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PubMed1984

Atriopeptin release from the isolated perfused rabbit heart.

Mammalian atrial extracts have been shown to contain bioactive peptides which exert natruiretic, diuretic, and smooth muscle relaxant effects. These extracts include several low molecular weight (less than 5,000 Mr) atrial peptides (atriopeptins) which exhibit identical sequences over a central core region which are derived from the high molecular weight peptide (atriopeptigen) precursor which has been purified and sequenced. In the current study we found that extracts of rabbit atria possess both high and low molecular weight bioactive atrial peptides, however, the coronary venous effluent obtained from the isolated perfused rabbit heart only contained the low molecular weight peptide. This trypsin labile activity causes a dose-dependent relaxation of rabbit aorta and chicken rectum assay strips. Separation of the bioactivity with gel filtration chromatography and reversed phase HPLC indicates the heart releases a single substance similar to atriopeptin III. There was no evidence that atriopeptigen was released from the isolated perfused rabbit heart. We suggest that atriopeptigen is proteolytically processed in the atria to an atriopeptin which is subsequently the released form of the atrial peptide.

Animals↗
PubMed1999

The toxic and metabolic effects of 23 aliphatic alcohols in the isolated perfused rat liver.

We investigated the acute toxic and metabolic effects of 23-aliphatic alcohols (16 saturated and 7 unsaturated) in the isolated perfused rat liver at a concentration of 65.1 mmol/l (approximately 0.3% ethanol). The capacity of the straight chain primary alcohols (methanol, ethanol, 1-propanol, 1-butanol and 1-pentanol) to release the enzymes glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH) and glutamate dehydrogenase (GLDH) into the perfusate was strongly correlated with their carbon chain length. The secondary alcohols were less active in this respect whereas branching of the carbon chain did not consistently change alcohol toxicity. Unsaturation in the straight chain but not in the branched chain alcohols was accompanied by an increase in toxicity. An increased enzyme release was in general accompanied by, and correlated to, reductions in oxygen consumption, bile secretion, and perfusion flow of the isolated livers. Statistically significant correlations exist between parameters of alcohol-induced hepatotoxicity and the membrane/buffer partition coefficents of the alcohols. With the exception of methanol, all alcohols tested increased the lactate/pyruvate ratio of the perfusate, although this effect was not correlated to the degree of hepatic injury. Hepatic ATP concentrations decreased in most cases in line with hepatic injury and were particularly correlated with changes in oxygen consumption. Hepatic concentrations of reduced glutathione (GSH) were only diminished by the unsaturated alcohols, whereas an increase in hepatic oxidized glutathione (GSSG) occurred only with some of the saturated alcohols. Hepatic concentrations of malondialdehyde (MDA) increased after two saturated and three unsaturated alcohols but did not correlate with other parameters of hepatotoxicity. In conclusion, alcohol-induced hepatotoxicity is primarily due to membrane damage induced by the direct solvent properties of the alcohols. The consequences and relative contributions of alcohol metabolization to the overall hepatotoxicity of higher alcohols requires further study.

3,4-Methylenedioxyamphetamine↗
PubMed1982

Cold acclimation in insulin secretion of isolated perfused pancreas of the rat.

The secretory function of the endocrine and exocrine pancreas in the process of cold acclimation has been studied in rats fed at an ambient temperature of 2 degrees C. In anesthetized rats, plasma glucose decreased immediately after cold exposure and increased again toward the basal level after 20 days of continuous cold exposure. Plasma insulin level in these rats also decreased immediately after cold exposure, and the low level was maintained throughout the whole period of cold exposure. In the isolated perfused rat pancreas, the basal insulin output estimated before the stimulation with glucose decreased immediately after the cold exposure and increased gradually during the continuous cold exposure. In these preparations, the initial and the second phases of insulin output were induced by sustaining stimulation with 16.7 mM glucose. Changes in the glucose-induced initial and second phases showed a diphasic pattern during the course of cold exposure. Thus, there was temporary decrease within a week of cold exposure followed by a gradual increase after 3 wk of this condition. The diphasic insulin output in the preparation isolated from rats fed during cold exposure for 6 wk was twice as much as that in the preparation isolated from the rats fed during exposure to 23 degrees C for 5 wk. In the isolated perfused rat pancreas, a monophasic insulin output was induced by sustaining stimulation with 0.1 microM ACh. The monophasic insulin output showed an increasing tendency during cold exposure, but the increase was insignificant because of a larger individual variation.

