Thalidomide inhibits tumor necrosis factor alpha, decreases nitric oxide synthesis, and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats.
A hyperdynamic circulatory state frequently is observed in portal hypertension with liver failure or extensive portal-systemic shunting. Tumor necrosis factor alpha (TNF) causes marked hypotension in mammals by inducing nitric oxide synthesis and has been shown to play a role in the development of the hemodynamic changes observed in portal hypertension. Thalidomide selectively inhibits TNF production by enhancing messenger RNA degradation. We investigated the systemic and portal hemodynamic effects of thalidomide in a prehepatic model of portal hypertension and evaluated whether suppressing TNF synthesis decreases NO production. Portal hypertension was induced by partial ligation of the portal vein (PVL). Animals received thalidomide (T) (50 mg/kg/d) + water or water alone (W), orally, daily for 2 days before and 13 days after PVL operation, at which time hemodynamic studies were performed and TNF plasma levels were obtained. Sham-operated animals were studied identically. In an additional group of PVL animals, 24-hour urinary excretion of NO2- and NO3- was measured during treatment. PVL animals receiving T presented with a significantly higher mean arterial pressure and systemic vascular resistance and significantly lower portal pressure, TNF plasma levels, and 24-hour urinary excretion of NO2- and NO3-, in comparison with rats receiving W. A significant correlation (r = -0.61) was observed between TNF plasma levels and mean arterial pressure among PVL animals. Thalidomide did not have any significant effects on sham rats. Thalidomide inhibits TNF synthesis and reduces NO production, blunts the development of the hyperdynamic circulation, and decreases portal pressure in PVL-operated rats.
Lopez-Talavera
J C
JC
The Digestive Disease and Pulmonary Department, VA Medical Center, Yale University School of Medicine, West Haven, CT, USA.
Cadelina
G
G
Olchowski
J
J
Merrill
W
W
Groszmann
R J
RJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000652:urine; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013577:Syndrome; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D013792:Thalidomide