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PubMed1982

The role of ischemia in acute pancreatitis: studies with an isolated perfused canine pancreas.

Recent clinical studies have suggested that ischemia may be an important factor in the pathogenesis of acute pancreatitis. The effects of ischemia on the pancreas were investigated utilizing the isolated perfused canine pancreas. Six control glands were perfused with autologous blood with an arterial Po2 ranging from 250 to 350 mm Hg. During the 4-hour perfusion period, gross appearance remained normal, weight gain was minimal (7 gm), and mean amylase levels (853 Caraway units [CU]/dl) remained within normal limits (less than or equal to 1,000 CU/dl). Lowering the arterial Po2 (range 30 to 60 mm Hg) in six glands while maintaining the flow at control levels elicited no significant change. Similarly, decreasing the flow (25% of control) with the arterial Po2 at 250 to 350 mm Hg produced no significant change in gross appearance, weight gain, or mean amylase levels. Combining low flow and low arterial Po2 in six glands also elicited no significant change as compared with controls. Four glands were subjected to total ischemia for 1 hour before being perfused. The glands became hyperemic, but mean weight gain (13 gm) and mean amylase levels (740 CU/dl) wee similar to those of controls. In contrast, in six glands subjected to total ischemia for 2 hours gross edema developed during the subsequent 4-hour perfusion. Mean weight gain (52 gm) and mean amylase levels (1,825 CU/dl) were significantly higher than in controls. These experimental data demonstrate that in the isolated perfused canine pancreas severe ischemia can produced significant injury. They therefore support the hypothesis that ischemia can clinically initiate acute pancreatitis.

Acute Disease↗
PubMed1999

Function of the isolated perfused kidneys from young or adult rats with post-DOCA-salt hypertension.

The function of isolated perfused kidneys in post-DOCA phase of DOCA-salt hypertension was evaluated in rats subjected to DOCA-salt treatment either from youth or only in adulthood. Post-DOCA-salt hypertension was more severe in young than in adult animals. Kidneys isolated from young post-DOCA-salt hypertensive rats had higher renal vascular resistance when compared to adult ones. Perfusion of isolated kidneys over a wide range of perfusion pressure (110-170 mm Hg) has shown similar decrease of glomerular filtration, filtration fraction, diuresis and natriuresis in both age groups of DOCA-salt treated groups. Perfusion pressure-sodium excretion curves had reduced slope and were shifted to the right in both hypertensive groups, indicating huge glomerular damage. Nevertheless, the relative difference in glomerular filtration and sodium excretion between hypertensive rats and age-matched normotensive controls was always greater in younger animals. These results suggest that the more pronounced changes in glomerular hemodynamics and filtration could be involved in higher blood pressure-response of young animals to DOCA-salt treatment.

Aging↗
PubMed1978

Studies on the effect of tobacco smoke on the biotransformation of vasoactive substances in the isolated perfused rabbit lung. II. Angiotensin I conversion.

Cigarette smoke administration was previously found to have a pronounced inhibitory effect on metabolism of nicotine and benzo[a]pyrene in the isolated perfused rabbit lung. These observations suggest the possibility of tobacco smoke inhibition of biotransformations associated with non-ventilatory pulmonary functions such as the biotransformation of endogenous vasoactive substances. However, the present study provides no evidence of an effect of smoke on the conversion of angiotensin I to angiotensin II in the isolated perfused rabbit lung.

Angiotensin I↗
PubMed1984

Functional and metabolic effects of cardioplegia induced by a young's solution (YNG solution) as assessed in isolated atrial preparations and in isolated perfused heart preparations of the guinea pig.

