title: Effects of SEA0400 and KB-R7943 on Na+/Ca2+ exchange current and L-type Ca2+ current in canine ventricular cardiomyocytes.
abstract: SEA0400 and KB-R7943 are compounds synthesised to block transsarcolemmal Na+/Ca2+ exchange current (I(Na/Ca)); however, they have also been shown to inhibit L-type Ca2+ current (I(Ca)). The potential value of these compounds depends critically on their relative selectivity for I(Na/Ca) over I(Ca). In the present work, therefore, the concentration-dependent effects of SEA0400 and KB-R7943 on I(Na/Ca) and I(Ca) were studied and compared in canine ventricular cardiomyocytes using the whole-cell configuration of the patch clamp technique. SEA0400 and KB-R7943 decreased I(Na/Ca) in a concentration-dependent manner, having EC50 values of 111+/-43 nM and 3.35+/-0.82 microM, when suppressing inward currents, while the respective EC50 values were estimated at 108+/-18 nM and 4.74+/-0.69 microM in the case of outward current block. SEA0400 and KB-R7943 also blocked I(Ca), having comparable EC50 values (3.6 microM and 3.2 microM, respectively). At higher concentrations (10 microM) both drugs accelerated inactivation of I(Ca), retarded recovery from inactivation and shifted the voltage dependence of inactivation towards more negative voltages. The voltage dependence of activation was slightly modified by SEA0400, but not by KB-R7943. Based on the relatively good selectivity of submicromolar concentrations of SEA0400--but not KB-R7943--for I(Na/Ca) over I(Ca), SEA0400 appears to be a suitable tool to study the role of I(Na/Ca) in Ca2+ handling in canine cardiac cells. At concentrations higher than 1 microM, however, I(Ca) is progressively suppressed by the compound.
authors.affiliation: Department of Physiology, University Medical School of Debrecen, P.O. Box 22, 4012, Debrecen, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Birinyi
authors.forename: Károly
authors.initials: K
authors.lastname: Acsai
authors.forename: Tamás
authors.initials: T
authors.lastname: Bányász
authors.forename: András
authors.initials: A
authors.lastname: Tóth
authors.forename: Balázs
authors.initials: B
authors.lastname: Horváth
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Norbert
authors.initials: N
authors.lastname: Szentandrássy
authors.forename: János
authors.initials: J
authors.lastname: Magyar
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.forename: Péter P
authors.initials: PP
authors.lastname: Nánási
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010647:Phenyl Ethers / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000814:Aniline Compounds; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D013890:Thiourea; D002118:Calcium