Block of Na(+)/Ca(2+) exchanger by SEA0400 in human right atrial preparations from patients in sinus rhythm and in atrial fibrillation

TY - JOUR

T1 - Block of Na(+)/Ca(2+) exchanger by SEA0400 in human right atrial preparations from patients in sinus rhythm and in atrial fibrillation

AU - Christ, Torsten

AU - Kovács, Peter P

AU - Acsai, Karoly

AU - Knaut, Michael

AU - Eschenhagen, Thomas

AU - Jost, Norbert

AU - Varró, András

AU - Wettwer, Erich

AU - Ravens, Ursula

N1 - Copyright © 2016 Elsevier B.V. All rights reserved.

PY - 2016/10/5

Y1 - 2016/10/5

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.ejphar.2016.06.050

DO - 10.1016/j.ejphar.2016.06.050

M3 - SCORING: Journal article

C2 - 27373849

VL - 788

SP - 286

EP - 293

JO - EUR J PHARMACOL

JF - EUR J PHARMACOL

SN - 0014-2999

ER -