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.
Highlights
The cardiac autonomic nervous system (ANS) controls normal atrial electrical function
We investigated the electrophysiological effects of the neuropeptide Sub-P in isolated rabbit atrial myocytes, and in Langendorff-perfused and in situ rabbit hearts
We investigated the effects of Sub-P on the major membrane currents controlling atrial action potential (AP) duration in rabbit atrial cardiomyocytes, including steady-state and transient outward currents, L-type calcium currents, and calcium-dependent currents
Summary
The cardiac autonomic nervous system (ANS) controls normal atrial electrical function. The intracardiac ganglia located in fat pads on the heart produce a variety of neuropeptides including substance-P (Sub-P)[8,9,10,11], in addition to NA and ACh. While the actions of these neuropeptides on the cardiac neuron as effector cell are subject of ongoing investigation, their direct effects on atrial cardiomyocyte electrophysiology are largely unknown. We show that Sub-P produces a selective prolongation of atrial AP duration and refractoriness in a dose-dependent manner These effects were present at high pacing rates (typically observed in AF), and were absent in ventricular myocardium, indicating atrial-specific efficacy. We demonstrate that these effects are mediated through activation of the neurokinin-3 receptor (NK3R) and involve inhibition of a background K+ current. We propose NK-3R as a therapeutic target for reentry-based atrial arrhythmias, including AF
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