Tumor Angiogenesis after Heated Lipiodol Infusion via the Hepatic Artery in a Rabbit Model of VX2 Liver Cancer

Objectives

This study aimed to observe the changes in tumor angiogenesis after heated lipiodol (60°C) infusion via the hepatic artery in a rabbit model of VX2 liver cancer.

Materials and Methods

Twenty rabbits with VX2 hepatic tumors were randomly divided into 2 groups (10 rabbits in each group). Under anesthesia, a trans-catheter hepatic arterial infusion was performed, and lipiodol (37°C; control group) or heated lipiodol (60°C; treated group) was injected into the hepatic arteries of the animals. Then, changes in tumor angiogenesis were assessed using the following markers and methods. 1. Vascular endothelial growth factor receptor (VEGFR) and vascular endothelial growth factor (VEGF) expression levels in the tumor were assessed using western blotting and real-time quantitative polymerase chain reaction (PCR). 2. Proliferating cell nuclear antigen (PCNA) expression in the tumor was assessed through immunohistochemical staining. 3. The morphological changes in tumor vascular endothelial cells were observed using transmission electron microscopy (TEM).

Results

VEGFR and VEGF mRNA and protein expression levels were reduced in the treated group compared to the control group. PCNA protein showed reduced expression levels in the treated group compared to the control group. TEM indicated that the endothelial cell endoplasmic reticulum expanded, the chondriosome was swollen, and the endothelial cell microvilli were decreased after heated lipiodol infusion.

Conclusions

The tumor angiogenesis of rabbits with VX2 cancer was inhibited after arterial heated lipiodol infusion compared to lipiodol infusion.     

90Y-resin particles—Animal experiments on pigs with regard to the introduction of superselective embolization therapy

Resin particles (diameter 45–75 μm) were labelled with ⁹⁰Y, suspended in a glucose/dextran solution and infused into the kidneys of 3-month-old pigs (tumour model). Both kidneys of each animal were embolized with particles, but only one with active (⁹⁰Y loaded) particles and the other, for comparison, with inactive particles. The organ measurements showed < 1% of injected activity in bone, bone marrow, liver and lung compared to > 99% retention by the kidneys. Only minimal shunted activity was found in blood (<0.27%) and urine (<0.07%). There was a clear shrinkage of the ⁹⁰Y-treated kidneys with a reduction in weight of up to 50%. Histologically, the ischaemic lesions (infarcts and atrophy) were clearly more pronounced and extensive in the ⁹⁰Y-embolized kidneys than in the non-radioactive embolized kidneys. Furthermore, severe arterial wall changes and fibrotic necrosis due to radiation damage were observed in the ⁹⁰Y-treated kidneys. It is concluded that with intra-arterially applied particles a dose of about 100 Gy is sufficient to completely destroy tissue-specific structures. Complications due to acute necrosis or inflammatory reactions were not observed, and there were no shunt related alterations seen in the liver or lungs. The ⁹⁰Y-loaded resin particles are considered suitable for a super selective intra-arterial radioembolization.     

Embolization of the hepatic artery in cases of atypical anatomical structural variants in patients with malignant liver tumors

Therapeutic embolization of the hepatic artery was performed in 60 patients with nonresectable malignant liver tumors. Atypical topographical anatomical variants of the arterial system of the liver were revealed in 10 of them (16.7%). In 8 patients two hepatic vessels, one coming out of the celiac artery, the other--out of the upper mesenterial or left gastric artery supplied a tumor with blood. In three of them one vessel was embolized, in five patients both arteries were embolized. The blocking of the entire blood flow of a tumor brought about a positive clinical effect in all the patients. Embolization of one blood-supplying artery alone led to no improvement. A conclusion was made of a necessity to achieve arterial devascularization of the entire tumor tissue area during intravascular therapy.     

