Effects of potassium channel openers in the isolated perfused hypokalaemic murine heart

Abstract

AimWe explored the anti-arrhythmic efficacy of K+ channel activation in the hypokalaemic murine heart using NS1643 and nicorandil, compounds which augment IKr and IKATP respectively.MethodsLeft ventricular epicardial and endocardial monophasic action potentials were compared in normokalaemic and hypokalaemic preparations in the absence and presence of NS1643 (30 μm) and nicorandil (20 μm).ResultsSpontaneously beating hypokalaemic hearts (3 mm K+) all elicited early afterdepolarizations (EADs) and episodes of ventricular tachycardia (VT). Perfusion with NS1643 and nicorandil suppressed EADs and VT in 7 of 13 and five of six hypokalaemic hearts. Provoked arrhythmia studies using programmed electrical stimulation induced VT in all hypokalaemic hearts, but failed to do so in 7 of 13 and five of six hearts perfused with NS1643 and nicorandil respectively. These anti-arrhythmic effects were accompanied by reductions in action potential duration at 90% repolarization (APD90) and changes in the transmural gradient of repolarization, reflected in ΔAPD90. NS1643 and nicorandil reduced epicardial APD90 from 68.3 ± 1.1 to 56.5 ± 4.1 and 51.5 ± 1.5 ms, respectively, but preserved endocardial APD90 in hypokalaemic hearts. NS1643 and nicorandil thus restored ΔAPD90 from −9.6 ± 4.3 ms under baseline hypokalaemic conditions to 3.9 ± 4.1 and 9.9 ± 2.1 ms, respectively, close to normokalaemic values.ConclusionThese findings demonstrate, for the first time, the anti-arrhythmic efficacy of K+ channel activation in the setting of hypokalaemia. NS1643 and nicorandil are anti-arrhythmic through the suppression of EADs, reductions in APD90 and restorations of ΔAPD90.