The Levi laboratory investigates the role of substances which are endogenous to the heart and act on the terminals of the sympathetic nervous system to modulate the release of the neurotransmitters norepinephrine and ATP. Since excessive norepinephrine release can exacerbate ischemia and precipitate arrhythmic cardiac dysfunction, cardioprotection can be achieved either with agents that attenuate norepinephrine release or by antagonizing substances that enhance it. We have characterized a subset of histamine receptors, H3R, which are located on sympathetic nerve endings. H3R activation by selective ligands reduces norepinephrine and ATP release and alleviates cardiac dysfunction in animal and human myocardial ischemia models. Recently, we have demonstrated that the hearts of mice in which H3R have been genetically deleted are much more susceptible to severe arrhythmias when exposed to ischemia and reperfusion than hearts of congenic control mice. This loss of cardioprotection is associated with a massive release of norepinephrine. We are now investigating the transductional mechanisms associated with the H3R-mediated inhibition of norepinephrine release in sympathetic nerve endings in vitro (cardiac synaptosomes) expressing native H3R and in PC12 cells stably transfected with H3R. We are also exploring the role of an ecto-nucleotidase (ENTPDase1/CD39) which we have found to be present in sympathetic nerve terminals in the heart, and which inactivates the neurotransmitter ATP co-released with norepinephrine. Because ATP potentiates norepinephrine exocytosis, this ecto-nucleotidase displays cardioprotective effects. We find that this protection is also afforded by solCD39, a recombinant version of this enzyme. Recently, we have been studying a novel primary source of cardiac renin (i.e., mast cells). Renin is the rate-limiting enzyme in the activation of the renin-angiotensin system (RAS). We find that the release of active renin from cardiac mast cells is enhanced in ischemia/reperfusion, activating a local cardiac RAS resulting in norepinephrine release and arrhythmias. We are presently exploring means to prevent the activation of this local RAS in the heart. One promising avenue is represented by the selective activation of mitochondrial aldehyde dehydrogenase type 2 in cardiac mast cells. This prevents local renin release, RAS activation and arrhythmic cardiac dysfunction. The ultimate goal of our research is to generate novel and significant information towards the development of new therapeutic strategies in cardiovascular diseases.