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PubMed1996

Neuronal damage after hypothermic circulatory arrest and retrograde cerebral perfusion in the pig.

BACKGROUND: Antegrade and retrograde cerebral perfusion during hypothermic circulatory arrest (HCA) has been reported to provide better brain protection during operation than hypothermic circulatory arrest alone. However, the efficacy of these techniques remains to be fully determined, especially when used for prolonged periods. We used a pig model to evaluate the histopathologic consequences of HCA and the potential benefit of cerebral perfusion during HCA. METHODS: Twenty-two pigs were divided into four groups and exposed to either anesthesia alone, 120 minutes of HCA (15 degrees C), 120 minutes of retrograde cerebral perfusion at 15 degrees C during HCA, or 120 minutes of antegrade cerebral perfusion at 15 degrees C during HCA, and then reperfused for 60 minutes under cardiopulmonary bypass at 37 degrees C. The brains were perfusion fixed at the end of the experiments and examined by light microscopy. RESULTS: There were no morphologic changes in any areas of the brains in the anesthesia group, and very minor changes in some areas of the brains in the antegrade cerebral perfusion. group. Varying severity of neuronal damage was found in the brains of all the pigs in the HCA and retrograde cerebral perfusion groups. The severity of ischemic damage in the brain showed the following descending order: hippocampus (CA4), caudate nucleus, cerebral cortex, putamen, thalamus, Purkinje cells of the cerebellum, pons, and mesencephalic gray matter. In the hippocampus the order of damage was CA4, CA3, polymorphous layer of the dentate gyrus, prosubiculum, CA2, CA1, and granule cell layer of the dentate gyrus. The damage in the retrograde cerebral perfusion group was less severe relative to the HCA group in many areas (no significance except mesencephalic gray matter). CONCLUSIONS: These results demonstrate that the pattern of neuronal damage in pigs subjected to HCA and retrograde cerebral perfusion differs from the traditional pattern in that the caudate nucleus and hippocampal CA4 region are the most vulnerable to ischemia-hypoxia. Our results also suggest that antegrade cerebral perfusion prevented ischemic damage to the brain and retrograde cerebral perfusion provided some protection but moderately severe damage occurred.

Animals↗

PubMed1988

Uptake, metabolism and release of carnitine and acylcarnitines in the perfused rat liver.

The uptake and release of carnitine and isovalerylcarnitine have been studied in the perfused rat liver. Labelled carnitine accumulates in rat livers perfused with 50 or 500 microM [3H]carnitine. When alpha-ketoisocaproate (5 mM) is added to the perfusate after 30 min of perfusion, the net uptake of carnitine in the liver stops, and there is even a decrease in liver radioactivity. The decrease in liver carnitine can be attributed to an enhanced formation and efflux to the perfusate of short-chain acylcarnitines. Thin-layer chromatography of liver and perfusate extracts showed that efflux rates for branched-chain acylcarnitines (isovalerylcarnitine) formed are at least 2.5-fold the efflux rate for carnitine. Acetylcarnitine is released about twice as fast as carnitine from the liver. Perfusion with 50 microM [3H]isovalerylcarnitine showed that the influx rate of isovalerylcarnitine exceeds that of carnitine 1.5-fold. Since the efflux rate is still higher, a net loss of carnitine from the liver to the perfusate will result when branched-chain acylcarnitines are formed in the perfused liver. The addition of 500 microM unlabelled carnitine to the perfusate does not influence the release of labelled carnitine or acylcarnitines from the liver, showing that uptake and release are independent processes. Isovalerylcarnitine accumulates faster than carnitine does, also in the perfused rat heart. A mechanism for the development of secondary carnitine deficiencies associated with organic acidemia is proposed.

Acylation↗

PubMed1983

Acinar heterogeneity in hepatic transport of dibromosulfophthalein and ouabain studied by autoradiography, normal and retrograde perfusions and computer simulation.

