title: Presynaptic inhibition of norepinephrine release from sympathetic nerve endings by endogenous adenosine.
abstract: ATP is coreleased with norepinephrine from sympathetic nerve endings and subsequently broken down to adenosine. In animal preparations, adenosine can inhibit norepinephrine release by stimulation of presynaptic receptors. We tested this feedback mechanism in humans by using a specific nucleoside transport inhibitor (draflazine) as a pharmacological tool to allow accumulation of endogenous adenosine in the synaptic cleft. In a dose-finding study on draflazine infusions into the brachial artery (n=10), we identified an optimal dose of 250 ng/min per deciliter of forearm tissue that induced considerable local nucleoside transport inhibition (approximately 40%) without systemic effects. In the main study, we investigated the effects of this draflazine dose on sympathetic-mediated norepinephrine spillover during lower body negative pressure (-25 mm Hg) by the use of the [3H]norepinephrine isotope dilution technique (n=25). Lower body negative pressure induced a significant increase in total body norepinephrine spillover, forearm norepinephrine appearance rate, forearm vascular resistance, and heart rate. During draflazine infusion into the brachial artery, the responses to lower body negative pressure were preserved for all parameters, with the exception of the median increase in forearm norepinephrine appearance rate, which was reduced from 54% to 2% (P <.05). We conclude that accumulation of endogenous adenosine in the synaptic cleft during sympathetic stimulation can inhibit norepinephrine release from sympathetic nerve endings.
authors.affiliation: Department of Medicine, University Hospital, Nijmegen, Netherlands.
authors.forename: G A
authors.initials: GA
authors.lastname: Rongen
authors.forename: J W
authors.initials: JW
authors.lastname: Lenders
authors.forename: J
authors.initials: J
authors.lastname: Lambrou
authors.forename: J J
authors.initials: JJ
authors.lastname: Willemsen
authors.forename: H
authors.initials: H
authors.lastname: Van Belle
authors.forename: T
authors.initials: T
authors.lastname: Thien
authors.forename: P
authors.initials: P
authors.lastname: Smits
mesh_terms: D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000328:Adult; D005246:Feedback / Q000187:drug effects; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000378:metabolism*; D010865:Pilot Projects; D010879:Piperazines / Q000008:administration & dosage*; D017729:Presynaptic Terminals / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D010879:Piperazines; C072040:draflazine; D000241:Adenosine; D009638:Norepinephrine