p6e protective effects of Young's solution (YNG solution), a cardioplegic solution, on the myocardial function and metabolism were assessed in isolated atrial preparations and isolated perfused heart preparations of the guinea pig. In atrial preparations, the time to arrest of the contraction became shorter as the concentrations of the K+, Mg++, and K+-Mg++ solutions increased, while the time to resumption of the contraction was lengthened. There was no difference in the time to arrest between K+ and K+-Mg++ solutions, but the time to resumption was reduced with K+-Mg++ solution to about half the value with K+ solution. YNG solution represented an optimum solution for obtaining a quick cardiac arrest and quick resumption of contraction. In the isolated perfused heart, the time to arrest was similar for all the cardioplegic solutions used and the heart stopped in diastole. However, the time to arrest was longer with cold Krebs-Henseleit's solution (cold cardioplegia). The time to resumption of the contraction was the shortest with YNG solution, which yielded the highest mitochondrial respiratory control ratio (RCR) and ADP/O ratio. There was a negative correlation between the time to resumption of contraction and mitochondrial RCR or ADP/O ratio (r = -0.50 and -0.58, respectively).

Animals↗
PubMed1985

Inactivation of rabbit pulmonary cytochrome P-450 in microsomes and isolated perfused lungs by the suicide substrate 1-aminobenzotriazole.

The autocatalytic destruction of pulmonary cytochrome P-450 (P-450) by 1-aminobenzotriazole (ABT) was investigated in microsomes and in isolated perfused lungs from untreated and beta-naphthoflavone-induced rabbits. Microsomal benzphetamine N-demethylase (BND) and 7-ethoxyresorufin O-deethylation (ERF) activities, catalyzed by P-450 isozymes 2 and 6, respectively, and specific P-450 content were determined after incubation with ABT. In vitro destruction of P-450 was dependent on ABT concentration and required NADPH. Significant losses of BND and ERF activities were observed only at ABT concentrations above 10 microM. Percent losses of BND and ERF activities equaled those of total P-450 at 1 mM and surpassed them at 10 mM. The time and concentration dependence of the destruction of P-450 by ABT was investigated in isolated perfused rabbit lungs. The percent loss of total P-450 increased with increasing ABT concentration (18 +/- 8% loss at 1 microM to 85 +/- 4% at 10 mM). Although extensive losses of P-450 occurred after perfusion with 10 mM ABT for 60 min, no ABT-dependent losses of flavin-containing monooxygenase activity were observed under these conditions. Percent losses of BND activity in these experiments were similar to those of total P-450 at 1 and 10 mM ABT but were less than P-450 losses at 0.01 and 0.1 mM ABT. Losses of ERF activity in lungs from beta-naphthoflavone-pretreated animals were also substantial and dependent upon perfusion time. Perfusion with 1 mM ABT for 2 to 60 min resulted in time-dependent losses of P-450 (42.8 +/- 7.2% at 2 min to 70.5 +/- 2.5% at 60 min) with equal or somewhat lesser diminishment of BND and ERF activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Cardioprotective profile of MET-88, an inhibitor of carnitine synthesis, and insulin during hypoxia in isolated perfused rat hearts.

3-(2,2,2-trimethylhydrazinium) propionate (MET-88) is an inhibitor of carnitine synthesis. This study was carried out to investigate whether or not reduction of carnitine content could attenuate hypoxic damage in isolated perfused rat hearts. Rats were divided into four groups: 1) vehicle control; 2) pretreatment with MET-88 (MET-88); 3) application of insulin (500 muU/mL) in the perfusate (insulin); and 4) pretreatment with MET-88 and application of insulin (MET-88 + insulin). MET-88 (100 mg/kg) was orally administered once a day for 10 days until the day before the experiments. Hearts were initially perfused for a 10 min period under normoxia, followed by a 30 min period under hypoxia. Hearts were frozen at the end of hypoxia for the measurement of high-energy phosphates, carnitine derivatives, and glycolysis intermediates. In a separate series of untreated and MET-88 treated hearts, exogenous glucose and palmitate oxidation was measured. MET-88 decreased the extent of the depression of cardiac contractility (+dP/dt), and aortic flow during the hypoxic state. Insulin also improved cardiac function, and co-treatment of MET-88 and insulin additionally improved cardiac function during hypoxia. MET-88 prevented the decrease of high-energy phosphate and the increase of long-chain acylcarnitine after 30 min of hypoxic perfusion. In addition, MET-88 increased the steady state of glucose oxidation in hypoxic perfused rat hearts. These results indicate that MET-88 has cardioprotective effects on contractile function and energy metabolism of isolated perfused rat hearts in a hypoxic condition. Preventing the accumulation of long-chain acylcarnitine may serve to protect hypoxic hearts.

