Sports

613 NEBIVOLOL DETERIORATES PORTAL HEMODYNAMICS IN CIRRHOTIC RATS BY INCREASING SPLANCHNIC BLOOD FLOW

Description
613 NEBIVOLOL DETERIORATES PORTAL HEMODYNAMICS IN CIRRHOTIC RATS BY INCREASING SPLANCHNIC BLOOD FLOW
Categories
Published
of 2
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Related Documents
Share
Transcript
  POSTERS Conclusions:  Patient with liver cirrhosis are characterized bythe loss of intestinal barrier integrity, especially in the presenceof ascites. This is associated with an abnormal expression anddistribution of TJ protein Occludin and modification of intestinalmicrocirculation. Therapy with non selective beta-blockers couldamelioratetheseabnormalitiescorrectingfunctionalalterationsandpossibly reducing bacterial translocation. 611PROGRESSION OF HEMODYNAMIC CHANGES IN LIVER CIRRHOSIS. A MATHEMATICAL APPROACH L. Noiret 1,2 , S. Baigent 3 , R. Jalan 2 .  1 CoMPLEX, University CollegeLondon,  2 Liver Failure Group, University College London  –  Royal FreeHospital,  3 Mathematics, University College London, London, UK  E-mail: l.noiret@ucl.ac.uk Background and Aims:  Systemic and hemodynamic changes area consistent feature associated with severity of liver cirrhosisclassified using the Child–Pugh score and this leads to a majorredistribution of blood flow. Clinical measurements provide a cleartrend and order of magnitude of change for individual tissue, butfail to provide a coordinated picture as the disease progresses. Amathematical model simulating the evolution of distribution of blood flow subsequent to change in resistance was built. Methods:  A lumped model of systemic circulation wasimplemented. Only key components were represented: hepaticartery, splanchnic bed, porto-systemic (PS) collaterals, portal vein,liver, and one component representing “other organs” (brain,muscle, kidney, etc). Relationships between flow and pressure weredescribed using Ohm’s law. Different levels of cardiac output (CO)and several scenarios for PS collaterals implemented. Choiceof parameter values and selection of scenarios for blood flowdistribution were based on literature review. Results:  To observe a significant change in the distribution of blood flow, a decrease in splanchnic resistance was required.Decreased splanchnic resistance led to an increase in flow throughthe splanchnic bed, and therefore to a decreased perfusion of otherorgans (% CO) (see Table 1). Absolute perfusion could be maintainedthrough an increase cardiac output, but at the cost of worseningHVPG. Hepatic perfusion depended on the degree of PS collateralsallowed: 40% to 75% of splanchnic blood might by pass the liver. Table 1: Simulation results CO(ml/min)MAP(mmHg)HVPG(mmHg)PS shuntml/min(%CO)PVml/min(%CO)Liverml/min(%CO)Kidneyml/min(%CO)Brainml/min(%CO)Muscleml/min(%CO)Normal Value(literature)5500 95 4 0(0%)1045(19%)1402(25%)1045(19%)935(17%)660(12%)Early Child A 5500 94 7 0(0%)1104(20%)1449(26%)1033(19%)924(17%)653(12%)Child A 6050 92 9 710(12%)1020(17%)1366(23%)1014(17%)907(15%)640(11%)Child B 6600 88 11 1490(23%)1002(15%)1332(20%)964(15%)862(13%)609(9%)Late B Early C 7150 84 13 2685(38%)547(8%)863(12%)919(13%)822(11%)580(8%) Conclusion:  Systemic vasodilation is not necessary to observe ahyperdynamic state. Progression of liver disease is associated with afailure to fully compensate the splanchnic dilation by an increase incardiac output. Monitoring the evolution of patient hemodynamicstate may be used as a key marker for predicting its outcome. 612MIR-16 REVERSES ACTIVATED PHENOTYPE OF HEPATICSTELLATE CELL BY TRANSCRIPTOMIC REGULATION Q. Pan 1 , J. Wang 2 , Y.S. He 3 , J.G. Fan 1 .  