This study is aimed to investigate the relative involvement of periportal (zone 1) and perivenous (zone 3) hepatocytes in the uptake and biliary excretion of the organic anion dibromosulfophthalein (DBSP) and the uncharged cardiac-glycoside ouabain. The localization in the acinus of [35S]BSP (sulfobromophthalein, the tetra-bromo-analogue of DBSP) and [3H]ouabain administered to livers perfused with normal and retrograde flow, was detected by autoradiography. The plasma disappearance and biliary excretion rates of DBSP and [3H]ouabain were determined in normal and retrograde perfusions. In addition, computer simulations were performed to predict the effect of reversal of the perfusate flow on the plasma disappearance and biliary excretion rate curves and on the concentration of label in zones 1 and 3. Autoradiography showed that 2 and 10 min after injection of [35S]BSP to normally and retrogradely perfused livers, the label was uniformly distributed in the liver acinus. The same results were found 30 sec and 10 min after injection of [3H]ouabain to normally and retrogradely perfused livers. The plasma disappearance and biliary excretion rate of DBSP were slightly faster in retrograde perfusions compared to normal perfusions both with and without a basal bile salt infusion of 15 mumole/hr. This could not be explained by an acinar heterogeneity with respect to any of the DBSP transport steps (plasma to liver, liver to plasma, liver to bile) as was shown by computer simulations. The plasma disappearance and biliary excretion rate of ouabain were similar in normal and retrograde perfusions. It is concluded that periportal and perivenous hepatocytes are equally involved in the uptake of (D)BSP and ouabain from the medium. However, due to the particular distribution patterns no conclusions can be drawn from normal and retrograde perfusions about the relative involvement of these cells in biliary excretion, as was shown by computer simulation. The unaffected kinetic behaviour of the retrogradely perfused livers indicated that no liver damage occurs during retrograde perfusion with respect to transport function.

Animals↗

PubMed1976

Functional preservation of the mammalian kidney. IV. Functional effects of perfusion with dimethyl sulfoxide (DMSO) at normothermia.

Rabbit kidney were perfused at 37degreesC with various concentrations of DMSO in a K+-Mg2+-rich perfusate. The effects of DMSO on various functional parameters of the rabbit kidney perfused for 60 min were compared with the functional effects of perfusion without DMSO under the same conditions. DMSO produced deviations in vascular resistance and perfusate flow rate from control values. In kidneys perfused with 1.4 and 2.8 M DMSO these vascular changes resulted in changes in GFR at relatively unchanged filtration fractions. The closely parallel relationship between changes in GFR and urine flow in all groups indicates that perfusion per se or perfusion with DMSO may shift the regulation of urine flow rate from tubular reabsorption, which obtains in the in vivo situation, to glomerular filtration. This view was supported by the relatively unchanged parameters of Na+ reabsorption and fractional water excretion during perfusion with all concentrations of DMSO. Additionally, DMSO perfusion resulted in significantly greater weight gains than those observed in kidneys perfused without DMSO, and significantly depressed clearances of PAH, with 2.1 and 2.8 M DMSO.

Animals↗

PubMed1984

Comparison of the effect of 3- and 5-day hypothermic perfusion of dog kidneys on metabolism of tissue slices.

Hypothermic perfusion effectively preserves the viability of kidneys for 3 days. Long-term preservation (5 days or greater) has not been consistently obtained. In this study, the differences between kidneys perfused for 3 and 5 days were compared by determining the "integrated-metabolic" capabilities of tissue slices incubated in vitro at 30 degrees C. The "integrated-metabolic" parameters determined include (1) respiration rates, (2) cell volume regulation [total tissue water (TTW) and saccharide permeable space], (3) rate of reaccumulation of K+ and pumping of Na+, (4) maintenance of ATP concentrations, and (5) mitochondrial functions. Conditions that result in high and low concentrations of ATP following perfusion of kidneys for 5 days were also compared for effects on tissue slice metabolism. The results indicate that energy metabolism in tissue slices is well preserved under all conditions and times of perfusion of kidneys. This includes average respiration rates (315 +/- 50, 275 +/- 35, and 255 +/- 45 mumol O2/hr/g dry wt at 0, 3, and 5 days, respectively, mitochondrial function [respiratory control ratio (RCR) = 4.6, 4.0, and 4.1 for 0, 3, and 5 days, respectively], and steady-state concentration of ATP in slices after incubation (4.0 +/- 1.45, 3.9 +/- 1.28, and 3.3 +/- 0.81 mumol/g/dry wt, for 0, 3, and 5 days, respectively). The primary differences between 3- and 5-day perfused kidneys were the capability of the slices to regulate cell volume and reaccumulate K+. Slices from kidneys perfused for 3 days maintained the TTW at 3.8 kg/kg dry wt, a value similar to that of control tissue slices. However, slices from 5-day perfused kidneys remained swollen (TTW = 4.6 kg/kg dry wt). Also, slices from the 5-day perfused kidney pumped K+ at less than one-half the rate found in slices from control or 3-day preserved kidneys. No significant differences were apparent in the permeability properties of the tissue slices from kidneys perfused for 3 and 5 days to radiolabeled saccharides. The defects in membrane-linked transport functions, resulting from long-term kidney perfusion, were reduced in kidneys containing a high concentration of ATP. The results suggest that one factor which may limit successful preservation of kidneys is the increased membrane permeability (to electrolytes) which is partially prevented by maintaining elevated concentrations of tissue ATP during perfusion.

