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PubMed1969

Metabolism, sperm and fluid production of the isolated perfused testis of the sheep and goat.

1. A total of nineteen ram and three goat testes have been perfused in isolation at 34-35 degrees C for 3(1/2)-9 hr with heparinized blood and an added 5-HT antagonist (bromolysergic acid diethylamide) and their function compared with that of the normal ram testes in vivo.2. The metabolism of the perfused testes and the testes in vivo was similar but blood flow through the perfused testes was two to three times normal.3. Vasoconstriction was produced by adrenaline and noradrenaline (10-20 mug I.A.) and by electrical stimulation of nerves in the spermatic cord or of the lumbar sympathetic chain; these responses were abolished or reduced by phenoxybenzamine.4. Flow of fluid from the rete testis continued only if ischaemia was reduced to a minimum and glucose concentration in the blood perfusing the testis was kept above about 25 mg/100 ml.; the fluid secreted during perfusion was of normal composition.5. The perfused testis showed no evidence of autoregulation and the flow of fluid was not affected by changes in perfusion pressure.6. When the temperature of three testes was raised to 40 degrees C for 2 hr, metabolism increased but blood flow was unaltered; the flow of fluid and the concentration of spermatozoa decreased during heating.7. The testes perfused at normal scrotal temperatures (34-35 degrees C) were histologically normal but some abnormalities were observed in the heated testes.

Animals↗
PubMed1995

Development of an isolated perfusion circuit with double bypass using automatic blood pumps.

Isolated perfusion of the liver is a useful and promising therapeutic method for various hepatic diseases. However, conventional techniques using a roller pump require a large priming volume and cannot run at the low flow rate without complications. These disadvantages do not allow the use of conventional techniques in smaller pediatric patients. The authors solved these problems successfully for the first time by using unique sac-type air-driven automatic blood pumps with an oxygenator primed with a blood volume of 65 ml in the total circuit. The usefulness of these blood pumps for liver perfusion was evaluated in small animals weighing 3.5-6.0 kg. A hepatic perfusion circuit was established between the portal vein and the inferior vena cava. The blood pumps worked well without any trouble, and stable flow could be maintained. No hepatocellular damage or anaerobiosis of the liver was observed at a hepatic perfusion flow rate of 20 ml/min/kg. Isolated liver perfusion using these blood pumps can be applied in infants and young children.

Analysis of Variance↗
PubMed1995

Different pathomechanisms of altered biliary leukotriene C4 elimination in isolated perfused rat livers.

Hepatic retention of cysteinyl leukotrienes is a consequence of impaired bile secretion and may be involved in the pathogenesis of intrahepatic cholestasis. In order to assess the mechanisms of altered biliary leukotriene elimination, we studied the secretion and metabolic pattern of leukotriene C4 (LTC4) in bile early in the alterations of bile formation by xenobiotics. To this end, rats were pretreated with alpha-naphthylisothiocyanate (ANIT), ethionine (ETH), or estradiol valerate (EV) at doses which did not increase serum marker enzymes of cholestasis. Bile secretion was assessed in perfused livers isolated from the treated rats. In all models, the access of [14C]sucrose into bile was increased, indicating increased permeability of the bile tract. Biliary recovery of radioactivity infused as [3H]LTC4 was decreased by ANIT and ETH while 3H-efflux into the perfusate was increased concomitantly. The secretion rate of 3H-radioactivity into bile was correlated with that of [14C]taurocholate infused at the same time. After pretreatment with ANIT (but not in the other models) the venous efflux of [3H]LTC4-ANIT pretreatment was increased [14C]sucrose clearance into bile associated with greatly enhanced biliary access of [32P]phosphate. Thus, altered charge selectivity of the paracellular pathway appears to be a prerequisite for reflux of cholephilic anions. HPLC analysis of [3H]LTC4-derived radioactivity in bile revealed that in all models of altered bile secretion the relative amount of LTD4 in bile was elevated. These results demonstrate differential changes in hepatobiliary transport and metabolism of LTC4 in developing cholestasis. ANIT inhibits leukotriene secretion by increasing paracellular permeability with loss of charge selectivity. In contrast, ETH treatment inhibits transcellular transport while treatment with EV only results in enhanced LTC4 metabolism.

