Thalidomide inhibits tumor necrosis factor ?, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats

Abstract

A hyperdynamic circulatory state frequently is ob-Portal hypertension accompanied by anatomic or served in portal hypertension with liver failure or exten-functional portal-systemic shunting very often is assosive portal-systemic shunting. Tumor necrosis factor a ciated with a hyperdynamic circulatory state. The so-(TNF) causes marked hypotension in mammals by in-called hyperdynamic circulatory syndrome (HCS) is ducing nitric oxide synthesis and has been shown to play characterized by generalized vasodilatation with a dea role in the development of the hemodynamic changes crease in mean arterial pressure and systemic vascular observed in portal hypertension. Thalidomide selec-resistance and an increase in cardiac output and retively inhibits TNF production by enhancing messenger gional blood flows. Although the cause of this syndrome RNA degradation. We investigated the systemic and poris still a matter of controversy, it seems that vasodilatatal hemodynamic effects of thalidomide in a prehepatic model of portal hypertension and evaluated whether tion, induced by increased activity of endothelial-indesuppressing TNF synthesis decreases NO production. pendent and endothelial-dependent vasodilators, initiPortal hypertension was induced by partial ligation of ates the hyperdynamic state. 1 the portal vein (PVL). Animals received thalidomide (T)Various substances have been proposed as mediators (50 mg/kg/d) / water or water alone (W), orally, daily for of the HCS. Recently, a role for endogenous nitric oxide 2 days before and 13 days after PVL operation, at which in the regulation of blood flow and vascular tone of the time hemodynamic studies were performed and TNF systemic and splanchnic circulations in portal hypertenplasma levels were obtained. Sham-operated animals sion has been suggested by several in vivo and in vitro were studied identically. In an additional group of PVL animals, 24-hour urinary excretion of NO 0 2 and NO 0 3 was studies, implying that excessive synthesis of NO could measured during treatment. PVL animals receiving T be responsible for these circulatory abnormalities. 2,3 presented with a significantly higher mean arterial presTumor necrosis factor a (TNF), a 17-kd, mononusure and systemic vascular resistance and significantly clear-derived cytotoxic protein, causes marked hypolower portal pressure, TNF plasma levels, and 24-hour tension in mammals. 4 inhibiting TNF synthesis and decreasing NO synthesis,

Tumor necrosis factor ? regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats

“…21 These findings could be explained by the differences in TNF-␣ blood concentration or activity at baseline between PHT and sham-operated rats. Sham-operated rats have low levels of TNF-␣ blood concentration or activity 20,21 that would not contribute to regulation of NOS and hence the systemic circulation. Our results of TNF-␣ expression in blood and stomachs of sham-operated rats support this contention.…”

“…The same phenomenon was found in two previous studies. 20,21 Benoit et al 47 showed that increased portal venous pressure in PHT models is produced by both ''forward'' and ''backward'' flow mechanisms accounting for 40% and 60% of the pressure elevation, respectively. Increased ''forward'' flow results in hyperemia, and ''backward'' flow produces congestion.…”

“…20 Moreover, they used thalidomide, a selective inhibitor of TNF-␣, and showed that this treatment also decreases nitric oxide (NO) synthesis and ameliorates the hyperdynamic circulation of PHT rats. 21 Thus TNF-␣ may be a major contributor to the hyperdynamic circulation of portal hypertension through activation of the NO/L-arginine pathway.…”

Efecto de la pentoxifilina en la supervivencia, la función cardiaca y en la hemodinámica portal y sistémica de la cirrosis alcohólica avanzada: a randomized double-blind placebo-controlled trial

“…La causa exacta de estos cambios es desconocida, pero se cree que es el resultado de una disfunción autonómica con alteraciones funcionales de los receptores β-adrenérgicos (11) o de factores depresores cardiacos tales como endotoxinas o citoquinas, especialmente el TNF-α, que media la activación del óxido nítrico (NO) (12). La traslocación bacteriana intestinal desencadena un aumento de la síntesis de citoquinas proinflamatorias y una activación de la oxido nítrico sintetasa endotelial (eNOS) (13). Recientemente, West y cols.…”

“…observaron un aumento de la producción de NO y sobreexpresión de eNOS inducido por TNF-α en ratas cirróticas con translocación bacteriana (14,15). Además, la inhibición del TNF-α mejora la circulación hiperdinámica de la hipertensión portal en ratas (13,16) y se ha observado un aumento de la producción del TNF-α en los ganglios linfáticos mesentéricos de pacientes con cirrosis descompensada sometidos a trasplante (17).…”