During myocardial ischemia the activation of histamine H3-receptors (H3R) results in attenuation of norepinephrine (NE) release from sympathetic nerve endings. This action is cardioprotective because excessive NE release from sympathetic nerves causes cardiac dysfunction including arrhythmias and sudden cardiac death. The antiexocytotic effect of H3R is associated with decreased intraneuronal Ca2+ ([Ca2+]). A better understanding of the signaling involved in the cardioprotective effect of H3R may offer new therapeutic approaches to cardiovascular diseases characterized by hyper-adrenergic activity. This work is the first to demonstrate that H3R activation leads to a direct Gβγ-induced inhibition of voltage-operated calcium channels (VOCC). This action reduces Ca2+ influx and [Ca2+], thus playing a pivotal role in the H3R-mediated antiexocytotic effects. Additionally, these studies investigated the interactions between sensory nerves, mast cells and sympathetic nerves in the heart. This work established that in ischemia/reperfusion the neuropeptides CGRP and Substance P are released from sensory C-fibers. Once released, these peptides degranulate adjacent mast cells, releasing renin and activating a local cardiac renin-angiotensin system (RAS). Angiotensin (ANG) II generated by this local cardiac RAS causes severe arrhythmias, in part directly and in part by promoting the release of NE from sympathetic nerves via activation of angiotensin type 1-receptors (AT1-receptors). This work is the first to demonstrate a pathophysiological link between sensory C-fibers and cardiac mast cells in ischemia/reperfusion, resulting in the activation of a local cardiac RAS and the promotion of NE release from sympathetic nerve endings. Unveiling this link highlights an added complexity to nerve/mast cell interactions in myocardial ischemia. Since the activation of a local cardiac RAS and the consequent excessive release in NE result in detrimental cardiovascular effects, these findings may prove significant in the development of new and effective therapeutic strategies in conditions such as myocardial ischemia and congestive heart failure.