Administration, Oral↗
PubMed1979

THe formation of cytochrome P-450-metabolic intermediate complexes from amines, in the isolated perfused rat liver.

1. Cytochrome P-450-metabolic intermediate (MI) complexes were formed from SKF 525-A, propoxyphene, acetylmethadol, noracetylmethadol, norbenzphetamine, and N-hydroxyamphetamine, but not methadone, in the isolated perfused rat liver. 2. The amount of MI complex from SKF 525-A (8% of the cytochrome P-450) after 1 h exceeded that for all other compounds (1--2%). 3. Both MI complex and residual substrate contributed to the inhibition of mixed-function oxidase activity observed. No substrate altered the total cytochrome P-450 concentration of NADPH-cytochrome c reductase activity. 4. The formation of MI complexes in isolated perfused liver corresponds to that seen in whole animals, and contrasts with that seen in microsomal preparations.

Amines↗
PubMedDate not supplied

Taurochenodeoxycholic acid induced biphasic hepatotoxicity in isolated perfused rat liver: roles of Ca2+ and calpain.

BACKGROUND/AIMS: We examined taurochenodeoxycholic acid-induced hepatotoxicity with reference to Ca2+ and calpain involvement, intracellular bile acid content, and zone specificity in isolated perfused rat liver. METHODOLOGY: Taurochenodeoxycholic acid or chenodeoxycholic acid was infused into the portal vein and lactate dehydrogenase release, a marker of hepatocyte injury, in the effluent and bile acid output were measured in the presence and absence of either nickel, a membranous Ca2+ channel blocker, or calpain inhibitor in isolated perfused rat liver. RESULTS: Taurochenodeoxycholic acid induced a significant and transient increase (first peak; 4 min) and subsequent time- and dose-dependent elevation in lactate dehydrogenase release which was proportional to accumulated bile acids in the liver. Although the first peak was significantly suppressed by pretreatment with nickel, the subsequent release was not reduced. Lactate dehydrogenase release at 15, 20, and 25 min was significantly suppressed by the calpain inhibitor. Numbers of damaged hepatocytes stained with trypan blue were significantly increased in the periportal region (zone 1) compared with the pericentral region (zone 3) and these cells were consistently stained with anti-calpain antibody. CONCLUSIONS: Taurochenodeoxycholic acid causes both transient damage and subsequent increasing hepatotoxicity which are respectively dependent on Ca2+ influx via membranous Ca2+ channels and calpain, with the periportal region being more susceptible.

Animals↗
PubMed1980

Regulation of hepatic phosphoenolpyruvate carboxykinase (GTP). Role of dietary proteins and amino acids in vivo and in the isolated perfused rat liver.

The effect of protein feeding and the addition of amino acids on the activity of hepatic phosphoenolpyruvate carboxykinase (GTP : oxalacetate carboxylyase (transphosphorylating), EC 4.1.1.32) was investigated in vivo and in the isolated perfused rat liver. Protein feeding resulted in a considerable increase in phosphoenolpyruvate carboxykinase activity within 6 h. This rise was independent of the presence of glucocorticoids. In the isolated perfused liver system amino acids per se had a small effect on phosphoenolpyruvate carboxykinase activity and led to an increase by 20% when glucocorticoids were present, but resulted in a rise by 100% when glucocorticoids plus dibutyryl cyclic AMP were added to the perfusion medium. The effect of amino acids in the presence of dibutyryl cyclic AMP could also be observed in the liver of glucocorticoid-deprived rats. Cycloheximide, a translational inhibitor, totally blocked all effects of amino acids on enzyme activity. These results indicate that the concentration of amino acids in the portal vein modify the regulation of phosphoenolpyruvate carboxykinase by cyclic AMP.