Regulation of gallbladder cholesterol concentration in the hamster. Role of hepatic cholesterol level

The goal of this investigation was to determine how alterations in hepatic cholesterol metabolism influence the cholesterol content of gallbladder bile in hamsters. Although the rate of hepatic cholesterol synthesis was varied over 600-fold, there was no direct relationship between the rate of cholesterol synthesis and the cholesterol content of gallbladder bile. However, expansion of the hepatic cholesterol pool by 42-fold resulted in an 11-fold increase in gallbladder bile cholesterol. Examination of four subfractions of the hepatic cholesterol pool revealed that the cholesterol content of gallbladder bile was most consistently correlated with the free cholesterol level in both hepatic tissue and hepatic microsomes from all experimental groups. In most groups of animals in which gallbladder bile cholesterol was increased, plasma lipoprotein cholesterol levels were also increased. It was concluded that in hamsters, under these experimental conditions, changes in the cholesterol content of gallbladder bile were directly related to alterations in cholesterol content of the liver and most closely related to alterations in the free cholesterol content of that tissue.     

Long term phenobarbital administration does not promote the multiplication of hepatocytes replicating after single cyproterone acetate administration

Cyproterone acetate (CPA) is a synthetic antiandrogenic compound which is widely used in clinic but suspected to be hepatocarcinogenic. CPA is also mitogenic in rat liver. Using genetic labeling of dividing cells, we examined whether hepatocytes dividing in response to acute CPA administration could give rise to preneoplastic foci after administration of a tumor promoter: phenobarbital. CPA was administered orally to rats and dividing hepatocytes were genetically labeled using retroviral vectors carrying the beta-galactosidase gene. After labeling rats were given phenobarbital for 10 months and sacrificed. The presence of beta-galactosidase labeled hepatocytes as well as preneoplastic hepatocytes was assessed by immunohistochemistry. Genetic labeling of hepatocytes was obtained in all animals. At the end of phenobarbital administration, no hepatic tumors were observed. Preneoplastic foci were not increased in treated animals as compared to control rats. Moreover beta-galactosidase positive hepatocytes were never detected in preneoplastic foci. Finally, the size of the beta-galactosidase positive clusters was smaller in treated animals as compared to control rats. We conclude that acute CPA administration is not carcinogenic in rat liver and does not initiate preneoplastic hepatocytes capable to give rise to foci after phenobarbital promotion. Therefore the mitogenic property of CPA is distinct from its putative carcinogenic activity. Finally, analysis of the size of beta-galactosidase positive cells clusters demonstrate that phenobarbital does not induce hepatocyte proliferation in rats.     

Pregnancy and acute baroreflex resetting in conscious rabbits

To test the hypothesis that acute resetting of baroreflex control of heart rate (HR) is enhanced during pregnancy, we determined whether the rightward shift in the baroreflex relationship between arterial pressure and HR after arterial pressure is raised [~25 mmHg for 30 min, due to infusion of phenylephrine (PE) or methoxamine (Meth)] is greater in late pregnant compared with nonpregnant conscious rabbits. Baroreflex function was assessed by monitoring HR responses to both stepwise steady-state changes (n = 14) and rapid ramp changes (n = 10) in arterial pressure. Pregnancy decreased reflex gain, increased reflex minimum HR, and shifted the curves to a lower pressure level, when either the steady-state or ramp method was used (all changes, P < 0.05). When PE was used to increase pressure, resetting of steady-state curves was observed both before and during pregnancy, but the magnitude of the resetting was less in the pregnant rabbits. Further inspection of the data revealed that the size of the shift in pregnant rabbits was inversely related to the dose of PE. Because the pressure rise was the same in all experiments, PE appears to nonspecifically counteract acute resetting. When Meth was used instead to increase pressure, resetting of steady-state curves was similar in pregnant and nonpregnant rabbits and was unrelated to dose. Similarly, when reflex curves were generated using the ramp method, and either Meth or low doses of PE were used to increase pressure, no differences in the degree of resetting were observed between pregnant and nonpregnant rabbits. In summary, high doses of PE counteract acute resetting of baroreflex control of HR. More importantly, while baroreflex function is depressed, the ability of the baroreflex to reset appears to be preserved during pregnancy.     

