ENDOTHELIUM-DERIVED CONSTRICTING FACTORS IN HYPERTENSION

原发性高血压患者心输出量正常， 外周血管阻力增加。 许多因素可能会导致 与血管阻力升高有关 最近，很明显， 内皮可通过释放内皮源性的 舒张因子;内皮依赖性舒张似乎减少 在患有遗传性高血压的老鼠的动脉中。 在一定 在某些情况下（如缺氧），内皮细胞也可以释放收缩剂， 物质。 初步实验表明，乙酰胆碱和 血清素可以从主动脉释放血管收缩物质 内皮细胞的遗传性高血压大鼠（SHR），而不是从 正常血压对照组（WKY）。 本建议的主要目的是 探讨内皮源性收缩因子的重要性 在自发性高血压大鼠中。 实验将在 孤立的动脉（在某些情况下还有其他动脉和静脉）， 无内皮的SHR和WKY。 血管平滑肌的反应 将被记录为等长张力。 为了演示 乙酰胆碱和其他收缩因子从内皮 潜在的释放物（涉及高血压的神经体液介质， 血小板，Na+，K+ ATP酶抑制剂，缺氧，跨壁压）， 将使用分层制剂（“三明治制剂”）和生物测定 设备. 确定内皮源性收缩的性质 因素将需要检查花生四烯酸的代谢， 其他神经体液介质的参与，以及 氧自由基 为了确定细胞机制， 内皮源性收缩因子对血管平滑肌的作用 肌肉将需要测量膜电位和药理学 干扰Na+，K+ ATP酶，花生四烯酸代谢， Ca 2+运动。 高血压的危害有哪些？ 和老化的发生内皮依赖性收缩将 接受检查。 最后，我们将确定内皮依赖性 收缩发生在大鼠和狗的血管中， 高血压 内皮功能紊乱可能导致 外周阻力升高的高血压和并发症，如 心肌梗塞和中风。 人们希望获得的知识 从拟议的研究将提供新的见解的作用 内皮作为血管收缩信号的来源。

In established primary hypertension cardiac output is normal, while peripheral vascular resistance is increased. Many factors may contribute to the elevated vascular resistance. Recently, it became obvious that the endothelium can affect vascular tone by releasing an endothelium-derived relaxing factor(s); endothelium-dependent relaxations appear to be reduced in arteries from rats with genetic hypertension. Under certain circumstances (e.g. anoxia) the endothelium can also release a constrictor substance(s). Preliminary experiments suggest that acetylcholine and serotonin can release a vasoconstrictor material from the aortic endothelium of genetically hypertensive rats (SHR) but not from normotensive controls (WKY). The major purpose of the present proposal is to explore the importance of the endothelium-derived contracting factor(s) in spontaneously hypertensive rats. Experiments will be performed on isolated aortas (and in some cases other arteries and veins), with and without endothelium, of SHR and WKY. Responses of vascular smooth muscle will be recorded as isometric tension. To demonstrate the release of the contracting factor(s) from the endothelium by acetylcholine and other potential releasers (neurohumoral mediators involved in hypertension, platelets, inhibitors of Na+,K+ ATPase, hypoxia, transmural pressure) we will use layered preparations ("sandwich preparations") and a bioassay apparatus. To determine the nature of the endothelium-derived contracting factor(s) will require examination of the metabolism of arachidonic acid, of the involvement of other neurohumoral mediators, and of the role of oxygen-derived free radicals. To determine the cellular mechanism of action of the endothelium-derived contracting factor(s) on vascular smooth muscle will require measurement of membrane potential and pharmacological interference with Na+,K+ ATPase, the metabolism of arachidonic acid, and Ca2+ movements. The importance of chronic exposure to high blood pressure and of aging for the occurrence of endothelium-dependent contractions will be examined. Finally, we will determine whether endothelium-dependent contractions occur in blood vessels of rats and dogs with secondary hypertension. A disturbed endothelial function could contribute to the elevated peripheral resistance of hypertension and complications such as myocardial infarction and stroke. It is expected that the knowledge gained from the proposed research will provide new insight concerning the role of the endothelium as a source of vasoconstrictor signals.