1-Naphthylisothiocyanate↗
PubMed1986

Disposition of bumetanide in the isolated perfused rat kidney: effects of probenecid and dose response.

The isolated perfused rat kidney was used to study the pharmacokinetic-pharmacodynamic relation of bumetanide and furosemide. Diuresis, as indicated by the concomitant increase in urine volume and fractional excretion of sodium, was produced with both drugs. The action of furosemide was dependent on a high clearance resulting from combined glomerular filtration and tubular secretion. The site of furosemide action was the luminal side of the nephron and a large amount of drug was required in the tubular lumen to produce diuresis. A bidirectional transport of bumetanide was indicated. Although tubular secretion of bumetanide was demonstrated, the action of bumetanide was not dependent on secretion and the highest response was achieved when bumetanide was filtered and partially reabsorbed. The lack of dependency on secretion to produce a response may be indicative of bumetanide reaching its site of action from the luminal as well as the vascular side of the nephron. In the isolated perfused rat kidney, although both drugs had the same pharmacodynamic endpoint, each drug had a different pharmacokinetic profile that characterized its response.

Animals↗
PubMed1990

Isolated perfusion of pancreas with mitomycin C.

The current treatment of pancreatic cancer with resection and/or radiation is considered unsatisfactory because of a high incidence of failure and a moderate incidence of complications. A sizable number of these patients present with localized or regional disease. Regional high-dose chemotherapy, such as with isolated perfusion, may offer an alternative therapy with low treatment-related morbidity and mortality and better end results in this group of patients. In an effort to develop such a treatment modality, we evaluated the pharmacokinetics and toxicity of mitomycin C (MMC) during isolated perfusion of pancreas in a canine model. From this study, it appears that a dose of 0.25 mg MMC/kg body weight is most suitable for isolated perfusion of pancreas at 39 degrees C, maintaining flow rate and pressure within physiologic range. Isolated perfusion with a dose of 0.25 mg/kg body weight has very mild short- and long-term toxicities and markedly increases drug delivery to the pancreas, duodenum, and peripancreatic lymph nodes, making it the most suitable dose for possible clinical application.

Amylases↗
PubMed1977

A cat head model with isolated perfusion by the animal's own blood.

A model consisting of a cat head perfused in isolation with the animal's own blood is described. The use of endogenous blood allows the organ to function under physiological conditions for several hours. The blood is taken from the abdominal aorta of the anaesthetized animal and passed to the carotid arteries via an extracorporeal circulation system. The perfusion pressure can be varied at will and is regulated electronically. The volume of blood in the extracorporeal circulation system is only 6 ml. The tests performed on this model were designed to study the behaviour of the cortical EEG and the cortical micro flow. Neither of these parameters underwent any change after institution of the artificial perfusion, and the blood gases also remained fairly stable. The model is suitable for studying both physiological and pharmacological problems.

Animals↗
PubMed1994

Reactive oxygen inducing vasoconstriction in the isolated perfused rat liver.

The effect of reactive oxygen generation on intact livers was studied. Production of reactive oxygen species in perfused livers isolated from normal and endotoxin-treated rats was measured using chemically enhanced chemiluminescence. The resting state chemiluminescence of the livers increased on endotoxin administration and was maximal about 6 h after treatment. Chemiluminescence from the livers was further stimulated severalfold by inclusion of phorbol myristate acetate in the perfusion medium, reaching maximum intensity 3 h after endotoxin treatment. Oxygen consumption by the endotoxin-treated liver showed a transient increase followed by a significant decrease on phorbol myristate acetate stimulation, which was inhibited by dexamethasone. These results are consistent with the occurrence of a respiratory burst followed by oxygen-radical-species-induced vasoconstriction in the intact perfused liver. The evaluation of reactive oxygen species by resident and accumulated macrophages in the intact liver is made possible by these studies, and related effects on the liver could be conveniently and quantitatively followed using this model.

