CARDIAC DYSFUNCTIONS CAUSED BY HISTAMINE RELEASE

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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.