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， 证明了血清IgE水平与 心肌梗死、卒中和外周大血管病变的发生率 动脉疾病我们的目的是提供一个了解 免疫药理学机制负责这种关联。 我们建议研究腺苷，一种主要的促肾上腺皮质激素， 在心脏过敏反应期间与组胺（HA）一起释放。的相互作用 这两种药物之间的相互作用可能导致急性房室传导 阻滞、冠状动脉痉挛和收缩衰竭。我们计划评估 腺苷介导HA的负向传导效应， 确定负责HA诱发腺苷的心脏细胞类型 release.我们还将研究缓激肽在心脏中的作用， 过敏反应;缓激肽可能发挥保护作用， 怀疑可通过ACE抑制剂增强， 抗高血压药物 虽然从20世纪80年代初就知道， HA诱导的血管舒张是由内皮源性舒张血管内皮细胞介导的。 因子（EDRF），直到现在，随着EDRF被发现， 尼古丁衍生的一氧化氮（NO），特定的工具已经成为 可用于研究HA的血管作用的这种模式。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 血管舒张此外，我们计划定义条件和代理如何 调节心脏EDRF/NO合成，寿命和作用可以影响 HA释放NO和扩张冠脉血管的作用。我们将在下一个地址 EDRF/NO可能在全身过敏反应中起关键作用; 在这种情况下，HA和许多其他NO释放介质， 排放到循环中。过敏反应的较简单模型 将利用离体心脏和血管中的反应。 我们还将研究内皮功能障碍综合征， 已经发现在体内过敏反应后发生， 以选择性地取消对某些 内皮依赖性血管扩张剂（即，HA和乙酰胆碱，但不是 ADP）和对血管收缩剂的高反应性。我们计划全面 表征该内皮缺陷并确定因素 负责其诱导和潜在的分子基础。一个 对过敏后内皮脱敏的理解可能 与高血压相关的重要临床意义， 动脉粥样硬化和糖尿病，这是已知的， 内皮依赖性血管舒张能力降低。此外，委员会认为， 这些研究可能会为研究人类的 NO合成酶的受体激活和该系统的下调。的 一个功能齐全的内皮细胞的重要性是突出的事实， HA在动脉粥样硬化部位是一种有效的冠状血管收缩剂， 病变由于HA是由许多常用药物和心肌细胞释放的， 缺血时，EDRF系统功能障碍可促使HA诱导的 冠状动脉痉挛导致心肌梗死、心律失常和突发 心源性死亡因此，EDRF系统必须彻底 研究与心脏HA释放的关系。

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.