Acetylcholine↗
PubMed1990

Beneficial effects of low-flow perfusion resumed early after zero-flow ischemia on myocardial energy metabolism and mechanical function: 31P-NMR study in the isolated perfused rat heart.

Effects of low-flow perfusion after zero-flow ischemia on myocardial mechanical function and energy metabolism were studied with 31P nuclear magnetic resonance spectroscopy, using isolated perfused rat hearts. After control perfusion, hearts were randomly divided into five experimental groups: Groups I and II were subjected to zero-flow ischemia of 40 and 60 min, respectively. In groups III-V the perfusion was resumed at a rate of 0.1 ml/min after 40 (group III), 30 (group IV) and 20 (group V)-min of zero-flow ischemia in order to compare the effects of low-flow perfusion with those of persistent zero-flow. After these interventions all the hearts were perfused for 40 min at a normal flow rate. Compared with the hearts exposed to total ischemia of 60 min, the preservation of high energy phosphate compounds (HEP) was better in groups with early low-flow perfusion; Creatine phosphate (CrP) levels, which had decreased rapidly after induction of zero-flow ischemia, increased gradually after initiation of the low-flow perfusion and reached significantly higher levels at the end of ischemic period in groups IV and V than in group II (p less than 0.05). The decrease in adenosine triphosphate (ATP) was likewise significantly suppressed by low-flow perfusion (groups IV and V greater than group II). Restoration of CrP levels after complete reperfusion was also significantly greater in group V than in group II. The recovery of ATP after complete reperfusion was also much better in group V being comparable to those in group I, although the total duration of ischemia was longer in group V than in group I. These results indicate the beneficial effects of low-flow perfusion on the preservation during ischemia and recovery after reperfusion of myocardial HEP.

Adenosine Triphosphate↗
PubMedDate not supplied

Importance of solvent drag and diffusion in bile acid-dependent bile formation: ion substitution studies in isolated perfused rat liver.

Ion substitution studies were carried out in the isolated perfused rat liver to define the importance of solvent drag and diffusion in bile acid-dependent bile formation. Two different methods, namely single injection (20 mu moles) and continuous infusions at 0.4, 0.8, 1.2, and 1.6 mu moles per min taurocholate (TC), were used to determine the bile acid-dependent bile flow (BADF). Both methods gave essentially the same results. Replacement of Na+ (146mM) by 120 or 146 mM Li+ and Cl-(127mM) by 120 mM NO3- increased BADF significantly. On the other hand, replacement of Na+ by 120 mM choline and Cl- y 120 mM isethionate decreased the BADF. The osmolarity of TC solution was not different when Na+ was replaced by 120 mM Li+ or choline and TC did not affect the osmotic activity of NaCl, and choline-Cl differently. Thus, the observed effect of Na+ replacement on BADF is not due to any change in the osmotic activity of the secreted TC. Substitution of HCO3- by equimolar tricine also decreased BADF. Under this condition, BADF increased when NaCl was replaced by equimolar NaNO3. Thus, HCO3- does not seem to be essential for TC choleresis. Since Li+ and NO3- are more permeable, and choline and isethionate are less permeable than Na+ and Cl-, respectively, these results suggest that the BADF is dependent on the permeability of the substituting cations and anions and thus support the hypothesis that solvent drag and diffusion play an important role in BADF.

Animals↗
PubMed1989

Toxicity of dysprosium shift reagents in the isolated perfused rat kidney.

Sodium and water spectra were acquired from the isolated perfused rat kidney by using a double-tuned probe designed to have high X nucleus sensitivity and low 1H sensitivity. Both DyTTHA and DyPPP were used to distinguish intra and extracellular 23Na resonances before and after the onset of hypoxia. Only DyPPP was useful in separating the two compartments, with a maximal chemical shift difference produced at a concentration of 4.5 mM. Both shift reagents were nephrotoxic at concentrations under 5 mM and produced an immediate decrease in renal-concentrating capacity and increases in fractional sodium and potassium excretion and increased renal vascular resistance. These disturbances of renal physiological parameters were accompanied by progressive broadening of the renal H2O resonance. 1H NMR may be a subtle means of monitoring nephrotoxicity.

