PO-630-05 A NOVEL MECHANISM OF SMALL-CONDUCTANCE CA2+-ACTIVATED K+ CHANNEL ACTIVATION VIA NEURONAL NITRIC OXIDE SYNTHASE INHIBITION IN RAT ATRIA

Abstract

The presence of atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF itself. Small-conductance Ca2+-activated K+ (SK) channel is a key factor in the atrial electrical remodeling. However, the mechanism of its activation is unclear. A recent study showed that neuronal nitric oxide synthase (nNOS) expression and activity are reduced in AF patients and that nNOS depletion causes the abbreviation of APD, leading to increased AF vulnerability in animals. Decreased NO production, especially driven by nNOS inhibition, might play a key role in the atrial electrical remodeling, and the downstream alteration of SK channels might result from this process. We aimed to evaluate the potential of SK channel blocking to mitigate abnormal electrophysiological properties and the inducibility of atrial tachyarrhythmia which was induced by neuronal nitric oxide synthase (nNOS) depletion, and to describe the related mechanism. Atrial tachyarrhythmia (ATA) induction and optical mapping were performed on perfused rat hearts. nNOS was pharmacologically inhibited by S-methylthiocitrulline (SMTC, 100nM). The influence of the SK channel was examined by a specific channel inhibitor, apamin (100nM). Action potential duration (APD), conduction velocity, and calcium transient (CaT) parameters (CaTD, Rise time, T 1/2, Tau) were evaluated by voltage and calcium optical mapping. Dominant frequency was examined in the analysis of AF dynamics. SMTC increased the inducibility of ATA and apamin mitigated the nNOS inhibition-induced arrhythmogenicity. SMTC caused the abbreviation and enhanced spatial dispersion of APD, which was reversed by apamin. In contrast, conduction velocity was not affected by SMTC or apamin. Moreover, apamin reduced the dominant frequency of SMTC-induced ATA. In voltage and calcium optical mapping, STMC and apamin does not altered parameters associated with CaT, however, SMTC caused abbreviation APD, which was reversed by apamin. Acute nNOS inhibition abbreviated APD via activating SK channels. A specific SK channel blocker mitigated APD abbreviation without alteration of CaT, implying an underlying mechanism of post translational modification of SK channels.