1 Department of Gastroenterology, XinHua Hospital, School of Medicine, Shanghai Jiaotong University,  2 Department of Pharmacology, Second Military Medical University,  3 Department of Cardiology/Institution of Cardiovascular Research,RuiJin Hospital, School of Medicine, Shanghai JiaoTong University,Shanghai, China E-mail: pan_qin@yeah.net Background and Aims:  miR-16 takes a critical place during theactivation of hepatic stellate cells (HSCs). Although multiple targetshave been recognized, the global effect of miR-16 is still remainedto be clarified. Methods:  Quiescent, activated HSCs were isolated from normal andCCl 4 -induced fibrotic rats, respectively. miR-16 restoration was thencarried out in activated HSCs by lentivirus containing pre-rno-miR-16.Beingcomparedwithcontrols,theimpactofmiR-16onactivatedHSCs was further detected by high-throughout hybridizationand transcriptome analysis. According to the transcriptomiccharacteristics, cyclin D1 expression, cell cycle and CCK8 assaywere employed to evaluate the regulatory role of miR-16 onHSCs’ proliferation. Expression of smad-2 and downstream genes(collagen type I, III) was also measured to reflect its action onextracellular matrix (ECM) production. Moreover, the apoptosis-related property of miR-16 was assessed by Bcl-2 level, caspase 3/7activity and flow cytometry. Results:  Pre-rno-miR-16 administration significantly up-regulatedthe miR-16 level in activated HSCs. As a result, (1) Adipogenic genes,which characterized quiescent status of HSCs, hold the growing-up tendency in expression. (2) Descended fibrosis-inducingcytokines, collagens and ascended matrix metallopeptidasesfacilitated the normalization of ECM production/zymohydrolysis.(3) Cell-cycle-inhibitor up-regulation and cell-cycle-mediatordown-regulation retarded the activation-based over-growth.(4) Increased transcription of mitochondrial apoptosis-mediatinggenes attenuated the apoptosis resistance. Being consistent withtranscriptomic findings, both mRNA and protein loss of cyclin D1were documented in miR-16-treated HSCs, which in turn leadto G 0 /G 1  block and proliferation inhibition. In addition, miR-16treatment gave rise to smad-2 depression post-transcriptionally,and greatly reduced the supernatant concentration of collagen I, III.Another effect of miR-16 lied in the lowered level of Bcl-2. Elevationof caspase 3/7 ratio, and then apoptosis rate, occurred resultantlywithin activated HSCs. Conclusion:  miR-16 may reverse the phenotype of activated HSCsby inducing quiescent-like pattern of transcriptome. 613NEBIVOLOL DETERIORATES PORTAL HEMODYNAMICS INCIRRHOTIC RATS BY INCREASING SPLANCHNIC BLOOD FLOW  T. Reiberger 1 , B.A. Payer 1 , B. Angermayr 1,2 , V. Fuhrmann 1 ,P. Schwabl 1 , B. J¨ager 1 , T. Hummel 1 , T. Horvatits 1 , M. Mitterhauser 3 ,M. Peck-Radosavljevic 1 , Vienna Experimental Portal HypertensionStudy Group.  1 Internal Medicine III, Div. of Gastroenterology & Hepatology, Medical University of Vienna, Vienna,  2 Internal MedicineII, Div. of Gastroenterology & Hepatology, Zentralklinikum St. P¨olten,St. P¨olten,  3 Nuclear Medicine, Medical University of Vienna, Vienna, Austria E-mail: thomas.reiberger@meduniwien.ac.at Introduction:  Portal hypertension (P), as a function of Ohm’slaw (P=R  · I) is influenced by intrahepatic resistance (R) andsplanchnic blood flow (I). Non-selective beta-blockers (NSBB)decrease splanchnic blood flow and NO-donors (e.g. ISMN) decreaseintrahepatic resistance, thus both drugs are used for treatment of portal hypertension. We evaluated the effects of Nebivolol, a third S248 Journal of Hepatology  2011  vol. 54 | S209–S361  POSTERS generation beta-blocker capable of increasing NO bioavailability onsplanchnic and pulmonary hemodynamics in a cirrhotic rat modeldeveloping hepato-pulmonary syndrome (HPS). Methods:  Male Sprague Dawley rats underwent bile duct ligation(BDL) to induce cirrhosis. The animals were orally treated withNebivolol (NEBI; 10mg/kg) or vehicle (VEH) via feeding tube forseven days, starting three weeks after BDL, when cirrhosis was fullydeveloped. 