NS8593 and UCL1684 prevented the induction of acetylcholine-mediated atrial fibrillation in 6/6 and 8/8 canine preparations, respectively, via atrial-selective inhibition of sodium channels.
Do the SK channel blockers NS8593 and UCL1684 prevent atrial fibrillation in preclinical models?
The SK channel blockers NS8593 and UCL1684 prevent atrial fibrillation through potent atrial-selective inhibition of sodium channel activity rather than SK channel inhibition.
The mechanisms underlying atrial-selective prolongation of effective refractory period (ERP) and suppression of atrial fibrillation (AF) by NS8593 and UCL1684, small conductance calcium-activated potassium (SK) channel blockers, are poorly defined. The purpose of the study was to confirm the effectiveness of these agents to suppress AF and to probe the underlying mechanisms. Transmembrane action potentials and pseudoelectrocardiograms were recorded from canine isolated coronary-perfused canine atrial and ventricular wedge preparations. Patch clamp techniques were used to record sodium channel current (INa) in atrial and ventricular myocytes and human embryonic kidney cells. In both atria and ventricles, NS8593 (3-10 µM) and UCL1684 (0.5 µM) did not significantly alter action potential duration, suggesting little to no SK channel inhibition. Both agents caused atrial-selective: (1) prolongation of ERP secondary to development of postrepolarization refractoriness, (2) reduction of Vmax, and (3) increase of diastolic threshold of excitation (all are sodium-mediated parameters). NS8593 and UCL1684 significantly reduced INa density in human embryonic kidney cells as well as in atrial but not in ventricular myocytes at physiologically relevant holding potentials. NS8593 caused a shift of steady-state inactivation to negative potentials in atrial but not ventricular cells. NS8593 and UCL1684 prevented induction of acetylcholine-mediated AF in 6/6 and 8/8 preparations, respectively. This anti-AF effect was associated with strong rate-dependent depression of excitability. The SK channel blockers, NS8593 and UCL1684, are effective in preventing the development of AF due to potent atrial-selective inhibition of INa, causing atrial-selective prolongation of ERP secondary to induction of postrepolarization refractoriness.
Burashnikov et al. (Wed,) conducted a other in Atrial Fibrillation. NS8593 and UCL1684 was evaluated on Induction of acetylcholine-mediated atrial fibrillation. NS8593 and UCL1684 prevented the induction of acetylcholine-mediated atrial fibrillation in 6/6 and 8/8 canine preparations, respectively, via atrial-selective inhibition of sodium channels.