Neuropeptide Substance-P Modulates Electrical Characteristics of Rabbit Atrial Myocytes

Abstract

Background: The cardiac nervous system plays an important role in the initiation and maintenance of atrial fibrillation (AF). Besides the classical neurotransmitters, the nerves innervating the atria also release a wide range of neuropeptides that may play a role in the pathophysiology of AF. Since the direct effect of these neuropeptides on atrial myocytes is largely unknown, we investigated the electrophysiological response of atrial myocytes to several neuropeptides, importantly substance-P (Sub-P).Methods and Results: Single left atrial myocytes from rabbit hearts were obtained by enzymatic dissociation and the effects of Sub-P, neuropeptide-Y (NPY), somatostatin-14 (SOM-14) and vasoactive intestinal peptide (VIP), were studied using patch-clamp and indo-1 fluorescence methodologies. NPY, SOM-14 and VIP (1 μM) did not affect atrial action potential (AP) characteristics. Sub-P however, reduced both resting membrane potential (RMP) and action potential amplitude, and increased action potential duration at 90% of repolarisation (APD90) by 40%. The effects on APD90 were dose-dependent and occurred from a concentration of 10 nM. Voltage-clamp analysis revealed that Sub-P significantly diminished L-type calcium current, inward rectifier K+ current (IK1) and an unknown steady-state outward current. Transient outward current, Ca2+- activated chloride current and Na+-Ca2+-exchanger current were unaffected, as was the intracellular calcium handling. The reduction in RMP and increase in APD90 are likely due to the decrease in IK1 and steady-state outward current, respectively. Our experiments indicate that the latter is probably carried by background-like potassium channels.Conclusion: Atrial myocyte electrophysiology is significantly modulated by the neuropeptide Sub-P, mainly characterized by a substantial AP prolongation due to inhibition of a background potassium current. Since lengthening of atrial repolarization is potentially anti-arrhythmic, we hypothesize that release of Sub-P may be beneficial to the prevention and/or termination of AF.