256A AASLD ABSTRACTS HEPATOLOGY October 1995

5 9 7 COMBINATION THERAPY OF NITRATES AND SPIRONOLACTONE IN EXPERIMENTAL PORTAL HYPERTENSION. M,Vaa lie Catteele. G.Vm Roev. F.Nevms. I Feverv. Lab. of Hepatology, Catholic ~ oeLmvm. 8-3oo0 Leuvm, Be~inm.

Prelimmry studies show that spirmoimme (Sp) and immCoida-5- mcmonitrate 0so5N) dacteam HVPG but that acete Im5N hag a negative effect on mini fum:tion. We investipted the effect of a omtbingien in the partial portal veia ligated rat 0PPVL). MaimS: 3 weeks alter PPVL, 24 nude Witar r m wewe r m d m ~ amgmd to one ofthe ~ trmtmmts by pvage for 8 days: placebo (2 ml mline)/d; lso5N 0.14 mg in 2 ml saline/d or h~ 'N 0,14 m8 combined with Sp 0.M mg in 2 ml saline/d. Mmdaofic foBow-up w u mnied out before and on day 7. Pored pmsutm aid plamna ~ohmm 0V Evam bhm) were m m u m l ,nd~ Nanlamd mmthmin on day 8. Plamm volume wm memxl by the mahod of IV Evans bhw: P,~al~: mmn + SEM; if Anova w~ signifg~ ,,- the 5 % level, mpeired t-tat was Wfcam~. *p<0.05 **p<0.01 ***p<0.0Ol.

PPVL phtc PPVL Isc$'N PIPVL IsoSN+Sp Mean~.hange (n=8) 01=8) (n~8~ to lsoSH alone

Portal prmsure (ram Hg) day 8:!0.4+1.2 7.8+0.6* 6.9+!.0' -I 1% NS

Plasma volume (ml) day 8: 13.1+0.3 1 2 . 8 + 0 . 4 9.4+0.4'** - 26 %***

Salt bahug~ (meq/24 h) day0:0.17+0.12 0.39+0.18 -0.03+0.19 -108 %NS day 7:0.21+0.16 0.36+0.23 -0.13+0.19' -162%*

Fmctiaml Excretion of Na (%) day 0: 0.65+0.07 0.53+0.04 0.61+0.03 +15 % NS day 7:0.58+0.02 0.54+0.04 0.63+0.1 +17 % NS

Condusioas: lso5N tmdad to a sak retmticm, where~ the addition of Sp leads to enhmced u3dium ~ a dacrea~ in plamnvetme and cardiac output (net drown) ami a fmthar lowering of pollal pmssuro.Thl~ n=ults m in favour o f us~ combi~l tlm~py in t m i ~ w~h v~ri~s: prcpmold, I ~ N ~ 1 Sp.

598 ACTIONS OF CARVED1LOL, A VASODILATING BETA- BLOCKIER, ON THE PORTAL AND RENAL CIRCULATIONS IN CIRRHOSIS. EH Forrest. IAD Bouchier, PC Hayes. Department of Medicine, The Royal Infirmary, Edinburgh. 5cotl and

Propranolol reduces variceal haemorrhage in portal hypertension but deterioration in renal function may occur in some patients. We investigated the haemodynamic actions of Carvedilol, a non-specific beta-bl0cker with alpha-1 antagonism, upon the splanchnic and renal circulations of patients with cirrhosis.

Free and wedged hepatic vein pressures (FHVP and WHVP), azygos blood flow (AzBF), unilateral renal vein flow [(RVF); reverse thermodilution method], heart rate (HR), and mean arterial pressure (MAP) were measured in twelve patients with cirrhosis before and 1 hour after 25mg oral Carvedilol.

Results: Time(rain) 0 60 HR (hpm) 81.3 (3.2) 73.8 (4.8)

MAP(mmHg) 95.7 (5.3) 84.5 (5.2)* HVPG(mmHg) 16.8 (1.0) 14.1 (1.1)** AzBF (ml/min) 440 (93) 410 (90) RVF (ml/min) 354 (119) 323 (84)

Mean (SEM); HVPG=WHVP-FHVP; *p<0.001, **p<0.0005. Conclusion: Carvedilol has a significant portal

hypotensive effect but unlike propranolol does not significantly reduce porto-systemic collateral flow. Alpha-adrenergic activity has been suggested as mediating the renal impairment of cirrhosis. Carvedilol cuased a fall in MAP but maintained renal perfusio n presumably by blocking this sympathetic nervous system effect.