Adenosine Triphosphate↗

PubMed1988

Inhibition of human placental aromatase in a perfusion model. Comparison with kinetic, cell-free experiments.

In vitro perfusion of human placenta was evaluated for characterization of aromatase inhibitors. The results were compared with those in kinetic experiments in cell-free system. Inhibition constants (Ki) were determined by measuring the release of tritiated water during coincubation of human placenta microsomes with varying amounts of [1 beta,2 beta 3H]androstenedione and inhibitor in the presence of NADPH-generating system. Irreversible inactivation constants (Kinact) were determined in a similar manner following preincubation of the microsomes with different amounts of inhibitor for varying times. Lineweaver-Burk plots indicated a competitive type of inhibition with Ki values of 37 nM for 4-hydroxy-androstenedione, 3,700 nM for testolactone, 15 nM for 1-methyl-androsta-1,4-diene-3,17-dione, and 7.5 nM for 19-azido-androstenedione. Additionally, irreversible enzyme inactivation by all four substances could be demonstrated with Kinact values of 3.64 x 10(-3), 0.57 x 10(-3), 0.34 x 10(-3), and 0.69 x 10(-3)sec-1, respectively. Perfusion of a single cotyledon of human term placenta was performed by infusing medium through catheters placed in a fetal artery and in the maternal intervillous space. Perfused medium was collected from a cannulated fetal vein and from the maternal basal plate. The medium was supplemented with [3H]androstenedione (4.2 nM) and inhibitor. The perfusates were analyzed for their [3H]estrone and estradiol content following phenolic partition and Sephadex-LH 20 chromatography. The main results were, (1) the recovery of labelled steroids increased rapidly after perfusion started and reached a plateau within 60 min, when 55 and 30% (mean values) of the infused radioactivity were recovered in the fetal and maternal perfusates, respectively, (2) similar amounts of estrone and estradiol were found in both effluates, whereas androgens (mainly androstenedione and lower amounts of 5 alpha-androstane-3,17-dione) were found nearly exclusively in the fetal perfusate, (3) formation of estrogens (estrone + estradiol) reached a plateau within 20 min of perfusion. (4) The percentage of estrogens formed was not changed by increasing androstenedione concentration in the perfusion medium unless this concentration exceeded 3.5 microM indicating limited capacity of aromatase. (5) The four aromatase inhibitors reduced estrogen formation by 50% at concentrations about 100-fold of their Ki determined in the cell-free system, (6) irreversible aromatase inhibition could not be demonstrated in the perfusion model. It was concluded that the human placenta perfusion model can be successfully used to evaluate aromatase inhibitors.

Androstenedione↗

PubMed1994

Pretreatment of renal transplants with anti-CD45 antibodies: optimization of perfusion technique.

Pig kidneys were perfused ex vivo with a monoclonal anti-pig CD45 antibody to determine optimum conditions for human kidney anti-CD45 perfusion, as such pretreatment may prolong renal allograft survival. Efficacy of perfused antibody uptake was assessed by immunohistochemical double-labelling of multiple renal biopsies. Antibody uptake by CD45+ cells was rapid, and maximal within one hour of perfusion. An antibody concentration of 40 micrograms/ml more effectively saturated available CD45 binding sites than lower concentrations. Whilst cortical perfusion was homogeneous (median uptake > 99%, minimum 90.0%) after 25, 50 or 100 ml perfusion with 40 micrograms/ml monoclonal antibody (mAb), the medulla was less evenly perfused with 25 ml (median uptake 82.6%) than with 50 or 100 ml (median uptake 98.5% and 98.7%, respectively). Prolongation of renal cold ischaemia of up to 46 hours prior to mAb perfusion did not adversely affect antibody binding. Clamping of the renal vein during and after mAb perfusion was associated with better cortical and medullary mAb uptake than if the vein was left unclamped. These data show that the vast majority of the kidney's CD45+ antigen-presenting cells can be bound by anti-CD45 mAb perfused ex vivo, if an adequate volume and concentration of mAb perfusate is employed and the renal vein is clamped during and after the process.

