Block of Na⁺/Ca²⁺ exchanger by SEA0400 in human right atrial preparations from patients in sinus rhythm and in atrial fibrillation

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• 作者：Torsten Christ^a ; ^b ; ^{t.christ@uke.de" class="auth_mail" title="E-mail the corresponding author} ; Peter P. Ková ; cs^c ; ^{pekka.p.seppa@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Karoly Acsai^d ; ^{acsai.karoly@med.u-szeged.hu" class="auth_mail" title="E-mail the corresponding author} ; Michael Knaut^e ; ^{Michael.Knaut@herzzentrum-dresden.com" class="auth_mail" title="E-mail the corresponding author} ; Thomas Eschenhagen^b ; ^{t.eschenhagen@uke.de" class="auth_mail" title="E-mail the corresponding author} ; Norbert Jost^c ; ^d ; ^{jost@phcol.szote.u-szeged.hu" class="auth_mail" title="E-mail the corresponding author} ; Andrá ; s Varró ; ^c ; ^d ; ^{varro@phcol.szote.u-szeged.hu" class="auth_mail" title="E-mail the corresponding author} ; Erich Wettwer^a ; ^{Erich.Wettwer@tu-dresden.de" class="auth_mail" title="E-mail the corresponding author} ; Ursula Ravens^a ; ^{Ursula.Ravens@tu-dresden.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Sodium-calcium exchanger ; NCX current ; SEA0400 ; Human right atrial cardiomyocytes ; Atrial fibrillation
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：5 October 2016
• 年：2016
• 卷：788
• 期：Complete
• 页码：286-293
• 全文大小：1498 K

文摘

The Na⁺/Ca²⁺ exchanger (NCX) plays a major role in myocardial Ca²⁺ 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 Ni²⁺-sensitive current during ramp pulses. In ruptured-patch experiments, NCX current was activated by changing the extracellular Ca²⁺ concentration from 0 to 1 mM in Na⁺-free bath solution (100 mM Na⁺ intracellular, “Hilgemann protocol”). Although SEA0400 was effective in rat cardiomyocytes, 10 µM did not influence action potentials and contractility, neither in SR nor AF. SEA0400 (10 μM) 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 Ni²⁺-sensitive current in human atrial cells unless unphysiological conditions are used. We speculate that block of NCX with SEA0400 depends on intracellular Na⁺ concentration.