599 C I R C U L A T I N G T U M O R NECROSIS FACTOR-(~ AND I N T E R L E U K I N , 6 C O N C E N T R A T I O N S AND HYPER- DYNAMIC CIRCULATION IN CIRRHOSIS. FY Lee. RH Lu. YT Tsai, HC Lin. MC H0u. CP Li. DM Liao. LF Lin. SS Wan,,. SD Lee. Div. of Gastroenterology, Dept. of Medicine, Veterans General Hospital- Taipei and National Yang-Ming University School of Medicine, Talpei, Taiwan, R.O.C.

Liver cirrhosis with portal hypertension is associated with a hyperdynamic circulation characterized by generalized vasodilatation and an increased cardiac output and regional blood flows. Cirrhotic patients show elevated circulating tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) levels, at least partly mediated by endotoxemia. Treatment with anti-TNF-a antibodies reduces IL-6 release during experimental bacteremia and prevents the development of the hyperdynamic circulation in portal hypertensive rats. In this report, we investigated whether elevated plasma tumor necrosis factor-a (TNF-a) and/or interleukin-6 (IL-6) levels contribute to the pathogenesis of hyperdynamic circulation observed in cirrhotic patients and whether they are correlated'with plasma endotoxin concentrations. Plasma TNF-a, IL-6, and endotoxin levels were significantly higher in cirrhotic patients (n=58, 7.3_+0.2 pg/ml, 6.4_+0.8 pg/ml, and 7.6+1.2 pg/ml, respectively, p<0.01) than in healthy subjects (n=34, 5.8+0.1 pg/ml and 2.0-2_0.2 pg/ml, and 2.8-+0.3 pg/ml, respectively). In cirrhotic patients, the plasma levels of TNF-a, IL-6, and endotoxin progressively increased in relation to the severity of liver dysfunction (p<0.005). A significant correlation was observed between plasma TNF-a and IL-6 levels (r=0.48, p<0.001), whereas no correlation was observed between plasma endotoxin levels and plasma TNF-a and IL-6 levels (p>0.05). In addition, plasma IL-6 levels negatively correlated with systemic vascular resistance in patient with cirrhosis (n=521 r=-0.5, p<0.01). Neither plasma levels of TNF-~ nor IL-6 correlated with hepatic vein pressure gradient (r=0.05 and r=0.25, respectively, p>0.05). These results demonstrate that plasma TNF-~ and IL-6 levels are increased in patients with cirrhosis. The severity of liver cirrhosis is an important factor for the occurrence of enhanced cytokine levels. Both TNF-a and IL-6 may play a role in the hemodynamic abnormality observed in patients wi~ cirrhosis.

600 ROLE OF TUMOR NECROSIS FACTOR-ALPHA IN THE CIRCULATORY ABNORMALITIES OF CIRRHOTIC RATS. J.G. Looez-Talavera. G. Cadelina. W. Merrill. R.J. Groszmann. V.A.M.C., West Haven and Yale University School of Medicine, New Haven, Connecticut.

Several reports have documented elevated tumor necrosis factor- alpha (TNF) plasma levels in liver disease. Recently, we have demonstrated that TNF mayplay a role in the hyperdynamic circulatory state characteristic of an animal model of pre-hepatic portal hypertension. The aim of the present study was to investigate the role that TNF may play in the circulatory abnormalities observed in rats with liver cirrhosis. Methods: Male rats with liver cirrhosis induced by carbon tetrachloride inhalation were used. Animals were divided into 2 groups: rats treated with a rabbit anti-mouse polyclonal antibody (Ab- treated, N=9) or placebo (sterile rabbit serum) (Pla-treated, N=8), Both treatments were administered i.v. at a dose of 0.5 ml 4 days and 1 day before the hemodynamic studies. Mean arterial pressure (MAP mmHg) heart rate (HR, b/min) and portalpressure (PP, mmHg) were measured by indwelling catheters. Cardiac output (CI, ml-min'l-100g -1) Was estimated by thermodilution. Plasma TNF levels were measured using a bioassay with the cell line WEHI 164. Resul ts: The Ab-treated group demonstrated a statistically significant increase in MAP (153_+3.6 vs. 130+3,1, p<0.001) and HR (394_+7.5 vs. 363_+5.4, p<0.01) in comparison with the Pla.treated group (unpaired t-test). TNF plasma levels were lower in the Ab-treated group (42.5+_28.29 U/mL) vs. the Pla-treated group (78.6_+29.1 U/mL), although this difference was not statistically signif cant (p>0.05). In a simple regression analysis, TNF plasma levels in the Pla-treated rats demonstrated a significant (p<0.05) inverse correlation with MAP and CI (R=-0.8 and -0.73, respectively) and a direct correlation with PP (R=0;62). This correlation was not observed among the Ab-treated animals. Conclusion: TNF plasma levels are increased in cirrhotic rats and they correlate inversely with MAP and CI and directly with PP. Anti-TNF treatment significant!y increases the MAP and HR. TNF plays a role in the hemodynam~c abnormalities observed in cirrhotic rats.