Neurokinin-3 receptor activation selectively prolongs atrial refractoriness by inhibition of a background K+ channel

Marieke W. Veldkamp, Guillaume S. C. Geuzebroek, Antonius Baartscheer, Arie O. Verkerk, Cees A. Schumacher, Gedeon G. Suarez, Wouter R. Berger, Simona Casini, Shirley C. M. van Amersfoorth, Koen T. Scholman, Antoine H. G. Driessen, Charly N. W. Belterman, Antoni C. G. van Ginneken, Joris R. de Groot, Jacques M. T. de Bakker, Carol Ann Remme, Bas J. Boukens, Ruben Coronel

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The cardiac autonomic nervous system (ANS) controls normal atrial electrical function. The cardiac ANS produces various neuropeptides, among which the neurokinins, whose actions on atrial electrophysiology are largely unknown. We here demonstrate that the neurokinin substance-P (Sub-P) activates a neurokinin-3 receptor (NK-3R) in rabbit, prolonging action potential (AP) duration through inhibition of a background potassium current. In contrast, ventricular AP duration was unaffected by NK-3R activation. NK-3R stimulation lengthened atrial repolarization in intact rabbit hearts and consequently suppressed arrhythmia duration and occurrence in a rabbit isolated heart model of atrial fibrillation (AF). In human atrial appendages, the phenomenon of NK-3R mediated lengthening of atrial repolarization was also observed. Our findings thus uncover a pathway to selectively modulate atrial AP duration by activation of a hitherto unidentified neurokinin-3 receptor in the membrane of atrial myocytes. NK-3R stimulation may therefore represent an anti-arrhythmic concept to suppress re-entry-based atrial tachyarrhythmias, including AF.
Original languageEnglish
Article number4357
JournalNature communications
Issue number1
Publication statusPublished - 2018

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