TYROSINE KINASE INHIBITION AMELIORATES THE HYPERDYNAMIC STATE AND DECREASES NITRIC-OXIDE PRODUCTION IN CIRRHOTIC RATS WITH PORTAL-HYPERTENSION AND ASCITES

Tumor necrosis factor-alpha (TNF) causes vasodilatation and a hyperdyn amic state by activating nitric oxide (NO) synthesis. Tyrphostins, spe cific inhibitors of protein tyrosine kinase (PTK). block the signaling events induced by TNF and NO production, A hyperdynamic circulatory s yndrome (HCS) is often observed in portal hypertension (PHT), TNF and NO seem to mediate these hemodynamic changes, The aim of this work was to study the effect of PTK inhibition on the systemic and portal hemo dynamics, TNF and NO production, in cirrhotic rats with portal hyperte nsion. Rats with liver cirrhosis induced by chronic inhalation of carb on tetrachloride were used, Animals were treated daily with tyrphostin AG 126 (alpha-cyano-(3-hydroxy-4-nitro) cinnamonitrile) or placebo fo r 5 d, Mean arterial pressure (MAP), heart rate (HR). and portal press ure (PP) were measured by indwelling catheters, Cardiac output (CI) an d stroke volume (SV) were estimated by thermodilution, systemic vascul ar resistance (SVR) was calculated (MAP/CI), and portal systemic shunt ing (PSS) was quantitated using radioactive microspheres, Serum and me senteric lymph node (MLN) TNF levels were measured using an immunoassa y kit, and serum NOx was determined photometrically by its oxidation p roducts, The AG l26-treated group showed a statistically significant i ncrease in MAP and SVR, and decreases in CII SV, MLN TNF, and serum NO oxidation products nitrite and nitrate (NOx) in comparison with the p lacebo-treated rats, No significant differences were noticed in HR, PP , PSS, or serum TNF, Significant correlations were observed between MA P and NOx, MAP and MLN TNF, PSS and NOx, and serum TNF and serum NOx, The HCS observed in PHT seems to be mediated, at least in part, by TNF and NO by the activation of PTKs and their signaling pathways, PTK ac tivity inhibition ameliorates the hyperdynamic abnormalities that char acterize animals with cirrhosis and PHT.