Isolated, perfused rat liver preparations (IPRL), obtained from rats with carbon tetrachloride-induced cirrhosis and normal controls, were used to investigate responses to the vasoactive peptide endothelin-1 (ET-1). The mean perfusion resistance (R) of cirrhotic IPRL was significantly greater than that of controls (2.63 +/- 0.24 vs 1.54 +/- 0.14 mmHg/mL per min per g; P < 0.01). Both control and cirrhotic IPRL demonstrated a concentration-related increase in resistance (delta R) in response to ET-1, with a minimum effective concentration of approximately 3 x 10(-11) mol/L. The EC50 (-log of the 50% effective concentration) was not significantly different between cirrhotic and control IPRL (8.48 +/- 0.19 and 8.79 +/- 0.11, respectively); however, the maximum response to ET-1 was significantly greater in cirrhotic preparations (R: 10.4 +/- 2.2 vs 4.4 +/- 0.5 mmHg/mL per min per g, P < 0.01; DR, 7.8 +/- 2.1 vs 2.8 +/- 0.4 mmHg/mL per min per g, P < 0.01). Following maximal stimulation by ET-1, the mean portal-hepatic venous pressure gradient at a physiological flow rate of 1 mL/min per g was approximately 90% greater across cirrhotic IPRL than that across normal IPRL (11.2 +/- 2.0 vs 5.9 +/- 0.9 mmHg, respectively; P < 0.05). These results support the hypothesis that endogenously released ET-1 has a significant influence on the portal vascular resistance of cirrhotic liver in vivo and has an important role in the pathogenesis of portal hypertension.

The relationship between the perfusion pressure (P) and resistance (R) of the intrahepatic portal vascular bed was determined in isolated rat liver preparations perfused with fresh, heparinized rat blood (hematocrit 30%), with rat blood containing a vasodilator agent (sodium nitroprusside, 1 X 10(-3) mol/L), or with 2.5% bovine serum albumin in Krebs-Henseleit buffer (BSA-KH). Pressure-flow curves were constructed over an extended range of portal venous inflow (0 to 70 mL.min-1, corresponding to a flow rate per gram liver wet weight, Q, of approximately 0 to 7 mL.min-1.g-1). Subsequent analysis showed that two mathematical expressions adequately described the data over the full range of flow. Thus, the pressure-flow curve could be represented by (a) the sum of a linear plus a hyperbolic function, i.e., P = Q.R' + Pmax.Q/(Q + Km), where R', Pmax, and Km are constants, or (b) by the simple equation G = C.P, where G is the conductance (Q/P), and C is a conductivity constant. The values of R', Pmax, Km, and C were significantly different under each of the circumstances investigated, but the form of the curve was not altered. Hence, it is proposed that these parameters can be used to describe the fundamental hemodynamic properties of the portal vascular bed of the isolated rat liver. The results are discussed in terms of the microvascular recruitment and distensible resistance vessel models of the hepatic microcirculation.

Humoral vasoconstrictor factors in portal venous blood have an important influence on hepatic vascular tone. The aim of this study was to determine whether there is altered reactivity of the intrahepatic portal vascular bed of cirrhotic livers to such factors. Isolated perfused rat liver preparations (IPRLP) obtained from rats with carbon tetrachloride-induced cirrhosis and from normal controls were treated with small aliquots of fresh, heparinized venous blood (4% vol/vol) added to a synthetic perfusate composed of 2.5% bovine serum albumin in Krebs-Henseleit buffer. Compared with blood from the inferior vena cava, portal venous blood produced a greater increase in perfusion resistance of normal IPRLP (2.8 +/- 0.7 vs 15 +/- 3%, P less than 0.05). There was no significant difference in the response of normal IPRLP to portal venous blood obtained from cirrhotic animals compared with portal blood from normal controls (10 +/- 4 vs 15 +/- 3%). However, cirrhotic IPRLP were significantly (P less than 0.05) more responsive to portal venous blood than were control livers, regardless of whether the blood was obtained from control (28 +/- 6%) or cirrhotic (24 +/- 6%) rats. The response of both control and cirrhotic IPRLP to portal blood could be partially inhibited by the alpha-adrenoceptor antagonist phentolamine (5 x 10(-6) mol/L) and cirrhotic IPRLP were more responsive than controls to exogenous noradrenaline (518 +/- 27 vs 363 +/- 21%, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Sublethal injury of the liver with carbon tetrachloride (CCl4) induces the modulation of hepatic stellate cells to their myofibroblast (MFB) phenotype. Pretreatment or concomitant treatment with interferon gamma (IFNgamma) has been shown to inhibit this phenomenon. The aim of this study was to investigate the influence of IFNgamma treatment (50000 IU s.c. each day for 5 days) in rats with an established cirrhosis. Cirrhosis was induced with nine doses of CCl4. Comparison of biopsies before and after treatment with IFNgamma showed that the number of MFB present, identified by their alpha-smooth muscle actin immunoreactivity, was markedly reduced. Pressure-flow curves were constructed in isolated perfused liver preparations from IFNgamma-treated and saline-treated cirrhotic rats and analysed to obtain the extrapolated zero-flow intercept (Po, an index of hepatic vascular distensibility) and the vasodilator-induced change in resistance at a flow rate of 1 mL/min per g (deltaR1, an indication of the level of intrinsic vascular tone). In IFNgamma-treated rats, portal venous pressure measured in vivo was significantly reduced compared with controls (11.9+/-1.2 vs 16.0+/-0.5 mmHg, P< 0.05), Po was lower (2.03+/-0.18 vs 2.87+/-0.32 mmHg, P<0.05) and deltaR1 was decreased (0.39+/-0.15 vs 1.02+/-0.19 mmHg/mL per min per g, P< 0.05). The findings indicate that treatment with IFNgamma is effective in reducing MFB density in established CCl4-cirrhosis in the rat and results in a marked improvement in intrahepatic haemodynamics.