Effects Of The Novel Compound Pivanampeta Against Atherosclerosis Through Modulating The Function Of The Endothelium

Effects of the novel compound pivanampeta against atherosclerosis through modulating the function of theendotheliumPostgraduate: Qian WANG Mentor: Professor Hai WANG Application: Master of MedicineOrganization: Academy of Military Medical SciencesAtherosclerosis is a common disease which is characterized by hiddenness, gradualation and harmfulness. Although based on pathophysiology of atherosclerotic development and progreess, the studies of drug targeting the elevated lipid levels and lipid peroxided, have obtained certain progress, drug with clinical anti-atherosclerosis indication are not available now. Therefore, it is important to develop the preventive and therapeutic drug of atherosclerosis.Endothelial dysfunction is responsible for atherogenetic progress. Endothelium-dependent vasodilation mediated by the endothelial target for acetylcholine(ETA) is considered as the marker of endothelial functions. Systematic research on pharmacological profile of ETA and the relationship between functions of ETA and atherosclerosis found that dysfunctions of ETA significantly affected the development of atherosclerosis. The rabbits were fed with high cholesterol food containing arecholine, a potent ETA agonist, which could suppressed the atherosclerotic progress. New compound pivanampeta which showed antiatherosclerotic effects was screened out in the experiment of model in vitro. The pharmacodynamics characteristics and the pathway involved in antiatherosclerosis of new compound pivanampeta were evaluated on rabbit and quail atherosclerotic models induced by high cholesterol food.1. Investigation of the novel compound pivanampeta against atherosclerosis through modulating the function of endothelium1.1 Effects of pivanampeta on the atherosclerosis induced by high blood cholesterol in rabbitsWhen fed with high cholesterol food for 12 weeks, rabbits showed accumulation of lipids on the intima of aorta which forms the atherosclerosis plaque. The microscopically-recognizable change of coronary artery include the intima thickening, atheroma partly protruding in luminal, conjunction of endothelial being breaken, intima being damage, arrangement of smooth muscle cells being disordered and hyperplasia.New compound pivanampeta could significantly attenuate the atherosclerotic lesions of aorta at the doses of 1 and 5 mg/kg when cholesterol level of rabbits were equal to those of the models described above. In the pivanampeta 1 mg/kg group, the intima was smooth and complete, and endothelial conjunction was close. In addition, media became thick, and the nucleus of smooth muscle cells proliferated which is a sign of hyperplasia. In the pivanampeta 5mg/kg group, arrangement of smooth muscle cell is in order and its structure is similar to that of the normal.1.2 Effects of pivanampeta against quails atherosclerosis induced by high blood cholesterolThe aorta intima surface showed the fatty streaks when quails were high cholesterol-fed for 14 weeks. The pathological changes mainly appeared in the thoracic aorta and obdominal aorta and also could extend to aorta extreme segments. Under the photomicrograph, the endothelial cells shed off, the conjunction of not shed off endothelial cells were loose, The intima obviously was thickened, part of intima protruded into luminal. In the scan electron microscope, intima surface of normal groups is smooth and the arrangement of the endothelial cell was orderly along the blood flow, while in the intima surface of model groups monocyte attaching intima, endothelial cell transformation, endothelium like leaf and cell cleft aggrandizement. It was indicated to give the quail high cholesterol food can induce atherogenesis in quails.Compound pivanampeta at the doses of 3, 6 and 9mg/kg can obviously alleviated severity of atherosclerosis of aorta in a dose-dependent manner when cholesterol level of quails were equal to those of the models described above(P<0.01 vs model). Moreover, significantly alleviatived severity of atherosclerosis of brachiocephalic aorta intima by dos...