Histamine Receptor/Norepinephrine in Cardiac Dysfunction

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DESCRIPTION (provided by applicant): In myocardial ischemia, arrhythmias due to excessive norepinephrine (NE) release cause high morbidity and mortality. Thus, reduction of NE release from cardiac sympathetic nerve endings (SNE) in myocardial ischemia is a critical goal. We will study how endogenous modulators regulate cardiac sympathetic neurotransmission in normal and ischemic conditions. In Aim 1, we will investigate the transductional mechanisms by which histamine H3-receptors (H3R) attenuate Ca2+- dependent NE exocytosis and carrier-mediated NE release, associated with short-term and protracted ischemia/reperfusion (I/R), respectively. This will be studied in H3R-transfected cells and in SNE from guinea-pig hearts expressing native H3R. For NE exocytosis and short-term I/R we will assess how H3R activation limits Ca2+ entry through N-type Ca2+-channels, and the roles of PKC and PLAa in implementing this. For carrier-mediated NE release and protracted I/R, we will investigate the coupling of H3R activation to Na+/H+ exchanger (NHE) inhibition, and will assess the interaction between H3R and angiotensin ATI receptors at the NHE level in SNE. Mouse hearts lacking H3R will be studied. The contribution of endogenous histamine to the cardioprotective effects of H3R activation will be determined in ischemic hearts from mast-cell-deficient mice. Among the transductional signals involved in the H3R-mediated reduction of NHE activity and carrier- mediated NE release, PKC and calmodulin will be investigated. In Aim 2, we will determine by which mechanisms tissue plasminogen activator promotes NE release in normal and ischemic hearts. Mice with genetic deletions of various components of the fibrinolytic cascade will be used. These studies will elucidate the mechanisms for endogenous control of NE release. Since reduction of NE release is protective in myocardial ischemia, identification and characterization of the factors controlling NE release will help in the development of novel therapeutic strategies in cardiovascular diseases.