Chronic thalidomide administration enhances vascular responsiveness to vasopressin in portal-systemic collaterals of bile duct-ligated rats.
BACKGROUND
Arginine vasopressin (AVP) controls gastroesophageal variceal bleeding, partly due to its vasoconstrictive effect on portal-systemic collaterals. It has been shown that chronic thalidomide treatment decreases portal pressure, attenuates hyperdynamic circulation and inhibits vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-alpha in partially portal vein-ligated rats. This study investigated the effects of chronic thalidomide treatment on portal-systemic collateral vascular responsiveness to AVP in common bile duct-ligated (CBDL) cirrhotic rats.


METHODS
In the first series, CBDL-induced cirrhotic rats received thalidomide (50 mg/kg/day orally) or distilled water (control) from the 35th to 42nd day after ligation. On the 43rd day after ligation, the body weight, mean arterial pressure, portal pressure, and heart rate were measured. An in situ collateral vascular perfusion model was used to obtain the cumulative concentration-response curves of collateral vessels to AVP (10(-10) to 3 x 10(-7) M). Plasma levels of VEGF and TNF-alpha were measured, and expressions of VEGF and TNF-alpha mRNA in the left adrenal veins were also determined. In the second series, the cumulative concentration-response curves of collateral vessels to AVP in CBDL rats with or without thalidomide (10(-5) M) preincubation in the perfusate were obtained.


RESULTS
The thalidomide and control groups were not significantly different in terms of heart rate, mean arterial pressure and portal pressure (p > 0.05). The collateral vascular perfusion pressure change to AVP was significantly enhanced at 10(-8) M after thalidomide treatment (p = 0.041). Compared with the control group, thalidomide-treated rats had significantly lower plasma VEGF levels (p < 0.001), accompanied by an insignificant reduction in plasma TNF-alpha levels (p > 0.05). The expressions of VEGF and TNF-alpha mRNA in the left adrenal veins of thalidomide-treated CBDL rats were not significantly changed compared with those of the control group. In addition, thalidomide did not significantly elicit changes in vascular responsiveness to AVP in collateral vessels of CBDL rats when it was added into the perfusate.


CONCLUSIONS
In cirrhotic rats, chronic thalidomide treatment improves the portal-systemic collateral vascular responsiveness to AVP, which was partly related to VEGF inhibition.
Chang
Ching-Chih
CC
Department of Medicine, Taipei Veterans General Hospital, Taiwan, R.O.C.
Wang
Sun-Sang
SS
Huang
Hui-Chun
HC
Lee
Fa-Yauh
FY
Lin
Han-Chieh
HC
Lee
Jing-Yi
JY
Chen
Yi-Chou
YC
Lee
Shou-Dong
SD
D000818:Animals; D001652:Bile Ducts / Q000502:physiology; D003097:Collateral Circulation / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000209:etiology / Q000503:physiopathology; D008297:Male; D011168:Portal System / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013792:Thalidomide / Q000008:administration & dosage*; D014667:Vasopressins / Q000494:pharmacology*
D014667:Vasopressins; D013792:Thalidomide