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.
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