Amino Acids↗
PubMed1995

Pulmonary toxicity of alpha tumor necrosis factor in patients treated by isolation perfusion.

We studied pulmonary function in 22 patients affected by in-transit metastases from cutaneous melanoma and metastases from soft tissue sarcoma of the limbs who were treated with isolation perfusion in extracorporeal circulation with rTNF alpha at doses ranging from 0.5 to 4 mg/m2 in mild hyperthermia. Seventeen patients suffered from respiratory insufficiency which required assisted ventilation (7 mechanical ventilation for 1 day, 8 for 2 days and 2 patients on synchronized intermittent mandatory ventilation). Spirometric parameters recorded 7 to 15 days after treatment did not change from baseline values; in contrast, lung transfer factor for carbon monoxide significantly declined in a dose dependent fashion. These data confirm that rTNF alpha administered by isolation perfusion technique induces pulmonary side effects. Further studies are required to better define time course and reversibility of impairment in pulmonary function.

Adult↗
PubMed1991

Factors affecting inorganic mercury transport and toxicity in the isolated perfused proximal tubule.

The effects of cysteine (80 microM), glutathione (80 microM), rabbit albumin (100 microM), and an ultrafiltrate of rabbit plasma on the toxicity and transport of inorganic mercury (Hg2+; 18.4 microM) in isolated perfused S1, S2, and S3 segments of the renal proximal tubule from the rabbit were studied. Cellular and tubular injuries were assessed qualitatively by light microscopy observations and quantitatively by the tubular leak of the volume marker 3H-glucose. The lumen-to-bath transport of inorganic mercury was assessed by measuring both the rate of disappearance of inorganic mercury from the luminal fluid and the rate of appearance of inorganic mercury in the bath. When glutathione was added to the perfusate containing the inorganic mercury, no signs of epithelial cell necrosis or injury were detected in any of the three segments of the proximal tubule. There was also an absence of or a decrease in cellular injury in the epithelium of the same tubular segments when either cysteine or the ultrafiltrate was present in the perfusate. However, when rabbit albumin and inorganic mercury were present in the perfusate, severe degenerative and necrotic changes occurred very rapidly in the epithelium of all three segments of the proximal tubule. In almost every instance where glutathione, cysteine, or the plasma ultrafiltrate were present in the perfusate, the disappearance flux of inorganic mercury from the tubular lumen into the tubular epithelium was lowered. It was concluded that glutathione, cysteine, and the ultrafiltrate of rabbit plasma provide isolated perfused S1, S2, and S3 segments of the proximal tubule varying degrees of protection from the toxic effects of inorganic mercury. This protection appears to be related to a decrease in the movement of inorganic mercury across the luminal membrane of the tubular epithelial cells.

Albumins↗
PubMed1979

Effects of chlorpromazine and some of its metabolites on the EEG and on dopamine metabolism of the isolated perfused rat brain.

The study concerned the effects of chlorpromazine (CPZ), monodesmethyl-chlorpromazine (NOR1-CPZ), didesmethyl-chlorpromazine (NOR2-CPZ), and chlorpromazine-N-oxide (CPZ-NO) on the EEG and on dopamine metabolism of the isolated perfused rat brain. Isolated brains were perfused with 100 ml of a perfusion medium containing 30% bovine red cells (v/v), 2 g bovine serum albumin, 14 mM glucose as well as one of the agents in a concentration of 10 micrometers. The main dopamine metabolite homovanillic acid (HVA) was measured fluorimetrically in the striatum of the isolated brain. The EEG was recorded by two symmetrical bipolar leads from the parietal regions at various times during the 30 min perfusion period and was stored on magnetic tape. The recordings were evaluated visually and quantitatively by automatic analysis. CPZ-NO was found to be the most active agent both in changing the EEG and in elevating the HVA level in the striatum. The mean EEG amplitude and the slow wave activity increased significantly. The increase of the HVA level in the striatum was correlated with the increase of delta waves as well as excess of kurtosis and skewness calculated from the amplitude histography data. The desmethylated metabolites caused only moderate central effects.

