title: α2-Adrenergic agonists including xylazine and dexmedetomidine inhibit norepinephrine transporter function in SK-N-SH cells.
abstract: α2-Adrenergic agonists simulate norepinephrine (NE) action on α2 receptors of sympathetic neurons to mediate feedback inhibition of NE release. These agents are used as valuable adjuncts for management of hypertension and for anesthesia. Their action, equivalent to NE on α2 adrenergic receptors, raises the question whether α2 agonists may also target NE transporters (NETs), another major control mechanism for noradrenergic neurotransmission. We thus investigated the effect of α2 agonists on transport of the NE analog, (131)I-metaiodobenzylguanidine (MIBG). Results from this investigation showed that xylazine and dexmedetomidine dose-dependently blocked [(3)H]nisoxetine binding in neuron-like SK-N-SH cells. Furthermore, the agents acutely suppressed cellular MIBG uptake in a dose-dependent manner. This effect was uninfluenced by the α2 antagonist yohimbine, but was completely reversed by drug removal. There was no change in membrane NET density by the agents. Moreover, saturation analysis showed that xylazine and dexmedetomidine significantly increased Km without affecting Vmax, indicating competitive inhibition of MIBG transport. Thus, the α2 adrenergic agonists xylazine and dexmedetomidine, acutely suppress NET function through competitive inhibition of substrate transport, likely by direct interaction on a region that over-laps with the nisoxetine binding site.
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Park
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Chung
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Lee
authors.forename: Kyung-Ho
authors.initials: KH
authors.lastname: Jung
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Paik
authors.forename: Kyung-Han
authors.initials: KH
authors.lastname: Lee
mesh_terms: D019797:3-Iodobenzylguanidine / Q000378:metabolism; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D045744:Cell Line, Tumor; D020927:Dexmedetomidine / Q000494:pharmacology*; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D014991:Xylazine / Q000494:pharmacology*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D007457:Iodine Radioisotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; D018341:Receptors, Adrenergic, alpha-2; D005473:Fluoxetine; C011386:nisoxetine; D014991:Xylazine; D019797:3-Iodobenzylguanidine; D020927:Dexmedetomidine; D009638:Norepinephrine