Research Overview
CARDIOVASCULAR PHARMACOLOGY
Dr. Levi's 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 neurotransmitter norepinephrine. 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 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. Our postulate is that the H3R-induced attenuation of norepinephrine exocytosis (associated with acute ischemia) results sequentially from H3R-Gi/Go coupling, inhibition of adenylyl cyclase activity and decreased cAMP formation, leading to diminished PKA activity, decreased Ca2 influx through voltage-operated Ca2 -channels, and thus, attenuation of norepinephrine exocytosis. We are testing this hypothesis in sympathetic nerve endings in vitro (cardiac synaptosomes) expressing native H3R and in human neuroblastoma SH-SY5Y cells transfected with H3R. We are also exploring the mechanisms involved in the H3R-induced attenuation of "carrier-mediated" norepinephrine release (associated with protracted ischemia and Na /H antiporter activation). The hypothesis being tested in this case is that H3R activation leads to an inhibition of PI turnover and PKC activity. We are measuring Na /H activity using imaging techniques and pH sensitive dyes in cellular models of sympathetic neurons and we investigate which transductional step are involved in the H3R-induced inhibition of the antiporter. We are also exploring the role of an ecto-nucleotidase 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, in collaboration with the laboratory of Dr. Randi B. Silver of the Department of Physiology and Biophysics, Dr. Levi's laboratory has 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. We find that the release of active renin from cardiac mast cells is enhanced in ischemia/reperfusion and that the production of angiotensin is also increased, activating angiotensin AT1-receptors, resulting in a stimulation of neuronal Na /H , norepinephrine release and arrhythmias. We are therefore exploring means to interfere with the activation of this local renin-angiotensin system in the heart. The ultimate goal of our research is to generate novel and significant information towards the development of new therapeutic strategies in cardiovascular diseases.
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Dr. Levi's Lab Website: Levi Lab
