title: Block of Na(+)/Ca(2+) exchanger by SEA0400 in human right atrial preparations from patients in sinus rhythm and in atrial fibrillation.
abstract: The Na(+)/Ca(2+) exchanger (NCX) plays a major role in myocardial Ca(2+) homoeostasis, but is also considered to contribute to the electrical instability and contractile dysfunction in chronic atrial fibrillation (AF). Here we have investigated the effects of the selective NCX blocker SEA0400 in human right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF in order to obtain electrophysiological evidence for putative antiarrhythmic activity of this new class of drugs. Action potentials were measured in right atrial trabeculae using conventional microelectrodes. Human myocytes were enzymatically isolated. Rat atrial and ventricular cardiomyocytes were used for comparison. Using perforated-patch, NCX was measured as Ni(2+)-sensitive current during ramp pulses. In ruptured-patch experiments, NCX current was activated by changing the extracellular Ca(2+) concentration from 0 to 1mM in Na(+)-free bath solution (100mM Na(+) intracellular, "Hilgemann protocol"). Although SEA0400 was effective in rat cardiomyocytes, 10µM did not influence action potentials and contractility, neither in SR nor AF. SEA0400 (10μM) also failed to affect human atrial NCX current measured with perforated patch. With the "Hilgemann protocol" SEA0400 concentration-dependently suppressed human atrial NCX current, and its amplitude was larger in AF than in SR cardiomyocytes. Our results confirm higher NCX activity in AF than SR. SEA0400 fails to block Ni(2+)-sensitive current in human atrial cells unless unphysiological conditions are used. We speculate that block of NCX with SEA0400 depends on intracellular Na(+) concentration.
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, TU Dresden, Fetscherstr. 74, d-01307 Dresden, Germany; Department of Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: t.christ@uke.de.
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary. Electronic address: pekka.p.seppa@gmail.com.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Kovács
authors.affiliation: MTA-SZTE Cardiovascular Pharmacological Research Group, University of Szeged, Szeged, Hungary. Electronic address: acsai.karoly@med.u-szeged.hu.
authors.forename: Karoly
authors.initials: K
authors.lastname: Acsai
authors.affiliation: Clinic for Cardiac Surgery, Heart Center Dresden, Fetscherstrasse 76, 01307 Dresden, Germany. Electronic address: Michael.Knaut@herzzentrum-dresden.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Knaut
authors.affiliation: Department of Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: t.eschenhagen@uke.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; MTA-SZTE Cardiovascular Pharmacological Research Group, University of Szeged, Szeged, Hungary. Electronic address: jost@phcol.szote.u-szeged.hu.
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; MTA-SZTE Cardiovascular Pharmacological Research Group, University of Szeged, Szeged, Hungary. Electronic address: varro@phcol.szote.u-szeged.hu.
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, TU Dresden, Fetscherstr. 74, d-01307 Dresden, Germany. Electronic address: Erich.Wettwer@tu-dresden.de.
authors.forename: Erich
authors.initials: E
authors.lastname: Wettwer
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, TU Dresden, Fetscherstr. 74, d-01307 Dresden, Germany. Electronic address: Ursula.Ravens@tu-dresden.de.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000328:Adult; D000814:Aniline Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects; D010647:Phenyl Ethers / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger
keywords: Atrial fibrillation; Human right atrial cardiomyocytes; NCX current; SEA0400; Sodium-calcium exchanger