University of Surrey

Test tubes in the lab Research in the ATI Dance Research

Carrier-mediated transport of norepinephrine transporter substrates.

Smith, Neil C.E. (2000) Carrier-mediated transport of norepinephrine transporter substrates. Doctoral thesis, University of Surrey (United Kingdom)..

Full text is not currently available. Please contact sriopenaccess@surrey.ac.uk, should you require it.

Abstract

An overview of the noradrenergic system, including the identification of norepinephrine (NE) in animal tissue, its synthesis and metabolism, adrenoceptor classification, peripheral and central actions, uptake and storage, and mechanisms of NE release are presented. After characterizing the kinetic, ion dependence and inhibitor sensitivity of the norepinephrine transporter (NET) expressed in a recombinant cell line (LLC-NET cells), the influence of catecholamine (CA) metabolizing enzymes on studies of transport was assessed. Inhibitors of catechol-O-methyltransferase (COMT) potentiated the apparent uptake and retention of [3H]NE and [3H]DA. COMT inhibition had a greater influence on [3H]DA than [3H]NE uptake and retention, which corresponds to the higher spontaneous loss of radiolabel from cells exposed to [3H]DA than [3H]NE ([3H]methoxytyramine, is more lipophilic than [3H]normetanephrine). The monoamine oxidase inhibitor, pargyline, had no augmentary action on [3H]CA uptake, but actually inhibited substrate influx by blocking the NET. [3H]substrate specific differences were demonstrated for [3H]NE, [3H]DA and [3H]MPP+. For a given length of exposure to low Na+ or tyramine, [3H]NE release was the lowest, but most sensitive to NET inhibitors. Disparities in the kinetics of each [3H]substrate for the inwardly facing NET may account for this. Inhibitors of the NET were found to stimulate the efflux of [3H]substrates from preloaded cells incubated in a physiological HEPES buffer. Efflux was NET-dependent and differed greatly for each [3H]substrate. Inhibitor-induced release was greatest for [3H]MPP+ and least for [3H]NE. Finally, a functional model of carrier-mediated NE release in myocardial ischemia, was developed in this study. Release of [3H]MPP+ was stimulated by Na+-H+ exchanger (NHE) activation and modulated by inhibitors of the NET, NHE, Na+,K+-ATPase, and via a receptor-operated pathway. Excessive NE release contributes to severe myocardial arrhythmias, therefore an improved understanding of the carrier-mediated NE release process will ultimately enhance our ability to intervene and prevent the deleterious effects of excessive NE release.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors :
NameEmailORCID
Smith, Neil C.E.UNSPECIFIEDUNSPECIFIED
Date : 2000
Contributors :
ContributionNameEmailORCID
http://www.loc.gov/loc.terms/relators/THSUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Depositing User : EPrints Services
Date Deposited : 09 Nov 2017 12:12
Last Modified : 09 Nov 2017 14:40
URI: http://epubs.surrey.ac.uk/id/eprint/843076

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year


Information about this web site

© The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.
+44 (0)1483 300800