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. Amersfoorth, Koen T. Scholman, Antoine H. G. Driessen, Charly N. W. Belterman, Antoni C. G. Ginneken, Joris R. Groot, Jacques M. T. Bakker, Carol Ann Remme, Bas J. Boukens and Ruben Coronel
Additional contact information
Marieke W. Veldkamp: Heart Center, Academic Medical Center
Guillaume S. C. Geuzebroek: RadboudUMC
Antonius Baartscheer: Heart Center, Academic Medical Center
Arie O. Verkerk: Academic Medical Center Amsterdam
Cees A. Schumacher: Heart Center, Academic Medical Center
Gedeon G. Suarez: Biomedical Sciences VU University Medical Center
Wouter R. Berger: Heart Center, Academic Medical Center
Simona Casini: Heart Center, Academic Medical Center
Shirley C. M. Amersfoorth: Heart Center, Academic Medical Center
Koen T. Scholman: Academic Medical Center Amsterdam
Antoine H. G. Driessen: Heart Center, Academic Medical Center
Charly N. W. Belterman: Heart Center, Academic Medical Center
Antoni C. G. Ginneken: Academic Medical Center Amsterdam
Joris R. Groot: Heart Center, Academic Medical Center
Jacques M. T. Bakker: Heart Center, Academic Medical Center
Carol Ann Remme: Heart Center, Academic Medical Center
Bas J. Boukens: Academic Medical Center Amsterdam
Ruben Coronel: Heart Center, Academic Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06530-5

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