Animals↗
PubMedDate not supplied

Differential effects on sympathetic neurotransmission of mast cell degranulation by compound 48/80 or antigen in the rat isolated perfused heart.

The aim of the present study was to investigate whether or not release of endogenous mast cell mediators modulates exocytotic noradrenaline overflow. Therefore, we perfused rat isolated hearts with the right sympathetic innervation intact and investigated the effect of mast cell degranulation on the efflux of noradrenaline. Compound 48/80 (48/80), a mast cell degranulating agent, caused a large release of histamine and serotonin and a facilitation of evoked noradrenaline overflow. When 48/80 was introduced into the perfusion medium 4 min before sympathetic nerve stimulation (SNS), evoked noradrenaline overflow was increased by about 60%. In the presence of the uptake 1-blocker cocaine, facilitation was attenuated (increase by only 30%). This effect was abolished by the histamine H2 receptor antagonist cimetidine or the inhibitor of nitric oxide synthesis NG-nitro-(L)-(-)-arginine. When the preexposure time to 48/80 was reduced to 30 s, the facilitation was less pronounced (15%) and inverted to an inhibition in the presence of cocaine (plus idazoxan) by 17% and/or cimetidine (by about 30%). The resulting inhibition of noradrenaline efflux was attenuated by the serotonin 5-HT1/2 receptor antagonist methiothepin or the 5-HT2 antagonist ketanserin. Infusion of ovalbumin into hearts of not specifically sensitized, but sham treated rats (in vivo injection of a saline-alumina mixture 10-12 days before the in vitro experiment) did not affect histamine, serotonin or (basal and evoked) noradrenaline efflux. In hearts from rats that were previously sensitized by an injection of an ovalbumin-alumina adsorbate, ovalbumin induced a marked increase of histamine and serotonin efflux. When the infusion of the antigen started 30 s before SNS, evoked noradrenaline overflow was inhibited by about 60%. The inhibition was unaffected by histamine receptor antagonists, but attenuated by purinoceptor (suramin plus 1,3-dipropyl-8-cyclopentylxanthine), or serotonin receptor (methiothepin, rauwolscine or ketanserin) antagonists. When the preexposure time to ovalbumin was prolonged to 4 min before SNS, no significant change of stimulation-induced noradrenaline overflow was observed. Basal, immunologically and non-immunologically induced histamine and serotonin efflux were not significantly affected by SNS or any of the drugs tested. The results indicate a complex influence of various mediators released upon mast cell degranulation induced by two different stimuli on exocytotic noradrenaline release from rat heart. Depending on the stimulus and on the time interval between the start of the application of the mast cell degranulating agent and SNS, a histamine- and nitric oxide-mediated facilitation, or a serotonin- and purine-mediated inhibition prevails.

Animals↗
PubMed1978

Ultrastructural changes during cholestasis induced by chlorpromazine in the isolated perfused rat liver.

Addition of cholestatic doses of chlorpromazine-HC1 to the perfusate of isolated rat livers produces widespread changes in hepatocyte membrane structure. These findings include a marked increase in intrasinusoidal cytoplasmic bullae, appearance of intracellular vacuoles within hepatocytes at both sinusoidal and biliary poles, dilation of bile canaliculi and evagination of canalicular diverticuli, and the formation of myeloid bodies within hepatocytes. These findings obtained in the bile acid depleted perfused liver may result from physiochemical interactions between chlorpromazine or its metabolites and lipid-protein components of cell membranes, consistent with chlorpromazine's properties as a cationic detergent. They occur independently of the vasoconstrictive effects of chlorpromazine and suggest that chlorpromazine may produce cholestasis by altering hepatocyte membrane function.

Animals↗
PubMed1994

Degradation of heme IX in rats pretreated with cobaltous chloride. A study in isolated perfused liver.