Animals↗
PubMed1980

The effect of in situ isolated perfusion of experimental renal tumors with cytotoxic agents in high concentration.

In animal experiments the possibility of increasing the dosage of anticancer drugs by isolated in situ tumor perfusion without incurring systemic toxicity was studied. Isolated perfusion of normal kidneys with tris-ethylenimino-benzochinon (triaziquon, Trenimon) and amethopterin (Methotrexate) demonstrated that the kidney tolerates far higher antitumor drug concentrations than are achieved by systemic anticancer chemotherapy. Renal function, which was evaluated before and after cytotoxic perfusion by means of renal functional scintigraphy, decreased by less than 15%. Each kidney was examined histologically after perfusion. Isolated cytotoxic perfusion of renal tumors (Walker carcinosarcoma 256) using the combination of Trenimon (0.034 microgram/ml) and Methotrexate (0.034 mg/ml) led to complete tumor regression. Tumor perfusion without cytotoxic agents and systemic intravenous administration of the LD50 of the anticancer drugs did not achieve tumor control.

Animals↗
PubMed1994

Lidocaine extraction by the in vivo and isolated perfused pig liver.

Hepatic lidocaine elimination is increasingly being used to assess hepatic function. Although the isolated liver is extensively used as a model of in vivo function, it is necessary to determine whether this is a suitable model for in vivo lidocaine elimination. Fourteen male pigs (22-25 kg) were divided into two groups. Seven were anesthetized, and catheters and perivascular flow probes placed for transhepatic sampling and hepatic arterial and portal venous flow measurement. Sampling was performed at hourly intervals to determine hepatic function and plasma composition. Hepatic lidocaine elimination was determined during the second hour of a lidocaine infusion (1.41 mg.kg-1.min-1 for 10 min, then 0.165 m.kg-1.min-1), during which time the mean hepatic blood flow rates, plasma acid base status and body temperature were measured so that these could be emulated in the isolated perfused liver experiments. Seven male pigs were then anesthetized and the liver resected and cannulated for isolated liver perfusion. Hepatic arterial and portal venous blood flow and perfusate temperature were set to the mean in vivo values, and hepatic function and perfusate composition assessed at corresponding times. Hepatic lidocaine elimination was determined at a similar hepatic inflow whole blood concentration (+/- 5 micrograms.ml-1) to that in vivo over the second hour of lidocaine administration (40 mg bolus, then 2.8 mg.min-1). Lidocaine extraction ratio in vivo (0.61 +/- 0.04) [mean +/- SEM] and ex vivo (0.63 +/- 0.02) was similar, as was hepatic blood clearance (381 +/- 70 vs 363 +/- 16 ml.min-1) and hepatic blood intrinsic clearance (1132 +/- 280 vs 1069 +/- 109 ml.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1995

Metabolism and elimination of 5,6-dimethylxanthenone-4-acetic acid in the isolated perfused rat liver.

5,6-Dimethylxanthenone-4-acetic acid (DXAA) is a synthetic xanthenone derivative that is active against murine solid tumors and is being formulated for clinical trials. This study used the isolated perfused rat liver to compare the hepatic metabolism and biliary excretion of DXAA with flavone-8-acetic acid (FAA), a synthetic flavonoid undergoing clinical evaluation as an anticancer drug. Perfusate, bile, and liver samples were assayed for parent drug and metabolites by HPLC. Three FAA metabolites were present in bile, and one of these coeluted with FAA acyl glucuronide. Alkaline hydrolysis of high-dose DXAA bile samples resulted in the disappearance of 5 of 7 metabolite peaks. One biliary metabolite was identified by mass spectrometry as the acyl glucuronide and its presence in bile accounted for > 50% of the DXAA dose. A second compound that was resistant to alkaline hydrolysis was characterized as a hydroxylated DXAA metabolite. A total of 28% of the high dose DXAA was recovered unchanged in the perfusate, liver, and bile, compared with 11% of the low dose DXAA and 40% of the FAA dose. Protein binding of DXAA in perfusate was saturable, ranging from 94.5% at 112 microM to 72.4% at 1125 microM, whereas binding in human plasma was > 99% at concentrations between 11.5 and 1243 microM. This study demonstrates that DXAA undergoes extensive acyl glucuronidation followed by biliary excretion in the isolated perfused rat liver. Its hepatic metabolism may be saturable, and DXAA seems to be more extensively metabolized than FAA. Finally, DXAA protein binding in human plasma is high and not dose-dependent at concentrations likely to be clinically relevant.

