| Pulmonary Artery Hypertension is the pathophysiologic basis to incur, develope and carry on cardiopulmonary diseases, such as congenital heart diseases, cardiomyopathy, other kinds of cardiovascular diseases , respiratory diseases and thorax diseases. There are five typies about PAH, and hypoxic pulmonary hypertension(HPH) is a common one in which. Increasing heart afterload and hypobaric condition in HPH might lead to myocardium diastolic and systolic dysfunction, and injured the ventricle. With the development of the disease, possibilities of complications are increased, for example, right ventricular hypertrophy, arrhythmias, and heart failure. Some studies on some kinds of ventricular hypertrophy patients indicated that the change of myocardial connexin43 (Cx43) expression was closely related to the state of the disease. Bosentan (BST) is one of the most important drugs on treating PAP, which can effectively decrease pulmonary artery pressure and improve the conditions of the patients. However, none of studies is about the effect of BST on right ventricular remolding and Cx43 in chronic HPH rats. Through installing the chronic hypoxic pulmonary hypertension animal models, we have investigated the changes of right ventricle remolding and connexin43 in these HPH rats after the treatment of bosentan to explore the mechanism of bosentan action, which may provide the evidences to the treatment of HPH.ObjectiveIn these studies, we investigated the effects of BST on right ventricular hypertrophy , myocardial fibrosis, myocardial Cx43 and right ventricular function in HPH rats , and initially explored the mechanism of bosentan action.Methods40 SD rats were randomly divided into four groups:normoxia control group,hypoxic pulmonary hypertension group(HPH group),BST treatment group and placebo group. The rats in normoxia control group were put in normal environment for 6 weeks. The rats in 3 other groups were kept in hypobaric chamber with 5000 meters for 8 hours one day in six weeks. sodium chloride or bosentan was administrated every day for 3 weeks from the 4th week of hypobaric hypoxic treatment. At the end of 6 weeks, a micro-catheter was inserted into right ventricle and pulmonary artery through right external jugular vein, and the mean pulmonary arterial pressure(mPAP) the right ventricular systolic pressure( RVSP) and the maximal rates of right ventricular pressure rise and drop (±dp/dtmax) were determined. Electrocardiogram (ECG) and heart rate (HR) were simultaneously recorded by the polygraph (RM-6280). RV/(LV+S) and the weight ratio of right ventricle weight vs body weight: (RV/BW) were calculated. The right ventricle tissues were stained by Masson method to observe the degree of myocardial fibrosis, and by HE method to observe the pathological change .Expression of Cx43 were detected by immunohistochemical staining and western blot. The levels of NO and NOS in plasma were measured with nitrate reductase assay technique, while ET-1 with radioimmunoassay and BNP with elisa .Results1. Compared with normal SD rats, the PAP, RVSP,±dp/dtmax in HPH rats were significantly increased(P<0.05). After the treatment of bosentan, the PAP, RVSP,±dp/dtmax were significantly decreased(P<0.05).2. Compared with normal SD rats, the levels of ET-1, BNP in HPH rats were significantly increased(P<0.05), while the levels of NO, NOS were significantly decreased(P<0.05). After the treatment of bosentan , the levels of BNP were significantly decreased(P<0.05), while the levels of NO, NOS(P<0.05), and ET-1 were significantly increased(P<0.05).3.Compared with normal SD rats, the RV/(LV+S) ,RV/BW and the CVF of right ventricle in HPH rats were significantly increased(P<0.05), and the right ventricular pathology showed myocardial cells were hypertrophic and sparse. After the treatment of bosentan , the RV/(LV+S) ,RV/BW and the CVF of right ventricle were significantly decreased, (P<0.05) and the right ventricular pathology showed myocardial cells hypertrophy were improved.4. Compared with normal SD rats, expression of connexin43 in HPH rats was significantly decreased(P<0.05). After the treatment of bosentan, expression of connexin43 was significantly increased(P<0.05).Conclusions:1. After being in hypobaric chamber , myocardial cells of right ventricle in HPH rats were hypertrophic and sparse, myocardial fibrosis were increased, and Cx43 expression were induced. The mechanism is related to right ventricular pressure overload, the increases of plasma ET-1 and the decreases of plasma NO and NOS .2. BST can significantly decrease PAP, inhibit myocardial hypertrophy and fibrosis, restrain the inducing of myocardial Cx43 expression, improve right ventricular function. At the same time, BST can significantly decrease the levels of BNP in plasma, increase the levels of NO, NOS, ET-1 in plasma. The therapeutic mechanism of BST on right ventricle is related to decreasing right ventricular pressure-load and injury by ET through blocking the combination of ET and ETR .
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