The effects of prolonged ketamine-xylazine intravenous infusion on arterial blood pH, blood gases, mean arterial blood pressure, heart and respiratory rates, rectal temperature and reflexes in the rabbit

The prolonged and safe maintenance of general anesthesia in rabbits with commonly used injectable agents is difficult. Protracted, stable anesthesia with short recovery time has been described in humans using continuous intravenous infusion of ketamine with or without sedatives, muscle relaxants and paralytics. This study evaluated the anesthetic plane achieved and respiratory and cardiovascular effects produced with a ketamine-xylazine intravenous infusion in New Zealand White rabbits. Ten female rabbits were anesthetized with intramuscularly administered ketamine hydrochloride (35 mg/kg) and xylazine hydrochloride (5 mg/kg) after the preanesthetic, baseline measurements of arterial blood pO2, pCO2 and pH and heart and respiratory rates were recorded. The above parameters as well as mean arterial blood pressure, righting, palpebral, pedal, and jaw reflexes were monitored ten minutes after the intramuscularly administered dosage and throughout 4 hours of infusion. Results showed moderate hypotension (21.2% deviation from normal, p less than 0.008) and profound hypoxemia (45% deviation from baseline, p less than 0.001) 10 minutes after the intramuscularly administered induction dosage. Then, the 4 hour infusion of ketamine (1 mg/minute) and xylazine (0.1 mg/minute) was started. Hypotension progressed (49.1% deviation from normal, p less than 0.008), but hypoxemia and hypercarbemia gradually improved with no resultant change (p greater than 0.1) in arterial pH. There was no significant change (p greater than 0.1) in respiratory rate but varying qualities of respiration were observed. Both mean arterial pO2 and pCO2 values returned to baseline within 20 minutes after completion of infusion. Heart rate and rectal temperature remained stable during the trial. The righting reflex was abolished in all rabbits throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention of microvascular thrombosis with low-dose tissue plasminogen activator.

In a blind, randomized study, two groups, each of seven rabbits, were treated with either a very low dose of human melanoma cell line-derived tissue-type plasminogen activator (t-PA) or isotonic saline. t-PA (0.067 mg/kg of body weight) was administered intraaortically, 20 percent being given as a 30-second "bolus" infusion just prior to the reperfusion of intimectomized central ear arteries and the rest as a continuous infusion during the next 2 hours. Arteriotomic bleeding times, accumulations of 32P-labeled platelets, patency, and sizes of thrombus deposits 2 hours after reperfusion were recorded. To confirm the presence of tissue plasminogen activator in plasma, fibrin-plate lysis assays of arterial plasma were performed immediately before and 1/2 hour and 2 hours after starting drug infusion. Arteriotomic bleeding times were similar in both groups. Transient "oozing" from wound edges occurred in 40 percent of rabbits treated with tissue plasminogen activator. Patency was significantly increased and thrombus deposits were smaller in the tissue plasminogen activator group. Plasma from animals treated with tissue plasminogen activator caused massive lysis of fibrin plates, whereas plasma from control animals caused little or no lysis. Platelet accumulations were very similar in both groups, indicating that occlusive thrombi mainly consisted of other elements than platelets (e.g., fibrin and red cells). Scanning electron microscopy showed normally adhering and aggregating platelets in both groups. This study shows that mild fibrinolytic stimulation with tissue plasminogen activator significantly improves patency in severely traumatized small-caliber arteries and indicates that such treatment may be one approach to prevent thrombosis at microvascular anastomotic sites.     

