CARDIAC DYSFUNCTIONS CAUSED BY HISTAMINE RELEASE

组胺(HA)，在心脏肥大中存在显著浓度 细胞(MC)，通过免疫或通过缺血再灌注(I/R)释放， 导致严重的H2受体(H2R)介导的快速性心律失常。这些MC正在进入 离交感神经末梢很近，我们有 最近发现含有一种不同的HA受体亚型H3R， 下调去甲肾上腺素(NE)的释放。H3R静止，但完全 在高肾上腺素状态下激活，如心肌缺血，当HA 被大量释放。我们将测试假设H3R也是 在衰竭的心脏中被激活。因为心脏MC暴露在 邻近SNT释放的神经肽(如NPY)和感觉C- 纤维(如CGRP)，我们将研究NPY和CGRP对 正常和缺血状态下心脏HA的释放。此外，我们还将 直接研究与H3R相关的转导机制- 正常和缺血SNT对去甲肾上腺素释放的抑制作用 (突触体)从豚鼠心脏和心脏中分离的狗 失败和来自手术标本的人右心房。由飞行员帮助 数据显示，我们推测H3R可减弱NE的胞吐作用(与急性 缺血)和“载体介导的”释放(与延长有关 缺血和Na+/H+逆向转运体激活)，通过抑制PI周转和 PKC活性。事实上，我们发现缓激肽(BK)，它是已知的 刺激Na+/H+交换器，增加NE的释放 迁延性缺血。因此，我们建议对受体进行表征 BK诱导增强的亚型和转导机制 延迟性心肌缺血时NE释放的变化。在其他推定的 心脏交感神经传递的内源性调节剂，我们计划 在心脏突触体中研究一氧化氮(NO)的作用， 我们发现它作为其功能的一个函数来增强或减少NE的胞吐 集中精神。我们建议确定调解 NO的促进和抑制作用，重点是NO是否 通过钙离子依赖或独立机制促进去甲肾上腺素释放 NO是否通过激活高电导Kca抑制NE释放 从而使SNT超极化，减少Ca~(2+)进入和 胞吐。感染性休克是重症监护病房的主要死亡原因 单位，特点是没有生产过剩，心肌压低 收缩能力和肾上腺素能紊乱。在感染性休克模型中，我们将 确定主治性心力衰竭是否与 去甲肾上腺素释放减少反映了高NO浓度对 SNT。总的来说，拟议的研究将评估保护性的 心脏HA释放的有害效应及其调节 多种刺激，以及H3R涉及的转导机制 发信号。SNT功能的其他内源性调节因子的作用(BK和 否)将被定义。因此，拟议的研究将产生新颖的 以及对开发新的治疗方法的重要信息 心血管疾病的治疗策略。

Histamine (HA), present in significant concentrations in cardiac mast cells (MC), is released immunologically or by ischemia-reperfusion (I/R), causing severe H2-receptor(H2R)-mediated tachyarrhythmias. These MC are in close proximity to sympathetic nerve terminals (SNT), which we have recently discovered to contain a different HA receptor subtype, H3R, that downregulates norepinephrine (NE) release. H3R quiescent, yet fully activated in hyperadrenergic states, such as myocardial ischemia, when HA is copiously released. We will test the hypothesis that H3R are also activated in the failing heart. Because cardiac MC are exposed to neuropeptides released from neighboring SNT (e.g., NPY) and sensory C- fibers (e.g., CGRP), we will investigate the influence of NPY and CGRP on cardiac HA release in normal and ischemic conditions. Further, we will directly investigate the transductional mechanisms associated with H3R- mediated inhibition of NE release in normal and ischemic SNT (synaptosomes) isolated from guinea pig hearts, from dogs in cardiac failure and from surgical specimens of human right atrium. Helped by pilot data, we postulate that H3R attenuate NE exocytosis (associated with acute ischemia) and "carrier-mediated" release (associated with protracted ischemia and Na+/H+ antiporter activation), by inhibiting PI turnover and PKC activity. Indeed, we find that bradykinin (BK), which is known to stimulate the Na+/H+ exchanger, increases NE release associated with protracted ischemia. Accordingly, we propose to characterize the receptor subtype and transductional mechanisms mediating the BK-induced enhancement of NE release in protracted myocardial ischemia. Among other putative endogenous modulators of cardiac sympathetic neurotransmission, we plan to investigate in cardiac synaptosomes the effects of nitric oxide (NO), which we find to enhance or decrease NE exocytosis as a function of its concentration. We propose to determine the mechanisms mediating the facilitatory and inhibitory action of NO, focussing on whether NO facilitates NE release via a Ca2+-dependent or independent mechanism, and whether NO inhibits NE release by activating high-conductance Kca channels, thus hyperpolarizing SNT, and decreasing Ca2+ entry and exocytosis. Septic shock, the leading cause of death in intensive care units, is characterized by NO overproduction, depressed myocardial contractility and adrenergic derangement. In a septic shock model, we will determine whether the attending cardiac failure is associated with a decreased NE release reflecting the action of high NO concentrations on SNT. Collectively, the proposed studies will assess both the protective and deleterious effects of cardiac HA release and its modulation by multiple stimuli, as well as the transductional mechanisms involved in H3R signaling. The role of other endogenous modulators of SNT function (BK and NO) will be defined. Accordingly, the proposed studies will generate novel and significant information towards the development of new therapeutic strategies in cardiovascular diseases.