title: Amitriptyline has a dual effect on the conductive properties of the epithelial Na channel.
abstract: This study was undertaken with the aim of testing the action of amitriptyline on the epithelial Na channel (ENaC), which belongs to the same family (Deg/ENaC) as ASICs (acid-sensing ion channels) and many other putative members in the brain. We assumed that, having a common protein structure, characterization of the amitriptyline-ENaC interaction could help to elucidate the analgesic mechanism of this tricyclic antidepressant. Na-channel characteristics were derived from the analysis of blocker-induced lorentzian noise produced by amiloride. The effect of amitriptyline, present in the mucosal bathing solution, on the transepithelial short-circuit current (I(sc)) and conductance (G(t)), and on the blocker-induced noise of apical Na channels, was studied on isolated ventral skin of the frog Rana ridibunda. Amitriptyline exerted a dual effect on the macroscopic short-circuit current and conductance of the epithelia, increasing these two parameters in the concentration range 0.1-50 microM, while at higher concentrations (100-1000 microM) it showed an inhibitory action. The decrease in the association rate (k(01)) of amiloride to the apical Na channels from 15.6+/-4.2 microM(-1) s(-1) in control Cl-Ringer to 7.4+/-1.7 microM(-1) s(-1) at 200 microM amitriptyline in a concentration-dependent manner suggests a competitive binding of amitriptyline to the pyrazine ring binding site for amiloride.
authors.affiliation: Department of Animal Physiology and Biophysics, University of Bucharest, Faculty of Biology, Splaiul Independentei 91-95, Bucharest R-76201, Romania.
authors.forename: Florentina
authors.initials: F
authors.lastname: Pena
authors.forename: Emil
authors.initials: E
authors.lastname: Neaga
authors.forename: Bogdan
authors.initials: B
authors.lastname: Amuzescu
authors.forename: Alina
authors.initials: A
authors.lastname: Nitu
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Flonta
mesh_terms: D000465:Algorithms; D000584:Amiloride / Q000378:metabolism; D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D004594:Electrophysiology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D011895:Rana ridibunda; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D015222:Sodium Channels; D000639:Amitriptyline; D000584:Amiloride