Factors mediating the hemodynamic effects of tumor necrosis factor-alpha in portal hypertensive rats

Nitric oxide, prostacyclin, and glucagon have been implicated in promoting the hyperdynamic circulatory state of portal hypertension. Recent evidence also indicates that increased tumor necrosis factor-alpha (TNF-alpha) produ ction is involved in the pathogenesis of this hemodynamic abnormality. This study was aimed at investigating in rats with portal vein stenosis (PVS) t he effects on splanchnic hemodynamics of blocking circulating TNF-alpha and the factors mediating the vascular action of this cytokine in this setting . Anti-TNF-alpha polyclonal antibodies or placebo was injected into rats (n = 96) before and 4 days after PVS (short-term inhibition) and at 24 h and 4, 7, 10 days after PVS (long-term inhibition). Short-term TNF-alpha inhibi tion reduced portal venous inflow and cardiac index and increased splanchni c and systemic resistance. Portal pressure was unchanged, but portal-system ic shunting was decreased. After long-term TNF-alpha inhibition, portal ven ous inflow and portal pressure were unchanged, but arterial pressure and sy stemic resistance rose significantly. Anti-TNF-alpha PVS rats exhibited low er increments of systemic resistance after Nw-nitro-L-arginine methyl ester and indomethacin administration and lower serum levels of TNF-alpha, nitra tes-nitrites, and 6-keto-PGF(1 alpha), both over the short and the long ter m. Serum glucagon levels rose after long-term inhibition. In conclusion, th e specific role played by TNF-alpha in the development of the hyperdynamic state of portal hypertension appears to be mainly mediated through an incre ased release of nitric oxide and prostacyclin. Maintenance of the splanchni c hyperemia after long-term TNF-alpha inhibition could be due to a compensa tory release of glucagon.