Interventional radiological treatment of non-colorectal liver metastases

Transcatheter treatment was performed in 81 patients with unresectable non-colorectal liver metastases. Effectiveness increased in the following order: hepatic artery infusion--arterial chemoembolization--combined, arterial and portal vein oily chemoembolization. The mean survival rates for these methods were 8.2 +/- 5.3, vs 11.7 +/- 12.9 vs 13.6 +/- 6.8 mo, and 1-year survival rates 29% vs 46% vs 65%, respectively. Chemoembolization with doxorubicin-in-oil and gelatin sponge was the most effective technique. Interventional radiological procedures were effective in neuroendocrine liver metastases. The mean survival, 1- and 3-year survival rates were as high as 34 mo, 100% and 80%, respectively, for hepatic metastases from resected malignant carcinoid tumors. Also good results were achieved after chemoembolization of metastatic ovarian carcinoma and arterial infusion for gastric carcinoma metastatic to the liver. Transcatheter treatment was ineffective in liver metastases from pancreatic carcinoma, gallbladder cancer, and unknown (and non-resected) tumors. The initial results of the use of interventional radiological procedures in non-colorectal liver metastases are promising, so following clinical trails are needed.     

In vivo labelling with halogenated pyrimidines of squamous cell carcinomas and adjacent non-involved mucosa of head and neck region

The frequency and distribution of labelled cells were studied immunohistochemically in 37 squamous cell carcinomas (SCC) of head and neck after in vivo infusion of IdUrd and BrdUrd. Tumours were classified according to their labelling patterns. Low and moderate grade SCC consisted of tumour islands separated by interstitial tissue. In some tumours labelled cells only appeared near the basal layer while in others proliferative cells were evenly distributed within the neoplastic island. In anaplastic carcinomas labelled cells were distributed either randomly or around blood vessels (cord structures). While the basal layer in adjacent normal epithelium contained very few labelled cells (LI = 1.6 ± 0.2%), the LI of basal cells in tumour islands were much higher than the average LI of the tumour (47.2 ± 2.8% and 23.8 ± 1.6%, respectively). In patients who had received cytotoxic therapy up to two months before the biopsy, the LI in the basal layer of normal epithelium was 19.0 ± 3.5%. In sequential biopsies obtained 1–2 weeks after the infusion of IdUrd and BrdUrd some labelled tumour cells were found in necrotic foci and in pearl structures. Additionally, in six tumours, we found areas of cells labelled with IdUrd alone, even though the IdUrd infusion had been followed by a BrdUrd infusion 1 h later. This is in agreement with the phenomenon of intermittent tumour blood flow described earlier in experimental tumours.     

Microvascular pressures during hypoxia in isolated lungs of newborn rabbits

The purpose of this study was to determine the sites of hypoxic vasoconstriction in lungs of newborn rabbits. We isolated and perfused with blood the lungs from 19 rabbit pups, 7-23 days old. We maintained blood flow constant, continuously monitored pulmonary arterial and left atrial pressures, and alternated ventilation of the lungs with 95% O2-5% CO2 (control), and 95% N2-5% CO2 (hypoxia). Using micropipettes and a servonulling device, we measured pressures in 20-60-micron-diam subpleural arterioles and venules during control and hypoxic conditions. We inflated the lungs to a constant airway pressure of 5-7 cmH2O and kept left atrial pressure greater than airway pressure (zone 3) during micropuncture. In eight lungs we measured microvascular pressures first during control and then during hypoxia. We reversed this order in four lungs. In seven lungs we measured microvascular pressures only during hypoxia. We found a significant increase in pulmonary arterial pressure with no change in microvascular pressures. These results indicate that the site of hypoxic vasoconstriction in lungs of newborn rabbits is arteries greater than 60 micron in diameter.     

Hepatic Parenchymal Changes following Transcatheter Embolization and Chemoembolization in a Rabbit Tumor Model

Objective

To compare the effects of transcatheter arterial chemoembolization (TACE) with transcatheter arterial embolization (TAE) on liver function, hepatic damage, and hepatic fibrogenesis in a rabbit tumor model.

Materials and Methods

Thirty-nine New Zealand white rabbits implanted with VX2 tumors in the left liver lobes were randomly divided into three groups: TAE, TACE, and control group. In the TAE group (n = 15), polyvinyl alcohol particles (PVAs) were used for left hepatic artery embolization. In the TACE group (n = 15), the tumors were treated with left hepatic arterial infusions of a suspension of 10-hydroxycamptothecin and lipiodol, followed by embolization with PVAs. In the control group (n = 9), the animals received sham treatment with distilled water. Serum and liver samples were collected at 6 hours, 3 days and 7 days after treatment. Liver damage was measured using a liver function test and histological analyses. Liver fibrogenesis and hepatic stellate cell (HSC) activation were evaluated using Sirius Red and anti-alpha-smooth muscle actin (α-SMA) immunohistochemical stains.