Animals↗
PubMedDate not supplied

Controversies concerning adjuvant regional isolated perfusion for stage I melanoma of the extremities.

The use of isolated perfusion with melphalan in an adjuvant setting for stage I extremity melanoma continues to be controversial. In this article, 2 retrospective studies compare patients undergoing perfusion from Groningen, the Netherlands, with matched controls from the Sydney Melanoma Unit in Australia and from 5 hospitals in the Netherlands and Westphalia (a region of Germany bordering the Netherlands). All patients underwent wide local excision for a primary extremity melanoma of 1.5 mm or more in thickness. In the first study, women with a melanoma of the leg (excluding the foot) and treated with perfusion had a significantly higher survival than women treated with local excision alone. In the second study, a proportional hazards regression analysis for recurrent disease and survival identified no statistically significant difference in favor of adjuvant perfusion. Two other studies from the literature evaluating the efficacy of perfusion are examined. Patients treated at the M.D. Anderson Cancer Center, Houston, with wide local excision and perfusion are compared retrospectively with a group of patients individually matched for prognostic factors from the University of Alabama in Birmingham, U.S.A. and the Sydney Melanoma Unit. A small subset of patients with tumors greater than 2 mm thick benefited from perfusion. A prospective randomized study from the University Hospital, Cologne, West Germany found benefits for all perfused patients with tumors greater than 1.5 mm but their patients did not appear to be individually matched for tumor thickness. It is concluded after critical appraisal of all these studies that there is insufficient convincing evidence to date of an advantage of perfusion over wide local excision alone.

Chemotherapy, Adjuvant↗
PubMed1989

Mitochondria and xanthine oxidase both generate reactive oxygen species in isolated perfused rat liver after hypoxic injury.

Hypoxia caused severe damage in isolated perfused livers from fasted male Fischer rats without evidence of the formation of reactive oxygen species during hypoxia. Reoxygenation caused a significant increase in intracellular oxygen species in the injured liver, as indicated by increases in sinusoidal GSSG efflux and tissue GSSG levels. Both parameters were elevated further by addition of KCN (100 microM) or antimycin A (8 microM). Sinusoidal GSSG efflux was suppressed in part by addition of allopurinol (500 microM) and enhanced by hypoxanthine (250 microM). Xanthine oxidase appears to be a partial source, and damaged mitochondria a continuous and quantitatively greater source, of reactive oxygen as a result of liver injury following hypoxia.

Adenosine Triphosphate↗
PubMed1993

The effect of hypoxia on propranolol clearance during antegrade and retrograde flow in the isolated perfused rat liver preparation.

We investigated, using the single-pass isolated perfused rat liver preparation, whether the centrilobular location of hepatic oxidative drug metabolism could be a contributing factor to the marked sensitivity of drug oxidation to hypoxia. Livers (N = 7) were each perfused for 130 min with 2 micrograms/mL (+)-propranolol, a drug metabolized almost entirely by oxidation in the rat. The direction of flow was reversed after 60 min, the order of flow direction being randomized. Normal oxygenation was used during the first 30 min of antegrade and of retrograde perfusion, but in the second 30 min perfusate was equilibrated with a N2/O2 mixture designed to reduce hepatic oxygen delivery by half. During normal oxygenation there was no significant difference between antegrade and retrograde perfusion in hepatic oxygen delivery and physiological parameters such as oxygen consumption and extraction, perfusion pressure and bile flow. During hypoxia, mean oxygen delivery was slightly lower with retrograde perfusion (retrograde: mean = 2.37 mumol/min/g liver, range = 1.56-3.17; antegrade: mean = 2.90 mumol/min/g liver, range = 1.96-4.08; P = 0.04), but there was no significant difference in physiological parameters within each liver (P > 0.05). Propranolol clearance during normal oxygenation was similar to the perfusion rate (10 mL/min) and was the same for both directions of perfusion (antegrade 9.88 +/- 0.07 mL/min, retrograde 9.88 +/- 0.13 mL/min, P > 0.05). Hypoxia reduced propranolol clearance substantially, but the decrease was significantly greater with antegrade perfusion (5.65 +/- 1.89 mL/min) than with retrograde perfusion (6.76 +/- 1.95 mL/min, P = 0.014). Oxidative drug metabolism is located primarily in the centrilobular zone and sinusoidal oxygen concentration is lowest in the "downstream" zone with both antegrade and retrograde perfusion. These findings suggest that the centrilobular location of propranolol metabolism may influence the effect of hypoxia on propranolol elimination, but is not a major contributor to the marked sensitivity of propranolol elimination to hypoxia antegrade perfusion.

