dependent and is determined by glomerular filtration, active tubular secretion, and a substantial flow- and pH-dependent passive reabsorption.

Absorption↗
PubMed1996

Effects of gamma-aminobutyric acid agonists on the isolated perfused rat kidney.

The effects of gamma-aminobutyric acid (GABA) agonists were studied in the isolated perfused rat kidney. Perfusions were performed at constant flow with modified Ringer-Krebs solution. The GABAA agonist muscimol (0.1-75 microM) induced an increase in fractional excretion of water and sodium without promoting hemodynamic changes. These tubular changes were inhibited by atropine pretreatment. Thus, a possible modulation of tubular transport mechanisms via GABAA receptors acting on cholinergic system could be suggested. Muscimol was unable to modify the renal vascular resistance either at basal conditions or in noradrenaline-pretreated preparations. However, the GABAA antagonist bicuculline (50 microM) evoked an increased perfusion pressure. Despite the speculation that endogenous GABA could result in a maximal activation of these GABAergic processes, nonspecific binding sites for bicuculline should be considered. The GABAB agonist baclofen (0.05-500 microM) elicited a raised perfusion pressure and diminished glomerular filtration rate, accompanied by an increment in fractional excretion of water, sodium and glucose. These findings suggest a major GABAB receptor-mediated vasoconstriction at the afferent arteriole level. Proximal tubular structures seem to be a biological target for baclofen. GABA (0.05-1000 microM) evoked changes similar to those described for baclofen, although the glomerular filtration rate was not diminished. Data from this study indicate that the GABA system may be involved in the modulation of rat renal function.

Animals↗