Animals↗

PubMed2005

Confocal laser Doppler flowmeter measurements in a controlled flow environment in an isolated perfused eye.

The aim of this study was to improve our ability to interpret and validate Heidelberg Retina Flowmeter (HRF) flow images by recording flow measurements from specific regions of the retinal vasculature by taking advantage of the ability to precisely regulate perfusion flow in an isolated eye preparation. The retinal vasculature in 16 isolated perfused pig eyes was perfused with a 50%/50% Krebs/RBC solution at known flow rates ranging from 0 to 300 microl min(-1). At each flow rate, HRF images were obtained at a location approximately two disc diameters from the disc. After HRF image acquisition, the retinal vasculature was perfused with fluorescein isothiocyanate for fluorescence microscopy. Using the standard HRF software and a 10 x 10pixel measurement window, flow rates were measured from a retinal artery, vein, arteriole, venule, and the retinal capillary bed and a capillary-free-zone. The relationship between HRF measured flow and perfusion flow in the different measurement locations was determined. At zero perfusion flow the measured HRF flow was consistently greater than zero ( approximately 170 arbitrary units (AU)), and not significantly different at each measurement location except for the retinal vein, which had a significantly higher HRF flow value ( approximately 230AU). At higher perfusion flow rates the flow signal from the larger vascular elements (arteries and veins) increased rapidly thereafter to reach several thousand AU at a total perfusate flow of 50 microlmin(-1) and increased less rapidly at higher flow rates. In arterioles, the HRF flow was more linear over a broader range of perfusate flow rates but the peak flow signal was an order of magnitude smaller than that from the retinal artery. Both the linearity and magnitude of the flow signal in venules was less than that in arterioles. In capillary areas and in the capillary free zone, the HRF flow showed only a very weak relationship to perfusion flow when compared to the background noise. The choice of location for HRF flow analysis greatly influences the ability of the technique to measure changes in retinal blood flow. The major arteries and veins provide the strongest signal and greatest signal to noise ratio. However, the retinal arterioles produce an HRF signal that is more linear over a wider range of perfusate flow rates.

Animals↗

PubMed1995

Pharmacologic intervention for ischemic brain edema after retrograde cerebral perfusion.

Retrograde cerebral perfusion has recently been the focus of interest as a simple new technique of brain protection during aortic arch operations. We undertook the experimental protocol of 120 minutes of retrograde cerebral perfusion followed by antegrade reperfusion. Eighteen mongrel dogs were used. Retrograde cerebral perfusion was maintained at a flow rate of 150 to 250 ml/min to keep the perfusion pressure from 15 to 25 mm Hg. Animals were divided into three groups as follows: in group I, no treatment was received during and after retrograde cerebral perfusion; in group II, mannitol (2 gm/kg) was administered before cardiopulmonary bypass was restarted; and in group III, antivasospastic substance (1,2-bis nicotinamido]-propane) was continuously injected during and after retrograde cerebral perfusion (1 mg/kg per minute). Cerebral blood flow decreased during retrograde cerebral perfusion in all three groups. Cerebrovascular resistance showed marked increases 30 and 60 minutes after cardiopulmonary bypass was restarted in group I compared with the values in groups II and III (group I: 3.35 +/- 0.73 and 5.00 +/- 1.57 mm Hg/ml per 100 gm per minute; group II: 1.30 +/- 0.33 and 1.03 +/- 0.17 mm Hg/ml per 100 gm per minute; group III: 1.24 +/- 0.41 and 0.98 +/- 0.24 mm Hg/ml per 100 gm per minute). The oxygen extraction level was reduced by cooling, but it rose to a higher level as a result of significant desaturation of returned blood even in deep hypothermia during retrograde cerebral perfusion. Both cerebral metabolic rate of oxygen and cerebral metabolic rate of glucose remained at low levels during retrograde cerebral perfusion. Ratios of cerebral blood flow to cerebral metabolic rate of oxygen and cerebral blood flow to cerebral metabolic rate of glucose were markedly reduced during retrograde cerebral perfusion. Intracranial pressure showed significant increases 30 and 60 minutes after cardiopulmonary bypass was restarted in group I compared with values in group II or group III (group I: 22.7 +/- 2.8 and 20.6 +/- 5.1 mm Hg; group II: 6.3 +/- 1.8 and 5.3 +/- 1.3 mm Hg; group III: 4.2 +/- 1.7 and 7.7 +/- 2.8 mm Hg). Water content of the brain tissue in group I (77.54% +/- 0.29%) was significantly higher than that in group II (74.71% +/- 0.76%) or group III (74.14% +/- 0.48%). These data suggest that the supply of oxygen or glucose by retrograde cerebral perfusion is not enough to maintain sufficient cerebral metabolism, which may cause brain edema during antegrade reperfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Lung perfusion with chemotherapy in patients with unresectable metastatic sarcoma to the lung or diffuse bronchioloalveolar carcinoma.