Animals↗
PubMed1991

Galanin inhibition of vasoactive intestinal polypeptide release and circular muscle motility in the isolated perfused canine ileum.

The role of porcine galanin, infused arterially into isolated perfused canine ileal segments, in modulating the tonically elevated neural release of vasoactive intestinal polypeptide and possible concomitant motor actions dependent on vasoactive intestinal polypeptide modulation was studied. Galanin infusions (9-minute) inhibited vasoactive intestinal polypeptide release in a concentration-dependent manner (maximum during minutes 8-10) irrespective of the absence (quiescence) or presence of phasic circular muscle contractions induced by local electrical field stimulation of nerves. During quiescence, galanin induced phasic contractions in four of five segments beginning in the 8th minute of the infusion. During stimulated contractions, galanin inhibited phasic motor activity within 2 minutes of initiation of the infusion; this inhibition may result from direct smooth previously reported muscle inhibition. Thus galanin may inhibit both neural release of vasoactive intestinal polypeptide and circular muscle motility directly. The delayed period of phasic activity initiated by galanin during quiescence may be related to inhibition of vasoactive intestinal polypeptide release, freeing the muscle from tonic inhibition by vasoactive intestinal polypeptide. Because galanin and vasoactive intestinal polypeptide are colocalized in some enteric nerves, galanin may regulate vasoactive intestinal polypeptide release by negative feedback.

Animals↗
PubMed1986

Uptake, transfer and metabolism of prostaglandin E2 in the isolated perfused human placental cotyledon.

(3H) PGE2 uptake and transfer in the isolated perfused human placental cotyledon was assessed by a single pass paired isotope dilution technique utilising (14C) sucrose as an extracellular marker. Metabolism of (3H) PGE2 was measured by analysing maternal and fetal effluents from perfused human placental cotyledons after bolus injection of (3H) PGE2 into either the maternal or fetal sides. Maximal uptake of (3H) PGE2 was greater on the maternal (81 +/- 8%) than the fetal sides (42 +/- 12%) and showed saturation with increasing concentrations of PGE2 only on the fetal side with an apparent Km of 12 +/- 4.9 nmol/l and vmax of 1.5 +/- 0.2 pmol/min/g. Total recoveries of (3H) PGE2 were 84.6 +/- 11.8% and 32.6 +/- 6.3% of the injected dose after injection on the fetal and maternal sides respectively. Transfer of (3H) PGE2 was the same in both directions being 6.4 +/- 1.2% of the injected dose in the fetal-maternal direction and 5.8 +/- 2.7% of the injected dose in the maternal-fetal direction. Metabolism was greater on the maternal side (35% of injected (3H) PGE2) than the fetal side (18% of injected (3H) PGE2) and was principally to the 13,14-dihydro-15-keto-PGE2 metabolite. Metabolism of (3H) PGE2 after passage across the placenta was the same in both directions and was of the order of approximately 60%.

Biological Transport↗
PubMed1996

Release of vasoactive agents from the isolated perfused human ovary.