Animals↗
PubMed1995

Characterization of alpha 1-adrenoceptors mediating vasoconstriction to noradrenaline and nerve stimulation in the isolated perfused mesentery of rat.

1. The objective of this study was to investigate the alpha 1-adrenoceptor subtype(s) mediating vasoconstrictor responses to perfused and neuronally-released noradrenaline (NA) in the isolated perfused mesentery preparation of rat. 2. Isolated mesenteric preparations (with gut attached) from male Sprague Dawley rats (250-300g) were perfused via the superior mesenteric artery with oxygenated Krebs solution at approximately 6 ml min-1. The effects of antagonists on vasoconstrictor responses to either perfused (+/-)-NA or periarterial nerve stimulation (70 V, 2 ms pulse width, 10 s train) were determined. 3. Vasoconstrictor responses to perfused NA were antagonized by prazosin (pA2 = 9.3 +/- 0.1), WB4101 (pA2 = 9.6 +/- 0.1), 5-methyl urapidil (5-MU: pA2 = 9.0 +/- 0.1), (+)-niguldipine (insurmountable) and spiperone (pA2 = 7.7 +/- 0.1). The insurmountable nature of the antagonism by (+)-niguldipine (0.1 nM) was greatly reduced by co-perfusion with prazosin (10 nM). Chloroethylclonidine (CEC: 100 microM for 20 min, followed by 40 min washout) caused an approximate twofold increase in the EC50 for (+/-)-NA and reduced the maximum response by approximately 25%. Pre-treatment of tissues with CEC (100 microM as above) did not significantly alter affinity estimates for prazosin (pA2 = 9.2 +/- 0.1), WB4101 (pA2 = 9.3 +/- 0.1) or 5-MU (pA2 = 8.7 +/- 0.2). Vasoconstrictor responses to periarterial nerve stimulation were antagonized by WB4101 > 5-MU > prazosin >> spiperone. CEC (100 microM as above) reduced nerve-stimulated responses by approximately 50%. 4. The affinity estimates for the various antagonists studied suggest that vasoconstrictor responses to both exogenous and neuronally-released NA are mediated via the same a,-adrenoceptor subtype. The pharmacological profile most resembles the 'classical' alpha l A-adrenoceptor, which, in turn, appears to be a rat homologue of the cloned bovine alpha lc-adrenoceptor.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1981

Effects of porcine secretin on exocrine and endocrine function in the isolated perfused rat pancreas.

The effects of both synthetic and pure natural porcine secretin on immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) release and on pancreatic exocrine secretion were studied in the isolated perfused rat pancreas. Synthetic porcine secretin stimulated a significant increase in pancreatic juice flow and amylase output at concentrations as low as 0.01 and 0.1 ng/ml, respectively. The maximal peak rate of both juice flow and amylase output was observed at 1 microgram/ml synthetic secretin. Synthetic secretin at concentrations up to 2 micrograms/ml and pure natural porcine secretin at a concentration of 1 clinical unit/ml had no effect on IRI secretion regardless of the glucose concentration (50, 100, or 150 mg/100 ml) in the perfusate. Both types of secretin, however, elicited a concentration-dependent increase in IRG secretion in the presence of 50 mg/100 ml glucose. The lowest synthetic secretin concentration causing a significant increase in IRG release was 0.1 ng/ml, and maximal stimulation was observed at 1 microgram/ml. These concentrations were similar to those eliciting minimal and maximal amylase release. Thus, synthetic and pure natural porcine secretin have been shown to not only stimulate pancreatic juice flow and amylase secretion but also to elicit IRG release from the isolated perfused rat pancreas.

Amylases↗