The effect of the administration of cobaltous chloride on the degradation of heme IX was investigated using perfusions of isolated rat livers. The presence of biliverdin IX beta (2%) in the bile fluid of cobaltous chloride treated rats support the hypothesis of the presence of a chemical oxidation of heme IX induced by the cobalt salt. In control rats the absence of biliverdin IX beta in the bile fluid was observed. When biliverdin IX beta was added to the perfusate it was excreted in the bile fluid as bilirubin IX beta without conjugation. An increase from approximately twofold to three-fold of the total bilirubins in the bile fluids of cobaltous chloride pretreated rats in relation with control rats was observed due to heme oxygenase enhanced activity. Bilirubin IX alpha diconjugates increased ca. 15% in the bile fluids of cobaltous chloride pretreated rats, after the addition of hemin IX. The increase could reflect the presence of a new molecular form of UDP-glucuronosyltransferase, which favours the formation of bilirubin IX alpha diglucuronide and therefore its preferential excretion into the bile. In the bile fluid of the rats pretreated with cobaltous chloride, other diconjugates of bilirubin IX alpha were also detected 120 min after the addition of hemin IX to the perfusate, consisting of glucose and glucuronate (5%) and xylose and glucuronate (5%).

Animals↗
PubMed1980

Pulmonary tissue volume in isolated perfused dog lungs.

Lung tissue volume (Vt) and pulmonary capillary blood flow (Qc) were measured with an acetylene rebreathing technique in intact and isolated perfused dog lungs. Qc (1.73 +/- 0.17 l/min) was consistently greater than pump flow (0.87 +/- 0.10 l/min) in isolated perfused lungs because acetylene disappearance from the lung was increased by diffusion across the pleura into the room. In spite of the increased acetylene loss, Vt can be measured in isolated lungs with reproducibility similar to that in intact animals (Vt intact = 207 +/- 63 ml, Vt isolated perfused = 208 +/- 61 ml).

Animals↗
PubMed1986

Different effectiveness of glucagon on the pacemaker activity and contractility in intact dog hearts and in isolated perfused right atria.

In an isolated right atrial preparation, which was cross-perfused with heparinized arterial blood from a support dog, we investigated the effects of glucagon on heart rate and systemic arterial blood pressure of the support dog and on atrial rate and contractile force of the isolated perfused atrium when glucagon was injected into the external jugular vein of the support dog or into the sinus node artery of the isolated atrial preparation. Glucagon (0.3 to 3 micrograms/Kg i.v.) to the support dog dose-dependently induced a prominent increase in heart rate and a small increase in systemic arterial blood pressure. In the isolated, perfused atrium, marked positive chronotropic and slight, but significant, positive inotropic effects were evoked dose-dependently 1.5 min after intravenous injection of glucagon. These positive effects were not altered significantly by propranolol (1 mg/Kg i.v.). Direct injection of glucagon into the sinus node artery of isolated atria also induced marked positive chronotropic and small positive inotropic effects dose-dependently. CF/HR ratios, inotropic effect per chronotropic effect in isolated atria, of glucagon injected intravenously or intraarterially were less than 0.7 and they were much less than those of norepinephrine (more than 3.6). These results confirm that glucagon injected intravenously or regionally produces a prominent positive chronotropic effect and a small positive inotropic effect and suggest that glucagon may be less effective as a cardiotonic agent.

Animals↗
PubMedDate not supplied

[Comparative study of various biochemical and physiological parameters of isolated perfused liver of rabbits, guinea pigs and rats].

As shown in 24 experiments using 60-min normothermic perfusion of isolated liver tissue from rabbit, guinea pig and rat, the tissues from guinea pig and rat proved to be more resistant to the impairing effect of hypoxia; besides, there was the higher rate of main energy producing processes--tissue respiration and glycolysis. This suggests that resistance of isolated liver tissue to the effect of hypoxia, involved in the processes of tissue damage in storage, depended directly on intensity of energetic reactions in the tissue.

