MECHANISMS UNDERLYING ARTERIOLAR MYOGENIC CONTRACTION

肌源性机制在局部血流调控中的作用 近年来，血管阻力受到极大的关注。 然而，关于细胞内事件的信息很少，这些事件 将小动脉对血管急剧上升的收缩反应结合起来 血管内压。这项提案的总体目标是 研究细胞内信号转导通路参与 肌源性反应。四个具体的假设将被检验：1. 小动脉收缩装置的钙敏感性是一个函数 血管内压的变化，2.认为肌源性的维持 小动脉收缩依赖于蛋白质的参与 激酶C介导的通路，3.这种通路控制细胞内 血管平滑肌对Ca~(2+)的敏感性，以及由此产生的钙需求 在收缩的维持阶段的收缩装置，以及 4.在接触血管扩张剂后对钙离子的脱敏提供了 一种肌源性反应可以部分或完全 被适当的代谢刺激抑制的。这些组件中的一个必要组件 研究将描述细胞内的相互关系 钙水平和小动脉肌源性收缩的程度。一个 分离的微血管和图像分析技术的结合将是 用来研究这一假说。拟议的调查将 补充我们之前对微循环的活体研究 细胞生化事件与先前文献记载的整合 生理现象。对细胞内信号转导途径的了解 肌源性反应将使我们能够更充分地了解血液流动 自动调节，包括代谢和肌源性之间的相互作用 刺激，并将提供对基础基础的机制的洞察 小动脉张力。此外，了解这些基本机制将会， 协助解释生肌机制在血管中的作用 与高血压和糖尿病等疾病状态相关的病理学 微血管病变，并可能确定新的药理作用部位 干预。

The role of myogenic mechanisms in the control of local blood flow and vascular resistance has received a great deal of attention in recent years. However, little information exists as to the intracellular events which couple the contractile response of an arteriole to an acute rise in intravascular pressure. The overall goal of this proposal is to investigate intracellular signalling pathways which are involved in the myogenic response. Four specific hypotheses will be examined: 1. that Ca2+ sensitivity of the contractile apparatus in arterioles is a function of intravascular pressure, 2. that the maintenance of a myogenic constriction in small arterioles is dependent on the involvement of protein kinase C mediated pathways, 3. that such pathways control the intracellular Ca2+ sensitivity, and thus Ca2+ requirements, of the vascular smooth muscle contractile apparatus during the maintained phase of the contraction, and 4. that desensitization to Ca2+ following exposure to vasodilators provides a mechanism whereby the myogenic response can be partially, or completely, inhibited by appropriate metabolic stimuli. A necessary component of these studies will be the description of the relationship between intracellular calcium levels and the extent of arteriolar myogenic contraction. A combination of isolated microvessel and image analysis techniques will be used to investigate that hypotheses. The proposed investigation will complement our previous in vivo studies of the microcirculation by allowing the integration of cellular biochemical events with previously documented physiologic phenomena. Knowledge of the intracellular pathways involved in the myogenic response will enable us to more fully understand blood flow autoregulation, including the interactions between metabolic and myogenic stimuli, and will also provide insight into mechanisms which underlie basal arteriolar tone. Understanding these basic mechanisms will, in addition, assist in interpreting the role of myogenic mechanisms in the vascular pathology associated with disease states such as hypertension and diabetic microangiopathy and may identify sites for novel pharmacologic intervention.