Results

TACE caused liver injury with greater increases in serum alanine aminotransferase and aspartate aminotransferase levels on day 3 (P<0.05). Histological analyses revealed increased hepatic necrosis in adjacent non-tumorous liver tissue from day 3 compared to the TAE group (Suzuki score of 2.33±1.29 versus 1.13±1.18, P = 0.001). HSC activation and proliferation were significantly increased in the TACE group compared to the control group at 3 and 7 days after treatment (0.074±0.014 vs. 0.010±0.006, and 0.088±0.023 vs. 0.017±0.009, P<0.05). Sirius Red staining demonstrated a statistically significant increase in collagen deposition in the livers in the TACE group 7 days after embolization compared to the control group (0.118±0.012 vs. 0.060±0.017, P = 0.05).

Conclusion

The results of this animal study revealed that TACE induced prominent hepatocellular damage and hepatic fibrogenesis, which compromised liver function and may be responsible for chronic liver decompensation.     

Current x-ray studies in the diagnosis of colorectal metastases to the liver

Computed tomography was made in 90 patients to reveal the specific features of images of hepatic metastatic foci of colorectal cancer of various sites. All the patients were divided into three groups. Group 1 included patients with rectal cancer; Group 2 comprised patients with sigmoid cancer, and Group 3 consisted of those with transverse colon cancer. The study was performed in native, arterial, and venous, and delayed phases. The number of foci, their localization, sizes, and shape were analyzed. In addition, the density of a focus, its homogeneity, the presence of a cancer rim, inclusion of calcium salts, and outline sharpness were determined. Computed tomography revealed no substantial differences in the image of foci of hepatic metastases from rectal, sigmoid, and transverse colon cancers.     

89例巨块型原发性肝癌介入化疗栓塞治疗体会

目的探索巨块型原发性肝癌介入栓塞治疗的疗效。方法89例巨块型原发性肝癌患者,经皮股动脉穿刺插管至肝动脉,化疗栓塞治疗肝癌;碘油用量为20～50ml。再注入明胶海绵颗粒栓塞治疗。发现肝外肿瘤供血动脉,超选择捅管化疗栓塞后,注入适量明胶海绵栓塞治疗。结果本组病例中首次DSA造影发现11例存在肝外动脉供血;64例出现肝外供血动脉共计67支。术后甲胎球蛋白下降均〉50％。术后4～6周复查田,肿瘤最大直径缩小3．5～5．9cm。1、2、3年累计生存率分别为73．8％、48．3％和28．5％。结论巨块型原发性肝癌大剂量碘油栓塞联合肝外肿瘤供血动脉介入治疗,对于提高巨块型原发性肝癌的介入疗效具有重要意义。     

四氯化碳复合法诱导家兔肝纤维化模型的建立

目的建立一组家兔肝纤维化动物模型,并总结建模过程中所得到的经验。方法选用30只普通级家兔,随机选取2～4只家兔作为实验组,5只为对照组。饲养适应1周后,四氯化碳色拉油溶液以5%的起始浓度经腹腔注射法注入实验组家兔体内,对照组给予相同剂量的生理盐水。于造模4W、7W、10W、13W、16W末分别处死24只实验组及1只对照组家兔,以观察肝纤维化的发展程度。结果造模期间实验组家兔死亡7只,对照组家兔无死亡。家兔肝脏纤维化程度随着造模时间延长而逐渐加重。结论此方法成功地建立了一种兔肝纤维化动物模型。     

A nonlinear kinetic model of γ-aminobutyric acid metabolism in a rabbit model of acute liver failure