28 days after operation, heart rate (HR), mean arterialpressure(MAP),portalpressure(PP),andsuperiormesentericarteryblood flow (SMABF) were measured. Portosystemic collateral bloodflow (PSCBF) and intrapulmonary shunting (IPS) were quantified byradioactive microsphere technique. Results:  (Table-1): Body weight and MAP were similar in BDL-VEH and BDL-NEBI rats, whereas HR was signficantly reduced byNebivolol treatment. (p < 0.001). BDL-NEBI animals had significantlyhigher PP (p=0.005) and SMABF (p=0.016) than BDL-VEH animals.Nebivolol treatment did not affect IPS (p=0.996). Table 1Parameter Unit BDL-VEH BDL-NEBI p-valueAnimals n 12 12Weight g 359 ± 41 364 ± 40 0.545Heart rate bpm 286 ± 61 207 ± 30  < 0.001 MAP mmHg 87 ± 17 79 ± 11 0.377Portal pressure mmHg 12.6 ± 2.1 15.5 ± 2.6  0.005 SMABF mL/min/100g 4.3 ± 0.8 6.2 ± 0.5  0.016 PSCBF % 53 ± 18 50 ± 7 0.730IPS % 35 ± 10 36 ± 5 0.996Abbreviations:BDL,bileductligation;VEH,vehicle-treated;NEBI,nebivolol-treated; MAP, mean arterial pressure; SMABF, superior mesenteric arteryblood flow; PSCBF, porto-systemic collateral blood flow; IPS, intra-pulmonary shunting. Conclusion:  Nebivolol increases portal pressure in cirrhotic animalsby increasing splanchnic blood flow without affecting pulmonaryhemodynamics (IPS). Although no effects on PSCBF were observed,the safety of Nebivolol for treatment of cirrhotic patients withvarices should be carefully evaluated. 614PLATELET COUNT IN CIRRHOSIS DEPENDS ON SPLEEN SIZE AND PERIPHERAL THROMBOPOIETIN, BUT NOT ON HEPATIC VENOUS PRESSURE GRADIENT  R. Latorre 1 , C. Ripoll 1 , M. Puerto 1 , M.D. Ponce 2 , D. Rinc´on 1 , J.A. Matamoros 1 , E. Ram´on 2 , R. Ba˜nares 1 .  1 Digestive Diseases.CiberEHD,  2 Radiology, Hospital General Universitario GregorioMara˜n´on, Madrid, Spain E-mail: cristina_ripoll@yahoo.es Background:  Different mechanisms have been involved in thedevelopment of thrombopenia in cirrhosis. These are portalhypertension by means of hypersplenism and decreased secretionof thrombopoietin (TPO) due to hepatic insufficiency. However therelative contribution of each one is unknown.The  aim  of this study was to evaluate comprehensively themechanisms that determine platelet count in patients withcirrhosis. Methods:  This transversal study included cirrhotic patients(127) who had a hepatic hemodynamic study and right heartcatheterization between 1/08–6/09. Samples from peripheral (P)veins were obtained to evaluate TPO and other mediators involvedin thrombopoiesis [SCF (stem cell factor), HGF (hepatocyte growthfactor), TNF, IL1b, IL3, IL6 and IL11]. Samples from hepatic (H)veins were obtained to evaluate TPO. A subgroup (n=74) had a CTwithin 6 months of the hemodynamic study that allowed spleenvolumen estimation. Data are described as percentages or medians(interquartillic range). Results:  Patients [Child A 55, B 47, C 23; MELD 12 (9–15)and age 52yrs (47–59)] had mostly alcohol (38%) or HCV (46%)related disease. In these patients the median platelet count was82000/mm 3 (61000–113000), and correlated to P-TPO (r=0.18,p=0.05), and spleen volume (r=−0.38, p=0.001). No associationwas found between platelets and hepatic venous pressure gradient(HVPG), Child class or MELD. Unexpectedly, P-TPO was