CARDIAC DYSFUNCTIONS CAUSED BY HISTAMINE RELEASE

免疫超敏反应通常与严重的 心血管功能障碍。最近的流行病学研究表明 显示出血清IgE水平与 心肌梗死、卒中和大血管周围病变的发生率 动脉疾病。我们的目的是提供对 导致这种联系的免疫药理机制。 我们建议研究腺苷的作用，腺苷是一种主要的心律失常诱因， 在心脏过敏反应中与组胺(HA)一起释放。互动 这两种药物之间可能导致急性房室传导 阻滞、冠脉痉挛和收缩衰竭。我们计划评估其影响范围 腺苷介导透明质酸的负性亲水性作用 确定与HA诱发的腺苷有关的心肌细胞类型(S) 放手。我们还将研究缓激肽在心脏疾病中的作用。 过敏反应；缓激肽可能起到保护作用，我们 疑似患者可能会被常用的血管紧张素转换酶抑制剂增强 抗高血压药物。 虽然从20世纪80年代初就知道S是一个重要的组成部分 HA诱导的血管扩张是由内皮细胞衍生的松弛所介导的 因子(EDRF)，直到现在才发现EDRF是 精氨酸衍生的一氧化氮(NO)，这种特定的工具已经成为 可用于研究HA的这种血管作用模式。因此，我们建议 充分研究EDRF/NO在HA诱导的冠状动脉病变中的作用 血管扩张。此外，我们计划定义条件和代理如何 哪些调控心脏EDRF/NO的合成、寿命和作用可以影响 HA具有释放NO和扩张冠脉的作用。我们将在接下来的演讲 EDRF/NO在全身过敏反应中可能发挥的关键作用； 在这种情况下，HA和许多其他释放NO的介质 排入血液循环。不太复杂的过敏症模型 将利用分离的心脏和血管中的反应。 我们还将调查一种内皮功能障碍综合征，我们将 已经被发现发生在体内的过敏反应之后，这是 其特点是有选择地取消了对某些 内皮依赖性血管扩张剂(即HA和乙酰胆碱，但不是 ADP)和对血管收缩药的高反应性。我们计划全面 描述这种内皮细胞缺陷并确定其影响因素(S) 对其诱导和潜在的分子基础负责。一个 对过敏后内皮细胞脱敏的理解可能有 与高血压有关的重要临床意义 动脉粥样硬化和糖尿病，已知与 内皮依赖性血管松弛能力减弱。此外， 这些研究很有可能为研究高血压的发病机制提供新的见解。 NO合酶的受体激活和该系统的下调。这个 一个功能齐全的内皮细胞的重要性从以下事实中突显出来 HA在动脉粥样硬化部位是一种有效的冠脉血管收缩因子 损伤。由于HA是由许多常用药物释放的，因此在心肌中 缺血，EDRF系统功能障碍可沉淀HA诱导的 冠脉痉挛导致心肌梗死、心律失常和猝发 心源性死亡。EDRF系统必须彻底 研究与心脏HA释放有关的问题。

Immune hypersensitivity reactions are often associated with severe cardiovascular dysfunction. Recent epidemiological studies have demonstrated a significant association between IgE serum levels and incidence of myocardial infarction, stroke and large-vessel peripheral arterial disease. Our purpose is to provide an understanding of the immunopharmacologic mechanisms responsible for this association. We propose to investigate the role of adenosine, a major arrhythmogen, released with histamine (HA) during cardiac anaphylaxis. The interaction between these two agents may precipitate acute atrioventricular conduction block, coronary spasm and contractile failure. We plan to assess the extent to which adenosine mediates the negative dromotropic effect of HA and to identify the cardiac cell type(s) responsible for HA-evoked adenosine release. We will also investigate the role of bradykinin in cardiac anaphylaxis; bradykinin is likely to play a protective role which we suspect may be potentiated by ACE-inhibitors, commonly used antihypertensive medications. While it has been known since the early 1980's that a significant component of HA-induced vasodilatation is mediated by an endothelium-derived relaxing factor (EDRF), it is only now, with the discovery that EDRF is arginine-derived nitric oxide (NO), that specific tools have become available to study this mode of HA's vascular action. Thus, we propose to fully investigate the contribution of EDRF/NO to HA-induced coronary vasodilation. Furthermore, we plan to define how conditions and agents which modulate cardiac EDRF/NO synthesis, lifetime and action can influence HA's NO releasing and coronary-vasodilating actions. We will next address the critical role which EDRF/NO is likely to play in systemic anaphylaxis; a situation in which HA and many other NO-releasing mediators are discharged into the circulation. Less complex models of anaphylactic reactions in isolated heart and vessels will be utilized. We will also investigate a syndrome of endothelium dysfunction which we have discovered to occur following anaphylaxis in vivo, and which is characterized by a selective abolition of the response to certain endothelium-dependent vasodilators (i.e., HA and acetylcholine, but not ADP) and by a hyperresponsiveness to vasoconstrictors. We plan to fully characterize this endothelial defect and to identify the factor(s) responsible for its induction and underlying molecular basis. An understanding of post-anaphylactic endothelial desensitization may have important clinical implications in relation to hypertension, atherosclerosis and diabetes, which are known to be associated with a diminished capacity for endothelium-dependent vasorelaxation. Furthermore, these studies are likely to provide new insights into mechanisms of receptor activation of NO synthase and down-regulation of this system. The importance of a fully functional endothelium is highlighted by the fact that HA is a potent coronary-vasoconstrictor at sites of atherosclerotic lesions. Since HA is released by many commonly used drugs and in myocardial ischemia, dysfunctions of the EDRF system could precipitate HA-induced coronary spasm leading to myocardial infarction, arrhythmias and sudden cardiac death. It is imperative that the EDRF system be thoroughly investigated in relation to cardiac HA release.