A Study On The Effects Of Different Dose Of Losartan In Rats With Portal Hypertension

OBJECTIVE To evaluate the effects and study the mechanisms of losartan in rats with portal hypertension.METHODS Portal hypertension (PHT) model were induced by compound factors. PHT rats were randomly divided into one model group and three treatment groups. The treatment groups were given different doses of losartan respectively (10mg.kg-1.d-1,5mg.kg-1.d-1 and 2.5mg.kg-1.d-1 ). After treatment, the wedged hepatic venous pressure (WHVP), the free hepatic venous pressure (FHVP) and hepatic venous pressure gradient (HVPG) were measured by catheterization. Also the mean arterial pressure (MAP) and heart rate (HR) were measured. The blood were collected for liver function and homogenate NO,ET analysis. The liver histopathologies were explored with HE and VG staining. The levels of eNOS and iNOS in liver tissue were studied by means of immunohistochemical technique.RESULTS①Compared with normal rat, WHVP and HVPG of model group were significantly increased(P<0.05), but FHVP, MAP and HR had no change. The model had higher ALT and TBIL and lower Alb level (P<0.05). Also the index of hepatic fibrosis HA, PCⅢand the collagen area of liver tissue were significantly increased(P<0.05) in model group. The level of eNOS was significantly decreased in model group, but the iNOS was significantly increased. And the capacity of hepatic sinusoids reduced significantly.Hepatic homogenate NO were normal between the normal and the model group but the level of ET was significantly increased (P<0.05) in model group.②After 21 days of treatment, compared with model group, HVPG were significantly decreased in different doses of losartan groups, and WHVP was the lowest, but still higher than normal group. There weren't difference among the three treatment groups. However, the high dose group of losartan had mean arterial pressure(MAP) decreased from(94.44±11.23)mmHg to(70.81±12.57)mmHg.③Compared with model group, losartan could significantly attenuate collagen area of liver tissue and lower the levels of serum HA and ALT.④Compared with model group, the treatment groups had increased (P<0.05)in the level of liver tissue eNOS and hepatic homogenate NO. And the capacity of hepatic sinusoids increased.And at the same time the level of iNOS and ET were decreased significantly no matter what doses of losartan were given.CONCLUSIONS During the liver cirrhosis, the capacity of hepatic sinusoids reduced. Due to the eNOS expression of sinusoidal endothelial cells decreased and the iNOS increased, the level of hepatic NO/ET disordered which would cause the high hepatic resistance and portal hypertension. Losartan can level the eNOS and iNOS expression of liver which will increase the level of hepatic NO and lower the hepatic ET, and partly increase the capacity of hepatic sinusoids and adjust hepatic microcirculation. Besides losartan can significantly attenuate the degree of hepatic fibrosis, so losartan can decrease HVPG effectively. Our study showed that high dose of losartan can decrease HVPG effectively but lower the mean arterial pressure, while the medium and low doses of losartan have the same effect but have little influence to systemic hemodynamics.