Thalidomide inhibits tumor necrosis factor α, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats
✍ Scribed by J C Lopez-Talavera; G Cadelina; J Olchowski; W Merrill; R J Groszmann
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 281 KB
- Volume
- 23
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
Portal hypertension accompanied by anatomic or served in portal hypertension with liver failure or extenfunctional 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 incalled 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 selecresistance 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, initi-Portal 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 pres-Tumor 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] Several investigators have urinary excretion of NO 0 2 and NO 0 3 , in comparison with shown that the hypotension elicited by TNF is reversed rats receiving W. A significant correlation (r Å 00.61)
after inhibition of NO synthesis, suggesting that the Lwas observed between TNF plasma levels and mean artearginine-derived NO is a principal mediator of TNFrial pressure among PVL animals. Thalidomide did not have any significant effects on sham rats. Thalidomide induced hypotension. On this basis, studies from our inhibits TNF synthesis and reduces NO production, laboratory performed in a prehepatic rat model of porblunts the development of the hyperdynamic circulatal hypertension induced by partial ligation of the portion, and decreases portal pressure in PVL-operated tal vein (PVL) showed that treatment with specific rats. (HEPATOLOGY 1996;23:1616-1621.) anti-TNF polyclonal antibodies significantly blunts the development of the HCS and decreases portal pressure, suggesting that TNF may play an important role in the hemodynamic abnormalities observed in portal hyper-Abbreviations: HCS, hyperdynamic circulatory syndrome; TNF, tumor netensive rats. 9 crosis factor; PVL, partial ligation of the portal vein; MAP, mean arterial pressure; PP, portal pressure; CI, cardiac index; NOS, nitric oxide synthase;
Thalidomide, a derivative of glutamic acid, selec-T, thalidomide; W, water.
tively inhibits TNF production by stimulated human
From the 1 Digestive Diseases and 2 Pulmonary Departments, VA Medical monocytes. 10 Its inhibitory action on TNF is exerted by