PERIPHERAL VASCULAR CONTROL MECHANISMS

外周血管控制机制

• 批准号: 2217447
• 负责人: BARRY M CHAPNICK
• 金额: $ 19.15万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 1997-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2217447
• 关键词: artery; bioassay; cell membrane; dogs; hemodynamics; leukotrienes; nitric oxide; peripheral blood vessel; receptor binding; tissue /cell culture; vascular endothelium; vascular smooth muscle; vasodilators; vasomotion; veins

Leukotrienes (LT) C4 and D4 are the principal Components of slow reacting substance of anaphylaxis (SRS-A). Results of previous studies have shown that these substances have the capacity to produce endothelium dependent vasomotor relaxation, which, in arteries, is dependent on the release of an endothelium derived relaxing factor (EDRF). The factor released by LTD4 from arteries could not be distinguished by pharmacological criteria from the classical EDRF, considered to be nitric oxide (NO) or an unstable nitroso compound that releases NO. In contrast to these observations, it was found that LTD4 induced endothelium-dependent relaxation of the renal vein in a more potent and efficacious manner, but the vasorelaxant activity was due to a mechanism or mediator other than cyclooxygenase-derived products of arachidonic acid, the classic EDRF/NO, or vascular smooth muscle hyperpolarization consequent to ATP-sensitive K+ channel activation. More recent observations suggest that multiple signal transduction pathways and perhaps different LT receptors may account for the diverse activity of these substances in arteries and veins. Additionally, both LTC4 and LTD4 evoke marked endothelium- dependent relaxation of visceral capacitance veins. These latter observations appear to be consistent with the known hemodynamic changes which occur during anaphylactic shock, including hypotension and a fall in cardiac output associated with a reduction in venous return to the heart secondary to vasodilation of splanchnic venous capacitance vasculature. It was these aforementioned observations that led to the formulated working hypotheses: a) endothelium dependent relaxation evoked in veins by LTs is consequent to a mechanism/mediator that differs from EDRF/NO and b) receptors for LTs localized on venous and arterial endothelium differ. In order to evaluate these hypotheses, studies are proposed to: comprehensively characterize evoked changes in vasomotor tone in isolated vascular ring preparations; identify and characterize, via bioassay, vasomotor mediators derived from vascular segments or primary endothelial cell cultures; and define receptor binding characteristics of LTs on endothelial cell membranes. Overall knowledge gained from these studies will help to improve our understanding of the role of these potent endogenous substances in the regulation of vasomotor tone and peripheral hemodynamics.

白三烯(LT)C4和D4是慢反应的主要成分 过敏反应物质(SRS-A)。先前的研究结果表明 这些物质有能力产生内皮依赖性 血管舒张性松弛，在动脉中，依赖于释放 一种内皮衍生的松弛因子(EDRF)。由释放的因子 根据药理学标准不能区分来自动脉的LTD4 从经典的EDRF，被认为是一氧化氮(NO)或 释放NO的不稳定亚硝基化合物。与这些形成对比的是 观察发现，LTD4诱导内皮依赖 更有效地松弛肾静脉，但 血管松弛活性是由于一种机制或介质而不是 花生四烯酸的环氧合酶衍生产物，经典的EDRF/NO， 或由三磷酸腺苷敏感引起的血管平滑肌超极化 K+通道激活。最近的观察表明，多个 信号转导通路和可能不同的LT受体可能 解释了这些物质在动脉中的不同活性 静脉。此外，LTC4和LTD4都能激发标记的内皮细胞- 内脏电容静脉的依赖性松弛。这些是后者 观察结果似乎与已知的血流动力学变化相一致。 发生在过敏性休克期间，包括低血压和跌倒 与静脉回流减少相关的心输出量 内脏静脉电容血管扩张继发心脏 脉管系统。正是这些前述观察结果导致了 公式化的工作假设：a)诱发的内皮依赖性松弛 LTS在静脉中的作用是由于一种不同于 LTS的EDRF/NO和b)受体定位于静脉和动脉 内皮细胞不同。为了评估这些假说，研究包括 建议：全面描述血管运动诱发的变化 在分离的血管环制剂中的音调；鉴定和表征， 通过生物测定，来自血管节段或 原代内皮细胞培养；并定义受体结合 内皮细胞膜上LTS的特性。全面知识 这些研究将有助于我们更好地了解 这些强效内源性物质在血管运动调节中的作用 声调和外周血流动力学。