Effects of tumor necrosis factor,endothelin and nitric oxide on hyperdynamic circulation of rats with acute and chronic portal hypertension

AIM:To evaluate the effect of tumor necrosis factor (TNF),endothelin (ET) and nitric oxide (NO) on hyperdynamic circulation (HC) of rats with acute and chronic portal hypertension (PHT).METHODS: Chronic portal hypertension was induced in Wistar rats by injection of carbon tetrachloride. After two weeks of cirrhosis formation, L-NMMA (25mg/kg) was injected into one group of cirrhotic rats via femoral vein and the experiment was begun immediately. Another group of cirrhotic rats was injected with anti-rat TNFα (300mg/kg) via abdominal cavity twice within 48h and the experiment was performed 24h after the second injection. The blood concentrations of TNFα, ET-1 and NO in portal vein and the nitric oxide synthase (NOS) activity in hepatic tissue were determined pre-and post-injection of anti-rat TNFα or LNMMA. Stroke volume (SV), cardiac output (CO), portal pressure (PP), superior mesenteric artery blood flow (SMA flow) and lilac artery blood flow (IAflow) were measured simultaneously. Acute portal hypertension was established in Wistar rats by partial portal-vein ligation (PVL). The parameters mentioned above were determined at 0.5h,24h, 48h, 72h and 120h after PVL. After the formation of stable PHT, the PVL rats were injected with anti-rat TNFα or L-NMMA according to different groups, the parameters mentioned above were also determined.RESULTS:In cirrhotic rats, the blood levels of TNFα, NO in portal vein and the liver NOS activity were significantly increased (P<0.05) while the blood level of ET-1 was not statistically different (P>0.05) from the control animals(477.67±83.81pg/mL vs 48.87±32.79pg/mL, 278.41±20.11μmol/L vs 113.28±14.51μmol/L, 1.81±0.06μ/mg.prot vs 0.87±0.03μ/mg.prot and 14.33±4.42pg/mL vs8.72±0.79pg/mL, respectively). After injection of anti-rat TNFα,the blood level of TNFα was lower than that in controls (15.17±18.79pg/mL vs 48.87±32.79pg/mL). The blood level of NO and the liver NOS activity were significantly decreased, but still higher than those of the controls. The blood level of ET-1 was not significantly changed. PP,SV,CO, SMAflow and IAflow were ameliorated. After injection of L-NMMA, the blood level of NO and the liver NOS activity were recovered to those of the controls. PP and CO were also recovered to those of the controls. SV, SMAflow and IAflow were ameliorated. In PVL rats, the blood levels of TNFα NO in portal vein and the liver NOS activity were gradually increased and reached the highest levels at 48h after PVL. The blood level of ET-1 among different staged animals was not significantly different from the control animals. PP among different staged animals (2.4±0.18kPa at 0.5h, 1.56±0.08kPa at 24h, 1.74±0.1kPa at 48h,2.38±0.05 kPa at 72h, 2.39±0.16 kPa at 120h) was significantly higher than that in controls (0.9±0.16kPa). After injection of anti-rat TNFα in 72h PVL rats, the blood level of TNFα was lower than that in controls (14±14pg/mL vs 48.87±32.79pg/mL). The blood level of NO and the liver NOS activity were significantly decreased, but still higher than those of the controls. The blood level of ET-1 was not significantly changed. PP was decreased from 2.38±0.05kPa to 1.68±0.12kPa, but significantly higher than that in controls. SV, CO, SMAflow and IAflow were ameliorated.After injection of L-NMMA in 72h PVL rats, the blood level of NO and the liver NOS activity were recovered to those of the controls. PP, SV, CO, SMAflow and IAflow were also recovered to those of the controls.CONCLUSION:NO plays a critical role in the development and maintenance of HC in acute PHT and is a key factor for maintenance of HC in chronic PHT. TNFα may not participate in the hemodynamic changes of HC directly, while play an indirect role by inducing the production of NO through activating NOS. No evidence that circulating ET-1 plays a role in both models of portal hypertension has been found.