Animals↗
PubMedDate not supplied

The effects of 5-fluorouracil on contractility and oxygen uptake of the isolated perfused rat heart.

Clinical cardiotoxicity related to 5-fluorouracil (5-FU) simulates either myocardial ischemia or left ventricular dysfunction. In order to characterize the changes occurring in the heart following 5-FU administration, the isovolumic perfused rat heart model according to Langendorff has been used. Particular emphasis was laid on contractility and oxygen uptake. Perfusion of isolated hearts with 1 mg/L 5-FU for 80 minutes failed to show any differences in contractility and oxygen consumption in comparison with the control group. On the contrary, 5-FU pretreatment of Wistar rats (50 mg/kg I.P. for 5 consecutive days) led to a decrease in inotropism without any change in maximum relaxation rate. The most significant finding was the consistent increase in oxygen consumption throughout the 80 minutes of perfusion (p less than 0.05) associated with a decrease in the fractional extraction of oxygen. Mean coronary flow was consistently increased in the 5-FU-pretreated group. Lactate release and CK Leakage did not differ in the two groups. In the 5-FU-pretreated group the ratio of oxygen consumption to rate-pressure product remained significantly elevated throughout 80 minutes of perfusion in comparison with the control group (p less than 0.05). Inappropriately high oxygen uptake could be a reflection of cellular metabolic disturbances responsible for post-ischemic dysfunction.

Animals↗
PubMed2003

Anionic and cationic drug secretion in the isolated perfused rat kidney after neonatal surgical induction of ureteric obstruction.

OBJECTIVE: To study the pathophysiological changes of renal tubular drug transport mechanisms in congenital renal obstruction, by developing a model for perfusing the isolated kidney (IPK) after neonatal surgical induction of partial ureteric obstruction in Hanover Wistar rats. MATERIAL AND METHODS: Moderately severe obstruction of the right kidney of male rats was created by burying a segment of the right ureter under the psoas fascia at 5-7 days after birth. Different fluorescent substrates for renal organic anion and cation drug transport systems were added to the IPK, and the concentration of these substances with time analysed in perfusate and urine. RESULTS: The reproducibility in all groups of the glomerular filtration rate (GFR) and drug excretion was remarkably good. GFR was significantly lower in obstructed kidneys than in unobstructed kidneys. 123Rhodamine, a marker for organic cation and P-glycoprotein transport, had a significantly lower maximum excretion rate in the obstructed than in unobstructed kidneys. Renal fractional clearance (123rhodamine clearance corrected for diminished GFR) was also significantly lower in obstructed kidneys. There was no significant difference in maximum excretion (absolute and corrected GFR) for Lucifer Yellow, a marker for sodium-dependent organic anion transport. The maximum excretion rate of calcein, a marker for sodium-independent organic anion transport, was significantly lower in the obstructed than in the unobstructed kidneys, but significantly higher after correcting for reduced GFR. CONCLUSION: The IPK is a good model for studying the effect of neonatal renal obstruction on tubular drug transport. These results show that organic anion and cation transport mechanisms are affected differently by obstruction.

Animals↗
PubMed1967

Metabolic activities of the isolated perfused rat kidney.

1. A technique for perfusing the isolated rat kidney is described. It is primarily designed for the study of renal metabolism but is also suitable for studying some aspects of the secretory function; this was normal with respect to minimal glucosuria. The glomerular filtration rate as measured by creatinine clearance was lower than in vivo and slowly decreased with time. 2. Gluconeogenesis from a variety of precursors was rapid and similar to that in kidney-cortex slices, in contrast with liver where the perfused organ is more effective than slices. Whereas the maximal rates of gluconeogenesis from glycerol and pyruvate were similar in liver and kidney, the rates from succinate, malate and fumarate were 14-20 times, and those from glutamate and aspartate about three times, as high in the kidney. 3. The oxygen consumption of the perfused organ was about twice that of cortex slices, presumably because of the secretory work done in the perfused organ but not in slices. 4. The rate of acetoacetate oxidation was about the same in the perfused organ and in slices but, because of the higher rate of oxygen consumption, the percentage contribution of acetoacetate to the fuel of respiration was lower in the perfused organ. The results suggest that acetoacetate can supply energy for the basal requirements and for gluconeogenesis but not for the secretory work. 5. Glutamine was formed at a high rate from glutamate and at a lower rate from aspartate. The high rates indicate that, in the rat, the kidney is a major source of body glutamine.

