Bosentan in reversal of chronic high-altitude environmentally induced pulmonary hypertension in rats

AIM: To investigate the role of bosentan in the reversal of chronic high-altitude environmentally induced pulmonary hypertension in rats. METHODS: Fifty Male Sprague Dawley rats were randomly divided into five groups: control group, 3-week hypobaric hypoxic group (3 weeks), 6-week hypobaric hypoxic group (6 weeks), placebo group, and bosentan group. Rats in the control group were housed in an orthobaric environment. Rats in the experimental altitude groups were kept in a hypobaric chamber, which simulated the environment of a 5 000 m altitude for 8 h/d. In placebo group and bosentan group, the 3-week administration of sodium chloride or bosentan in hypobaric chamber commenced 3 weeks after hypobaric hypoxic environment. At the end of 3 weeks and 6 weeks, pulmonary arterial pressure (PAP) and right ventricular systolic pressure (RVSP) were recorded, and RV/(LV+S)% and the weight ratio of lung weight vs. body weight: (PW/BW)‰ were calculated. The lung tissues were stained with H/E. Morphometric parameters ［percentage of vascular wall thickness (WT%) and muscularization of non-muscularited peripheral pulmonary arterioles］ were used to assess the remodeling of small pulmonary arteries. The levels of NO and ET-1 in plasma and tissue and the activity of cNOS and total NOS in tissue were measured. RESULTS: PAP and RVSP significantly decreased in bosentan group compared with those in the 3-week group (P<0.05). The development of RV/(LV+S)% and (PW/BW)‰ were significantly inhibited in the bosentan group. Histological study showed that WT% and muscularization of non-muscularized peripheral pulmonary arterioles significantly decreased in the bosentan group compared with those in the 3-week group (P<0.05). The level of ET-1 in the lung homogenates significantly decreased in the bosentan group compared with that in the placebo group (P<0.05). The level of NO and the activity of cNOS and total NOS significantly increased in the bosentan group compared with placebo group (P<0.05). CONCLUSION: Bosentan effectively reverses the development of pulmonary hypertension, reduces the pulmonary vascular remodeling and prevents pulmonary edema in chronic high-altitude environmentally induced pulmonary hypertension in rats. The therapeutic effect of bosentan on chronic high-altitude environmentally induced pulmonary hypertension in rats may result from the decrease of ET-1 in lung and the increase of NO and cNOS in lung and plasma.