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Modulation of Norepinephrine Release by Endogenous Mediators in Myocardial Ischemia.

Mackins, Christina J. (2005) Modulation of Norepinephrine Release by Endogenous Mediators in Myocardial Ischemia. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

In myocardial ischemia, arrhythmias due to excessive norepinephrine (NE) release can cause cardiac dysfunction and sudden cardiac death. Therefore, it is essential to understand how endogenous mediators can influence NE release from cardiac sympathetic nerves (cSNE). This work primarily focuses on angiotensin II (ANG II), a positive modulator of NE release which is elevated in the ischemic heart. The origin of cardiac renin, the pivotal enzyme in the formation of ANG II, was investigated using renin-specific antibodies. These studies are the first to demonstrate that mast cells are a source of cardiac renin. This observation was extended to the human mast cell line HMC-1. Mast cell degranulation was found to release active renin which promotes NE release from cSNE via the formation of ANG II. Accordingly, a positive coupling was established between AT1-receptor activation and the trigger for carrier-mediated NE release, the neuronal Na+/H+ exchanger (NHE). Ischemia-reperfusion studies in ex vivo hearts from guinea pigs and mast cell-deficient mice confirmed that mast-cell-derived renin has the capacity to trigger the cardiac renin-angiotensin cascade, leading to local ANG II formation, enhanced carrier-mediated NE release and arrhythmic cardiac dysfunction. Cardiac histamine inhibits NE release via activation of H3-receptors located on cSNE. The signal transduction mechanisms responsible for H3-receptor-mediated attenuation of exocytotic NE release were studied in an H3-transfected neuroblastoma cell line. H3-receptor activation was found to ultimately result in attenuated protein kinase A (PKA) activity, which decreases Ca2+ influx through voltage-gated channels and consequently diminishes NE exocytosis. These studies have revealed a paradoxical role of mast cells as a source of both cardiac renin and histamine. Acting via AT1- and H3-receptors, respectively, ANG II and histamine have counteracting roles in the modulation of NE release from cSNE. Since minimizing NE release is protective in myocardial ischemia, novel therapeutic strategies should be directed towards inhibition of the cardiac renin-angiotensin system whilst simultaneously exploiting H3-receptor signaling mechanisms.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Mackins, Christina J.
Date : 2005
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 2005.
Depositing User : EPrints Services
Date Deposited : 06 May 2020 13:07
Last Modified : 06 May 2020 13:08
URI: http://epubs.surrey.ac.uk/id/eprint/855871

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