To investigate the mechanisms by which serum levels of γ-aminobutyric acid (GABA) become elevated in experimental acute liver failure, a multicompartmental model of GABA metabolism has been constructed and used to simulate previously generated data on the kinetics of ³H-GABA uptake by isolated hepatocytes from normal rats and the kinetics of ³H-GABA in the plasma of normal rabbits, rabbits with galactosamine-induced acute liver failure, and rabbits with divascularized livers. Modeling analysis revealed that acute liver failure was associated with values for the mean fractional catabolic rate of GABA, plasma volume, and hepatic extraction of GABA that were 29%, 12%, and 49% less, respectively, than the corresponding control values. The defect in hepatic tissue extraction of GABA was sufficient to account for only 60% of the 10-fold increase in serum GABA levels that occurs in acute liver failure. Furthermore the 10-fold increase in serum GABA levels occured in acute liver failure before the onset of overt hepatic encephalopathy when hepatic extraction of GABA was not appreciably different from that found in normal rabbits. Thus the increase in serum GABA levels that occurs in acute liver failure cannot be attributed to a defect in hepatic extraction of GABA alone. Indeed, the modeling analysis indicated that in acute liver failure there is a 3—8-fold increase in the rate of delivery of GABA to the systemic circulation, but did not indicate its source.     

Central mechanisms of acute ANG II modulation of arterial baroreflex control of renal sympathetic nerve activity

Short-term intravenous infusion of angiotensin II (ANG II) into conscious rabbits reduces the range of renal sympathetic nerve activity (RSNA) by attenuating reflex disinhibition of RSNA. This action of ANG II to attenuate the arterial baroreflex range is exaggerated when ANG II is directed into the vertebral circulation, which suggests a mechanism involving the central nervous system. Because an intact area postrema (AP) is required for ANG II to attenuate arterial baroreflex-mediated bradycardia and is also required for maintenance of ANG II-dependent hypertension, we hypothesized that attenuation of maximum RSNA during infusion of ANG II involves the AP. In conscious AP-lesioned (APX) and AP-intact rabbits, we compared the effect of a 5-min intravenous infusion of ANG II (10 and 20 ng x kg(-1) x min(-1)) on the relationship between mean arterial blood pressure (MAP) and RSNA. Intravenous infusion of ANG II into AP-intact rabbits resulted in a dose-related attenuation of maximum RSNA observed at low MAP. In contrast, ANG II had no effect on maximum RSNA in APX rabbits. To further localize the central site of ANG II action, its effect on the arterial baroreflex was assessed after a midcollicular decerebration. Decerebration did not alter arterial baroreflex control of RSNA compared with the control state, but as in APX, ANG II did not attenuate the maximum RSNA observed at low MAP. The results of this study indicate that central actions of peripheral ANG II to attenuate reflex disinhibition of RSNA not only involve the AP, but may also involve a neural interaction rostral to the level of decerebration.     

Unsaturated fatty acids differ between hepatic colorectal metastases and liver tissue without tumour in humans: Results from a randomised controlled trial of intravenous eicosapentaenoic and docosahexaenoic acids

IntroductionMediators derived from the n-6 polyunsaturated fatty acid (PUFA) arachidonic acid oxidation have been shown to have tumour promoting effects in experimental models, while n-3 PUFAs are thought to be protective. Here we report fatty acid concentrations in hepatic colorectal metastases compared to liver tissue without tumour in humans.MethodsTwenty patients with colorectal liver metastasis were randomized to receive a 72 h infusion of parenteral nutrition with or without n-3 PUFAs. Histological samples from liver metastases and liver tissue without tumour were obtained from 15 patients at the time of their subsequent liver resection (mean 8 days (range 4–12) post-infusion) and the fatty acid composition determined by gas chromatography.ResultsThere were no significant differences in fatty acid composition between the two intervention groups. When data from all patients were combined, liver tissue without tumour had a higher content of both n-3 and n-6 PUFAs and a lower content of oleic acid and total n-9 fatty acids compared with tumour tissue (p<0.0001, 0.0002,<0.0001 and <0.0001, respectively). The n-6/n-3 PUFA ratio was found to be higher in tumour tissue than tissue without tumour (p<0.0001).ConclusionsHepatic colorectal adenocarcinoma metastases have a higher content of n-9 fatty acids and a lower content of n-6 and n-3 PUFAs than liver tissue without tumour.     