Acetoacetates↗
PubMed1995

Functional evidence equating the pharmacologically-defined alpha 1A- and cloned alpha 1C-adrenoceptor: studies in the isolated perfused kidney of rat.

1. The present study characterizes and classifies alpha 1-adrenoceptor-mediated vasoconstriction in the isolated perfused kidney of rat using quantitative receptor pharmacology and compares the results to radioligand binding studies (made in cloned alpha 1-adrenoceptor subtypes, native alpha 1A-adrenoceptors in submaxillary gland of rat, and alpha 1A-adrenoceptors in several other tissues of rat). 2. Concentration-effect curves to noradrenaline in the presence of 5-methyl-urapidil were biphasic, indicating alpha 1-adrenoceptor heterogeneity. The alpha 1-adrenoceptor subtype mediating the first phase (low affinity for 5-methyl-urapidil) could not be 'isolated' for detailed pharmacological characterization but was defined by a sensitivity to inhibition by chloroethylclonidine and an inability of methoxamine to activate the site. Additionally, vasoconstriction mediated by this alpha 1-adrenoceptor subtype or subtypes was abolished by nitrendipine (1 microM), thereby allowing characterization of the second, high affinity site for 5-methyl-urapidil. 3. The following antagonists interacted competitively with noradrenaline at the alpha 1-adrenoceptor for which 5-methyl-urapidil exhibits high affinity (pKB value): WB 4101 (10.3) > prazosin (9.5) approximately HV 723 (9.3) approximately 5-methyl-urapidil (9.2) > phenotolamine (8.6) > spiperone (pA2 = 8.1) approximately oxymetazoline (7.9). In contrast, insurmountable antagonism was seen with S(+)- and R(-)-niguldipine, the S(+)-isomer being approximately 30 fold more potent than the R(-)-isomer. Receptor protection experiments indicated that S(+)-niguldipine interacted directly with alpha 1-adrenoceptors. Dehydroniguldipine acted as a competitive antagonist (pKB = 9.0). Thus, the results with antagonists define the alpha 1-adrenoceptor as an alpha 1A-adrenoceptor. 4. An agonist 'fingerprint' was constructed in the presence of nitrendipine to define further the alpha 1A-adrenoceptor. The following order and relativity of agonist potency was obtained: cirazoline (1) approximately adrenaline (2) > noradrenaline (5) > phenylephrine (23) approximately amidephrine (31) > methoxamine (71) >> isoprenaline (1456) approximately dopamine (2210). 5. A high correlative association was shown between the affinity of antagonists obtained functionally in the isolated perfused kidney of rat and pKi values obtained from binding experiments with the cloned bovine alpha 1C-adrenoceptor (R2 = 0.85), native alpha 1A-adrenoceptors in submaxillary gland of rat (R2 = 0.79), and alpha 1A-adrenoceptors from several other tissues of rat (values taken from the literature, R2 = 0.89). 6. The present study demonstrates that the alpha 1A-adrenoceptor is the predominant alpha 1-adrenoceptor subtype mediating vasoconstrictor responses to exogenously administered noradrenaline in the isolated perfused kidney of rat. More importantly, alpha 1A-adrenoceptors mediating vasoconstrictor responses to noradrenaline exhibited a pharmacological equivalency to the cloned bovine alpha 1 c-adrenoceptor. Thus,definitive functional pharmacological data are provided for equating the two receptors and support results derived recently from molecular and radioligand binding studies.

Adrenergic alpha-Agonists↗