Eight patients with metastatic sarcoma to the lung (n = 4) or diffuse bronchioloalveolar carcinoma of the lung (n = 4) underwent isolated lung perfusion with chemotherapy in a pilot study. Ages ranged from 18 to 60 years and half were female. The left lung was perfused in three patients (single lung perfusion) and both lungs in five patients (total lung perfusion). Perfusions ranged from 45 to 60 minutes at ambient or normothermic temperatures. One patient received perfusion at moderate hyperthermia (40 degrees C). Escalating doses of doxorubicin (1 to 10 micrograms/ml perfusate) was used in six patients, whereas two received cisplatin (14 and 20 micrograms/ml perfusate). There were two major complications and no objective responses. The isolated perfusion systems gave excellent separation between systemic and pulmonary circulations with zero to 15% of the measured peak drug concentration of the pulmonary perfusate detected in the systemic circulation. Drug concentrations in normal lung and tumor generally increased with higher drug dosages and drug was detectable in mediastinal lymph nodes of three out of four patients in whom sampling was done. Isolated lung perfusion with chemotherapy can be done safely in patients with lung malignancies and evidence suggests that higher drug dosages should be well tolerated.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed1996

Isolated lung perfusion with melphalan for the treatment of metastatic pulmonary sarcoma.

OBJECTIVE: Isolated lung perfusion allows the delivery of high-dose chemotherapy to the perfused lung and is an efficacious modality in the treatment of pulmonary metastases in the rat. Melphalan activity in this model was investigated. METHODS: TOXICITY STUDY: Maximum tolerated dose of melphalan delivered by means of isolated lung perfusion was determined by survival after contralateral pneumonectomy. PHARMACOKINETICS STUDY: Nineteen rats were treated with melphalan administered either by isolated lung perfusion (2 mg) or intravenously (2 mg or 1 mg). Lung, pulmonary effluent, and serum melphalan were analyzed by high-pressure liquid chromatography. EFFICACY STUDY: On day 0, 41 rats received an intravenous injection of 5 x 10(6) methylcholanthrene induced sarcoma cells. On day 7, rats either received intravenous melphalan (2 mg [n = 10]; 1 mg [n = 8]) or underwent left isolated lung perfusion with 2 mg of melphalan (n = 12). Isolated lung perfusion with buffered hetastarch in sodium chloride (Hespan, n = 11) was used as control. On day 14, pulmonary nodules were counted. RESULTS TOXICITY: Maximum tolerated dose of melphalan delivered buy means of isolated lung perfusion was 2 mg. PHARMACOKINETICS: Left lung melphalan level was significantly higher in the isolated lung perfusion group (62.2 +/- 34.3 microg/gm lung) than in the intravenous treatment groups (6.9 +/- 1.9 microg/gm lung and 3.3 +/- 0.9 microg/gm lung, respectively) (p = 0.0002). EFFICACY: Significantly fewer left lung nodules were found in animals receiving melphalan by means of isolated lung perfusion (7 +/- 10) than in the groups receiving intravenous melphalan (60 +/- 21) or buffered hetastarch by isolated lung perfusion (84 +/- 52) (p = 0.01 and p = 0.0001, respectively). CONCLUSION: Isolated lung perfusion with melphalan is safe and effective in the treatment of pulmonary sarcoma metastases in the rat.

Animals↗

PubMed1984

Effect of sodium nitroprusside on ventilation-perfusion mismatching in heart failure.