OBJECTIVE: To investigate local vascular control in the isolated perfused premenopausal human ovary by measuring flow-induced release of vasoactive substances. DESIGN: Release of adenosine 5' triphosphate (ATP), substance P (SP), endothelin (ET), and vasopressin (AVP) from the ovarian vascular endothelium was estimated in perfusate under basal conditions and during two periods of increased flow. MAIN OUTCOME MEASURES: Vascular resistance; ATP, SP, ET and AVP release. RESULTS: The mean ratio (pressure/flow during increased flow):(pressure/flow at basal flow) was 1.27 +/- 0.04 for the first, and 1.15 +/- 0.05 for the second period of increased flow (n = 10), indicating significant vasoconstriction (P < 0.01 and 0.05, respectively), present to a greater extent during the first period of increased flow compared to the second (P < 0.05). ATP release was seen in response to increased flow (n = 8, P < 0.05). From 12 ovarian bed preparations, five released ET and SP and three of these released AVP. Four of the five perfused ovaries that released peptides contained either a developing follicle or a corpus luteum while all those that showed no peptide release were inactive. CONCLUSIONS: ATP release may play a role in the local control of the human premenopausal ovarian vasculature independent of ovulatory status. Peptides may also contribute to local vascular control in the ovary and their release from predominantly active ovaries suggests a relationship between ovulation and vascular endothelial function.

Adenosine Triphosphate↗
PubMed1992

Superoxide dismutase and allopurinol prevent the pressor effects of angiotensin II and histamine in the guinea-pig isolated perfused lung exposed to hypoxia.

1. In the guinea-pig isolated perfused lung exposed to hypoxia by infusing N2-gassed Krebs solution, angiotensin II and histamine produced a reduced vasoconstrictor response when compared with the responses obtained in nonhypoxic lung. 2. These reduced vasoconstrictor responses were prevented by prior addition of superoxide dismutase or allopurinol to the medium. 3. These results were taken as evidence for the initiation of the cascade free radical formation in the guinea-pig lung during hypoxia and the primary role of the released intracellular xanthine oxidase. 4. Possible mechanisms of the reduced responses to angiotensin II and histamine and tissue protective activities of allopurinol and superoxide dismutase are discussed.

Allopurinol↗
PubMed2002

Inhibitory effect of nociceptin on somatostatin secretion of the isolated perfused rat stomach.

The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) has recently been isolated from porcine and rat brain and identified as the endogenous ligand of the N/OFQ receptor (NOP). It shows structural similarity with opioid peptides. N/OFQ has also been demonstrated in the gastrointestinal tract, where it inhibits gastrointestinal motility. The effect of N/OFQ on gastric neuroendocrine function is unknown as yet. In the isolated perfused rat stomach, N/OFQ 10(-6) M shows a small, but not significant decrease of basal somatostatin (SRIF) secretion. At the doses of 10(-12) M, 10(-10) and 10(-8) M N/OFQ has neither an effect on basal SRIF nor on basal vasoactive intestinal polypeptide (VIP), gastrin, substance P or bombesin secretion, respectively. However, gastric inhibitory polypeptide (GIP) 10(-9) M prestimulated SRIF secretion is significantly inhibited by N/OFQ 10(-8) M (-45+/-11%; p<0.05 vs. GIP). During concomitant infusion of the specific competitive NOP receptor antagonist [Nphe(1)]nociceptin(1-13)NH(2) 10(-6) M, the effect of N/OFQ is abolished (6+/-11%; p<0.05 vs. GIP and N/OFQ) while the opiate receptor antagonist naloxone 10(-6) M has no significant effect (-32+/-9%; ns vs. GIP and N/OFQ). At the higher concentration of N/OFQ 10(-6) M, the inhibition of prestimulated SRIF secretion (-58+/-6%; p<0.05 vs. GIP) is not influenced by the NOP receptor antagonist at the concentration of 10(-6) M (-49+/-9%; ns vs. GIP and N/OFQ) and 10(-5) M (-69+/-10%; ns vs. GIP and N/OFQ), respectively. On the other hand, infusion of naloxone 10(-6) M attenuates the inhibitory effect of N/OFQ 10(-6) M significantly (-21+/-6%; p<0.05 vs. GIP and N/OFQ).Thus, N/OFQ is an inhibitor of gastric somatostatin secretion. At the lower dose, this effect is transmitted via NOP receptors, while at the higher dose of 10(-6) M, the effect is at least in part mediated via opiate receptors.

Animals↗
PubMedDate not supplied

The elimination of aged glycoproteins by the isolated perfused rat liver.

