Tyrosine kinase inhibition ameliorates the hyperdynamic state and decreases nitric oxide production in cirrhotic rats with portal hypertension and ascites.

Abstract

Tumor necrosis factor-␣ (TNF) causes vasodilatation and a hyperdynamic state by activating nitric oxide (NO) synthesis. Tyrphostins, specific inhibitors of protein tyrosine kinase (PTK), block the signaling events induced by TNF and NO production. A hyperdynamic circulatory syndrome (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 hemodynamics, TNF and NO production, in cirrhotic rats with portal hypertension. Rats with liver cirrhosis induced by chronic inhalation of carbon tetrachloride were used. Animals were treated daily with tyrphostin AG 126 ( ␣ -cyano-(3-hydroxy-4-nitro) cinnamonitrile) or placebo for 5 d. Mean arterial pressure (MAP), heart rate (HR), and portal pressure (PP) were measured by indwelling catheters. Cardiac output (CI) and stroke volume (SV) were estimated by thermodilution, systemic vascular resistance (SVR) was calculated (MAP/CI), and portal systemic shunting (PSS) was quantitated using radioactive microspheres. Serum and mesenteric lymph node (MLN) TNF levels were measured using an immunoassay kit, and serum NOx was determined photometrically by its oxidation products. The AG 126-treated group showed a statistically significant increase in MAP and SVR, and decreases in CI, SV, MLN TNF, and serum NO oxidation products nitrite and nitrate (NOx) in comparison with the placebotreated rats. No significant differences were noticed in HR, PP, PSS, or serum TNF. Significant correlations were observed between MAP 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 activity inhibition ameliorates the hyperdynamic abnormalities that characterize animals with cirrhosis and PHT. ( J. Clin. Invest. 1997. 100:664-670.)

A novel model of CCl4-induced cirrhosis with ascites in the mouse

“…We decided to employ CCl 4 as the hepatotoxin since the corresponding model in the rat has been demonstrated to closely reproduce the events leading to ascites formation in man, such as hyperdynamic circulatory syndrome [15], renal sodium retention from the preascitic stage [4], and impaired renal water metabolism [16]. Based on the rat model, we also associated phenobarbital administration in the drinking water to selectively enhance CCl 4 hepatotoxicity.…”

Pivotal role of nitric oxide in the control of blood pressure after leptin administration.

“…Interestingly, leptin has been shown to present striking structural similarities to members of the long-chain helical cytokine family (20,21), and several investigators have demonstrated the existence of a cytokine-inducible Larginine/NO pathway (22,23). Apart from the direct actions of NO on vascular smooth muscle, additional roles for NO in the regulation of cardiovascular functions have been proposed.…”

Tyrphostin AG 126 inhibits development of postoperative ileus induced by surgical manipulation of murine colon

“…It is clear from a large body of literature concerning other systems and cell types that IL-1␤, either alone or in combination with other proinflammatory cytokines, can initiate the transcription of MCP-1, COX-2, and iNOS (4) and that NF-B activation plays a significant role in these processes (21,22,37), including the transcriptional regulation of the IL-1␤ gene itself (44). Indeed, tyrphostin AG 126 has been shown to inhibit the production of IL-1␤, COX-2, and iNOS in vivo in other models of local and systemic inflammation (5,6,10,23). Thus inhibition of the NF-B signaling pathway is a potential mechanism by which tyrphostin AG 126 reduced the surgically induced inflammatory responses observed in the present study during the development of colonic ileus.…”