Sodium nitroprusside has been shown to lower arterial partial pressure of oxygen (PaO2) in patients with congestive heart failure and respiratory failure. The multiple inert gas elimination technique was used to evaluate the effect of sodium nitroprusside infusion on pulmonary gas exchange in five patients with congestive heart failure. During sodium nitroprusside infusion, mean values of cardiac output increased and mean values of arterial pressure, pulmonary artery pressure, pulmonary artery wedge pressure and pulmonary vascular resistance decreased. Cardiac output increased in each patient and PaO2 decreased in all but one patient (mean 75.6 +/- 15.1 to 68 +/- 17.5 mm Hg, p = 0.032). Distributions of ventilation and perfusion showed increased perfusion of lung units with low (less than or equal to 0.1) ventilation-perfusion ratios in all subjects during sodium nitroprusside infusion (mean 3.89 +/- 1.52 to 11.33 +/- 7.42% of cardiac output, p = 0.027, paired t test). The amount of shunt (fractional perfusion of lung units with ventilation-perfusion ratio = 0) increased in the two patients with some shunt present in the baseline measurements. The mean total low ventilation-perfusion perfusion (shunt plus ventilation-perfusion less than or equal to 0.1) was significantly increased from 4.38 +/- 1.54 to 14.7 +/- 9.37% (p = 0.023) during sodium nitroprusside infusion. Total low ventilation-perfusion perfusion was negatively correlated with mean pulmonary artery pressure and pulmonary artery wedge pressure (r = -0.949 and -0.946, respectively). Although sodium nitroprusside infusion increased cardiac output and overall oxygen transport in all patients, it worsened ventilation-perfusion mismatching. The mechanism is probably pulmonary vasodilation or increased cardiac output, or both.

Aged↗

PubMed1998

Hepatic heterogeneity in the response to ATP studied in the bivascularly perfused rat liver.

The zonation of the purinergic action of ATP in the hepatic parenchyma was investigated in the bivascularly perfused rat liver by means of anterograde and retrograde perfusion. Livers from fed rats were used, and ATP was infused according to four different experimental protocols: (A) anterograde perfusion and ATP infusion via the portal vein; (B) anterograde perfusion and ATP via the hepatic artery; (C) retrograde perfusion and ATP via the hepatic vein; (D) retrograde perfusion and ATP via the hepatic artery. The following metabolic parameters were measured: glucose release, lactate production and oxygen consumption. The hemodynamic effects were evaluated by measuring the sinusoidal mean transit times by means of the indicator-dilution technique. ATP was infused during 20 min at four different rates (between 0.06-0.77 micromol min[-1] g liver[-1]; 20-200 microM) in each of the four experimental protocols. The results that were obtained allow several conclusions with respect to the localization of the effects of ATP along the hepatic acini: (1) In retrograde perfusion the sinusoidal mean transit times were approximately twice those observed in anterograde perfusion. ATP increased the sinusoidal mean transit times only in retrograde perfusion (protocols C and D). The effect was more pronounced with protocol D. These results allow the conclusion that the responsive vasoconstrictive elements are localized in a pre-sinusoidal region; (2) All hepatic cells, periportal as well as perivenous, were able to metabolize ATP, so that concentration gradients were generated with all experimental protocols. Extraction of ATP was more pronounced in retrograde perfusion, an observation that can be attributed, partly at least, to the longer sinusoidal transit times. In anterograde perfusion, the extraction of ATP was time-dependent, a phenomenon that cannot be satisfactorily explained with the available data; (3) ATP produced a transient initial inhibition of oxygen uptake when protocols A and B were employed. These protocols are the only ones in which the cells situated shortly after the intrasinusoidal confluence of the portal vein and the hepatic artery were effectively supplied with ATP. The decrease in oxygen consumption was more pronounced at low ATP infusions when protocol B was employed. These observations allow the conclusion that the former phenomenon is localized mainly in cells situated shortly after the intrasinusoidal confluence of the portal vein and hepatic artery. Oxygen consumption in all other cells, especially the proximal periportal ones, is increased by ATP; (4) In agreement with previous data found in the literature, glycogenolysis stimulation by ATP was more pronounced in the periportal region. The cells that respond more intensively are not the proximal periportal ones, but those situated in the region of the intrasinusoidal confluence of the portal vein and the hepatic artery.

Adenosine Triphosphate↗

PubMed1987

Effects of calcium entry blocker emopamil on postischemic energy metabolism of the isolated perfused rat brain.

