Study Of Preventive Effect And Mechanism Of Tetrandrine On Monocrotaline-induced Pulmonary Arterial Hypertension Rats

ObjectivePulmonary arterial hypertension (PAH) is a fatal disease characterized by a persistent elevation of pulmonary artery pressure and ventricular hypertrophy. Tetrandrine is a bisbenzylisoquinoline alkaloid that exerts tumor cell proliferation inhibition and apoptosis induction, but whether it has a therapeutic effect on PAH remains poorly defined. The present study was undertaken to investigate the efficacy of Tetrandrine on PAH.Methods48 male Sprague-Dawley rats were randomly and equally divided into 4 groups, Control group were injected with normal saline, while the others injected with Monocrotaline to induce PAH. Then treated with menstruum (liquid mixed with 5% ethanol and saline in 2:8), Tetrandrine and Vardenafil for 28 to 49 days respectively. At the end of the treatment, measure the mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RV/(LV+S)), then draw blood of the rat for a future test and killed the rat, stripping the heart completely, measure the index of right ventricular hypertrophy then keep the free wall of right ventricular for the test of pathology of myocardial cell. Cut the lung tissue completely along the hilus of lung, keeped in paraformaldehyde, glutaraldehyde and liquid nitrogen, for the need of different detections. Paraffin sections of lung tissue, staining the section in different ways, observed the pathological and physiological change of small arterial structure and endothelial cell under optical microscope. Observe the ultrastructure pathophysiology change of endothelial cell in small pulmonary arterial with transmission electron microscope. Made the lung tissue prevered in the liquid nitrogen into homogenate, test the change of the key factors in NO signaling pathway, cGMP-dependent protein kinase type Ⅰ (PKG-Ⅰ) and inducible nitric oxide synthase (iNOS), to make sure whether NO signaling pathway play a significant role in PAH. Also we test the change of the expression of indexes of oxidative stress in lung tissue homogenate, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and catalase (CAT), to measure the imbalanced of oxidative stress among groups.ResultsCompared with MCT group, rats treated with Tetrandrine attenuated mPAP and RV/(LV+S) (p<0.05), inhibited proliferation of pulmonary arterial smooth muscle cells, improved endothelial function. Tetrandrine also up-regulated the expression of protein PKG-Ⅰ, down-regulated the expression of protein iNOS (p<0.05), increased levels of SOD、GSH and CAT and decreased MDA (p<0.05).ConclusionTetrandrine alleviated MCT induced PAH via regulation of NO signaling pathway, antioxidant and anti-proliferation effects.