Effects of cardiac preload reduction and dobutamine on hepatosplanchnic blood flow regulation in porcine endotoxemia

Insufficient cardiac preload and impaired contractility are frequent in early sepsis. We explored the effects of acute cardiac preload reduction and dobutamine on hepatic arterial (Qha) and portal venous (Qpv) blood flows during endotoxin infusion. We hypothesized that the hepatic arterial buffer response (HABR) is absent during preload reduction and reduced by dobutamine. In anesthetized pigs, endotoxin or vehicle (n = 12, each) was randomly infused for 18 h. HABR was tested sequentially by constricting superior mesenteric artery (SMA) or inferior vena cava (IVC). Afterward, dobutamine at 2.5, 5.0, and 10.0 μg/kg per minute or another vehicle (n = 6, each) was randomly administered in endotoxemic and control animals, and SMA was constricted during each dose. Systemic (cardiac output, thermodilution) and carotid, splanchnic, and renal blood flows (ultrasound Doppler) and blood pressures were measured before and during administration of each dobutamine dose. HABR was expressed as hepatic arterial pressure/flow ratio. Compared with controls, 18 h of endotoxin infusion was associated with decreased mean arterial blood pressure [49 ± 11 mmHg vs. 58 ± 8 mmHg (mean ± SD); P = 0.034], decreased renal blood flow, metabolic acidosis, and impaired HABR during SMA constriction [0.32 (0.18-1.32) mmHg/ml vs. 0.22 (0.08-0.60) mmHg/ml; P = 0.043]. IVC constriction resulted in decreased Qpv in both groups; whereas Qha remained unchanged in controls, it decreased after 18 h of endotoxemia (P = 0.031; constriction-time-group interaction). One control and four endotoxemic animals died during the subsequent 6 h. The maximal increase of cardiac output during dobutamine infusion was 47% (22-134%) in controls vs. 53% (37-85%) in endotoxemic animals. The maximal Qpv increase was significant only in controls [24% (12-47%) of baseline (P = 0.043) vs. 17% (-7-32%) in endotoxemia (P = 0.109)]. Dobutamine influenced neither Qha nor HABR. Our data suggest that acute cardiac preload reduction is associated with preferential hepatic arterial perfusion initially but not after established endotoxemia. Dobutamine had no effect on the HABR.     

Indomethacin attenuation of hepatic perfusion and plasma 6-ketoPGF1 alpha elevations following glutathione depletion in rabbits

Glutathione (GSH) is important in detoxification and regulating cyclooxygenase activity. Since the liver has high levels of GSH, xenobiotic-induced changes in hepatic GSH could affect hepatic tissue blood perfusion (HP) via alterations in prostaglandin synthesis. In anesthetized male New Zealand rabbits, elevating GSH with GSH monoethyl ester had no affect on HP. Treatment of rabbits with diethyl maleate to deplete GSH also had no affect on HP in animals previously given GSH monoethyl ester. However, HP increased within 20 min in rabbits treated with diethyl maleate prior to GSH monoethyl ester. In another experiment, a similar rise in HP following GSH depletion was accompanied by arterial plasma 6-ketoPGF1 alpha (the stable metabolite of prostacyclin) levels that were 4-times higher than in the controls. Plasma TxB2 (the stable metabolite of thromboxane) also increased following diethyl maleate, but only to levels that were 25-times lower than for 6-ketoPGF1 alpha. Since indomethacin blocked the rise in HP, as well as the increases in 6-ketoPGF1 alpha and TxB2, these results indicate changes in HP may occur following GSH depletion as a result of increased synthesis of one or more arachidonic acid metabolites and implicate prostacyclin as a possible mediator of this phenomenon.