The effects of emopamil on postischemic energy metabolism and electroencephalographic (EEG) recovery were investigated in the isolated rat brain perfused at either constant pressure or, alternatively, at constant flow rate. Flow rate and perfusion pressure were monitored continuously. The brains were perfused with a fluorocarbon emulsion for 30 min, and after 30 min of ischemia, perfusion was reinstituted for 5, 30, or 60 min. Global cerebral perfusion rate was increased by emopamil throughout the perfusion period and, accordingly, in brains perfused at a constant flow rate, perfusion pressure was reduced by the drug. At constant pressure perfusion, after 5 min after ischemia, cortical levels of creatine-phosphate, adenosine triphosphate (ATR), glucose, glucose-6-phosphate, and fructose-6-phosphate were higher in emopamil-treated brains than in controls, although the levels of adenosine diphosphate (ADP) and adenosine monophosphate (AMP) were reduced. When brains were perfused at constant flow rate, however, emopamil exhibited no effect on brain energy metabolism in the early reperfusion period. Postischemic restoration of high-energy phosphates proved to depend on the flow rate used. After 30 min of postischemic reperfusion, cortical levels of lactate were lower in emopamil-treated brains compared to controls at both constant pressure and constant volume perfusion. Postischemic lactate levels were independent of flow rate and were also reduced when emopamil was only present during reperfusion. The postischemic restoration of cortical EEG activity was improved by the calcium entry blocker.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1970

Glucose metabolism in the mucosa of the small intestine. Changes of hexokinase activity during perfusion of the proximal half of rat small intestine.

1. The effect of perfusion on the activities of hexokinase and lactate dehydrogenase was studied in the proximal half of the small intestine of fed and starved rats. 2. Perfusion of preparations from starved rats with a medium containing glucose caused a significant increase in hexokinase activity of the particle-free supernatant. The increase in activity was observed as early as 5min after the start of perfusion and persisted for up to 66min of perfusion. No increase in hexokinase activity of the particle-free supernatant was observed when a medium containing mannitol was used. As a further control, preparations from fed rats were perfused under the same conditions. With the medium containing glucose, the hexokinase activity of the particle-free supernatant remained unchanged during the first 15min of perfusion and thereafter fell gradually until, after 66min of perfusion, 73% of the original activity was retained. 3. The activity of lactate dehydrogenase in the particle-free supernatant prepared from the proximal half of the untreated small intestine of starved rats was significantly lower than in corresponding preparations from fed animals. However, it did not change significantly on perfusion with media containing either mannitol or glucose. 4. The distribution of hexokinase activity between total particulate fraction and particle-free supernatant was measured in preparations from starved rats after perfusion for 5-10min. In preparations that had not been perfused the ratio of hexokinase activity in total particulate fraction/particle-free supernatant was significantly higher in starved than in fed animals. After perfusion with a medium containing glucose, the total homogenate activity had not changed significantly, whereas the ratio of hexokinase activity in total particulate fraction/particle-free supernatant decreased significantly and approached the value obtained with fed animals. 5. The results agree with the view that the glucose-dependent increase of hexokinase activity in the soluble cell compartment as observed in vivo and in vitro in the intestinal mucosa of starved rats is brought about by a release of hexokinase activity from a particulate subcellular structure(s).

Animals↗

PubMed2000

Hypoperfusion causes increased production of interleukin 6 and tumor necrosis factor alpha in the isolated, dually perfused placental cotyledon.

OBJECTIVE: Our purpose was to determine whether exposure of the isolated, perfused human placental cotyledon to different fetal circuit perfusion rates, and to concomitant pressure differences, alters placental production of interleukin 6 and tumor necrosis factor alpha. STUDY DESIGN: The maternal and fetal circulations of 2 cotyledons from 5 placentas were perfused for 4 hours. The fetal circulation of 1 cotyledon was perfused at a low rate of 1 mL/min, and the other at a high rate of 10 mL/min. The maternal circulation of each cotyledon was perfused at 10 mL/min. Effluents from the fetal circulation were collected at hourly intervals, and concentrations of interleukin 6 and tumor necrosis factor alpha were determined by enzyme-linked immunosorbent assay. Concentrations of interleukin 6, obtained from a prior study with an estimated physiologic fetal circulation rate of 4 mL/min, were compared with the low and high perfusion rate results. RESULTS: Concentrations of interleukin 6 and tumor necrosis factor alpha were greater at the perfusion rate of 1 mL/min, in comparison with the perfusion rate of 10 mL/min, with statistically significant differences achieved at 2 and 4 hours for interleukin 6 and at 4 hours for tumor necrosis factor alpha. Concentrations of both cytokines increased exponentially with time. Placental perfusion pressures were significantly greater at the perfusion rate of 10 mL/min. CONCLUSION: Placental hypoperfusion results in an increased production of both interleukin 6 and tumor necrosis factor alpha. This finding links placental perfusion abnormalities to the myriad of disorders associated with elevated concentrations of inflammatory cytokines, including cerebral palsy.