higher thanH-TPO in most patients (78%). Although P-TPO was not associatedto Child or MELD, H-TPO was lower with greater Child score(r=−0.20, p=0.04), and MELD (r=−0.33, p=0.001). Furthermorepatients with more advanced Child had greater HGF and IL-6(p < 0.001). A negative correlation between HGF and H-TPO wasobserved (r=−0.2, p=0.04). The difference between P-TPO andH-TPO was correlated with IL-11 (r=0.39, p < 0.001) and with SCF(r=−0.27, p=0.007). Spleen volume correlated to cardiac output (r=0.26, p=0.04) and P-TPO (r=−0.26, p=0.03), but surprisingly notto HVPG. Conclusion:  Platelet count in cirrhosis is associated to P-TPO andspleen volume, although not to the degree of portal hypertension.Although H-TPO correlated to liver failure and other mediatorsof thrombopoiesis, P-TPO did not and was greater than H-TPOsuggesting a compensatory extrahepatic production of TPO. 615NA-K-CL COTRANSPORTER IS IMPLICATED IN THE PATHOGENESISOF BRAIN EDEMA IN RATS WITH BILE DUCT LIGATION  J. Huynh, C.R. Bosoi, C. Parent-Robitaille, M. Tremblay, C.F. Rose. Neurosciences Research Unit, CRCHUM (Hˆopital St-Luc), Universit´e deMontreal, Montreal, QC, Canada E-mail: christopher.rose@umontreal.ca Background:  Brain edema is a serious complication associatedwith hepatic encephalopathy (HE) due to chronic liver failure(CLF) and its pathogenesis remains undefined. NKCC1, a Na-K-Clcotransporter, located on the blood-brain barrier (BBB) has beendemonstrated to be implicated in the pathogenesis of brain edemain experimental models of ischemia. Therefore, our aim was to1. investigate the relationship of hyperammonemia,2. study the integrity of the BBB and3. determine the role of NKCC1, in association with brain edema inrats with CLF. Methods:  Two distinct animal models of CLF and HE were used;i. biliary cirrhosis model (6 weeks bile duct ligation (BDL))ii. portacaval shunt model (4 weeks portacaval anastomosis(PCA)).Brain water content was measured using the specific gravimetricmethod. BBB breakdown was assessed by measuring brainextravasation of injected BBB permeability tracers (Evans blueand sodium fluorescein). Expression of BBB tight junction proteins(occludin, claudin-5, ZO-1 and ZO-2) were assessed by immunoblot.Levels of brain NKCC1 mRNA were evaluated by RT-PCR in isolatedcerebral microvessels. Rats were treated with bumetanide (an NKCCinhibitor; administered (i.p) for 10 days). Results:  Similar degree of hyperammonemia was measured in bothBDL and PCA rats however brain edema was only found in BDL rats. In brains of both BDL and PCA rats, extravasation of Evansblue and sodium fluorescein was not detected and no significantchange in the levels of all tight junction proteins was found. Brainwater content was reduced in bumetanide-treated BDL vs BDL-nontreated (77.35 ± 0.18% vs 78.89 ± 0.25%). A 2.4 fold increase in NKCC1mRNA was detected in BDL vs BDL-sham rats whereas no changewas found in PCA vs PCA-sham rats. Conclusions:  Chronic hyperammonemia independently does notlead to an increase in brain water. Brain edema, present in BDL rats,is not associated with a change in either BBB integrity or expressionof BBB tight junction proteins and is therefore not of vasogenicsrcin. Furthermore, an increase in NKCC1 mRNA and attenuation  Journal of Hepatology  2011  vol. 54 | S209–S361 S249
Search
Similar documents
View more...
Tags
Related Search
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks
SAVE OUR EARTH

We need your sign to support Project to invent "SMART AND CONTROLLABLE REFLECTIVE BALLOONS" to cover the Sun and Save Our Earth.

More details...

Sign Now!

We are very appreciated for your Prompt Action!

x