The isolated livers of Sprague-Dawley rats aged ten months were perfused with nine different glycoproteins (coeruloplasmine, haptoglobin, transferrin, alpha2-mocroglobulin, apolipoprotein A, plasminogen, acid alpha1-glycoprotein, alpha1-antitrypsin, beta2-glycoprotein), which were suspended in a basic medium free of hemoglobin and other proteins. Besides a control group two other groups were formed to give a model for aging: one group of glycoproteins was desialysed, another was desilysed and incubated with immunoglobulins before the perfusion. In spite of the application of two procedures which are supposed to produce a model of old glycoproteins, neither treatment resulted in the recognition, binding and elimination of the glycoproteins from the perfusion medium.

Journal Article↗
PubMed1972

Carbohydrate metabolism in the isolated perfused rat kidney.

1. Anaerobic formation of lactate from glucose by isolated perfused rat kidney (411mumol/h per g dry wt.) was three times as fast as in aerobic conditions (138mumol/h per g). 2. In aerobic or in anaerobic conditions, the ratio of lactate production to glucose utilization was about 2. 3. Starvation or acidosis caused a decline of about 30% in the rate of aerobic glycolysis. 4. The rate of formation of glucose from lactate by perfused kidney from a well-fed rat, in the presence of 5mm-acetoacetate (83mumol/h per g dry wt.), was of the same order as the rate of aerobic glycolysis. 5. During perfusion with physiological concentrations of glucose (5mm) and lactate (2mm) there were negligible changes in the concentration of either substrate. 6. Comparison of kidneys perfused with lactate, from well-fed or starved rats, showed no major differences in contents of intermediates of gluconeogenesis. 7. The tissue concentrations of hexose monophosphates and C(3) phosphorylated glycolytic intermediates (except triose phosphate) were decreased in anaerobic conditions. 8. Aerobic metabolism of fructose by perfused kidney was rapid: the rate of glucose formation was 726mumol/h per g dry wt. and of lactate formation 168mumol/h per g (dry wt.). Glycerol and d-glyceraldehyde were also released into the medium. 9. Aerobically, fructose generated high concentrations of glycolytic intermediates. 10. Anaerobic production of lactate from fructose (74mumol/h per g dry wt.) was slower than the aerobic rate. 11. In both anaerobic and aerobic conditions the ratio [lactate]/[pyruvate] in kidney or medium was lower during perfusion with fructose than with glucose. 12. These results are discussed in terms of the regulation of renal carbohydrate metabolism.

Acetoacetates↗
PubMed1988

31P nuclear magnetic resonance study of steady-state adenosine 5'-triphosphate levels during graded hypoxia in the isolated perfused rat kidney.

1. A model of controlled hypoxia in the isolated perfused rat kidney has been used to compare the extent of reduction in the steady-state level of adenosine 5'-triphosphate (ATP) from that initially observed with alterations in renal function and with the development of tubular cell injury. 2. ATP depletion was observed in response to decreased total oxygen delivery even when delivery greatly exceeded consumption and the venous oxygen tension remained in excess of 150 mmHg. 3. Increases in the fractional excretion of sodium occurred progressively below an apparent threshold value of whole kidney ATP of approximately 80% of the baseline. 4. With modestly decreased oxygen delivery, cellular injury was confined to deep proximal tubule and medullary thick ascending limb of Henle's loop. Severely decreased oxygen delivery rates were associated with cellular damage spreading throughout the cortex. 5. Even the smallest reductions in whole kidney ATP were associated with morphological damage to tubular cells. The extent of reduction in whole kidney ATP was closely correlated and approximately equivalent to the calculated volume of injured cells. 6. Our results indicate that reduction in whole kidney ATP during decreased oxygen delivery is a valid marker of the extent of injurious cellular hypoxia and are consistent with the view that cellular ATP concentrations in hypoxia are markedly inhomogeneous. They support the hypothesis that specific regions of the perfused kidney become critically hypoxic and develop cellular injury while overall oxygen delivery remains high. Areas at risk include deep proximal tubule as well as the medullary thick ascending limb of Henle's loop.

Adenosine Triphosphate↗