Blood Circulation↗

PubMed2002

Flow rate-perfusion pressure relationships in situ in the uterine circulation of pregnant rats.

OBJECTIVE: Our purpose was to study the effects of inhibition of nitric oxide synthesis on perfusion pressure and flow rate-perfusion pressure relationships in the rat uterine circulation in situ. STUDY DESIGN: Nonpregnant, midpregnant (day 14), and late pregnant (day 21) Sprague-Dawley rats were studied. The vascular bed of the intact uterus and its contents were isolated and perfused with Krebs buffer (37 degrees C, pH approximately 7.4, 2% dextran and indomethacin, 10(-5) mol/L) through a cannula inserted into the abdominal aorta close to the iliac artery bifurcation, and perfusion pressure was monitored. After equilibration, the flow rate was increased from 1 mL/min to 8 or 16 mL/min, in the absence and presence of N(omega)-nitro-L-arginine methyl ester (L-NAME), phenylephrine, or both. RESULTS: The flow rate-perfusion pressure relationship in midpregnant rats (n = 9) was not significantly different from that in late pregnant rats (n = 12), but the latter was significantly greater than the relationship in nonpregnant animals (n = 5). L-NAME did not influence perfusion pressure and flow rate-perfusion pressure relationships in any of the groups. However, L-NAME enhanced the phenylephrine-induced and flow rate-induced increase in perfusion pressure in the vascular beds from nonpregnant and midpregnant animals, and to a lesser extent in late pregnant rats. L-arginine did not influence perfusion pressure or the flow rate-perfusion pressure relationship in any group. CONCLUSIONS: Vasoconstriction produced by phenylephrine uncovers basal release of endothelium derived nitric oxide. Vasoconstriction increases perfusion pressure responses to increases in flow rate in the uterine vascular beds of nonpregnant, midpregnant, and late pregnant rats. The release of endothelial nitric oxide in the uterine vascular beds depends on the basal contractile state of the vasculature.

Animals↗

PubMed2000

Prevention of paraplegia in pigs by selective segmental artery perfusion during aortic cross-clamping.

PURPOSE: During thoracoabdominal aortic aneurysm repair, a prolonged interruption of the spinal cord blood supply can result in irreversible spinal cord damage. The aim of this study was to investigate whether selective segmental artery perfusion during aortic clamping could prevent paraplegia in pigs. METHODS: Specially designed segmental artery perfusion catheters, which could be attached to an extracorporeal bypass graft system, were used. In experiment I (n = 10), it was assessed whether selective segmental artery perfusion could reverse electrophysiologic evidence of spinal cord ischemia and maintain transcranial motor evoked potentials (tc-MEPs) during 60 minutes of aortic cross-clamping. The abdominal aorta, containing critical segmental arteries, was bypassed through use of an aortoaortic bypass graft system. After the disappearance of tc-MEPs, an aortotomy was followed by selective segmental artery perfusion. In experiment II (n = 10), the aim was to determine whether selective segmental artery perfusion could prevent paraplegia. In five animals (group A), aortic cross-clamping was followed by selective segmental artery perfusion; five control animals (group B) underwent segmental artery blockade only. Postoperative hind limb function and spinal cord histopathology were evaluated on the third postoperative day. RESULTS: In experiment I, tc-MEPs disappeared within 3.7 +/- 3.7 minutes after cross-clamping and returned in all animals in 8.5 +/- 5.3 minutes after selective perfusion. During the study period, tc-MEP amplitudes recovered to a median of 49% (range, 28%-113%) of baseline values. Total bypass graft flow was 880 +/- 294 mL/min, of which 184 +/- 54 mL/min was directed to the selective perfusion catheters. The flow in individual catheters was 52 +/- 13 mL/min. In experiment II, all perfused animals demonstrated normal hind limb function, whereas four of five control animals were paraplegic on day 3 (P =.04) In the perfused animals, histopathologic examination showed either no spinal cord damage or eosinophilic neurons only, whereas in paraplegic controls there was infarction in large areas of the cord (P <.0001). CONCLUSION: In pigs, selective segmental artery perfusion can provide sufficient spinal cord blood flow to prevent paraplegia resulting from 60 minutes of aortic clamping, as shown by clinical outcomes and histopathologic examination.

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