Pharmacological Blockade of <I>I</I><SUB>Ks</SUB> Destabilizes Spiral-Wave Reentry Under <I>&beta;</I>-Adrenergic Stimulation in Favor of Its Early Termination

Abstract

Abstract. We tested a hypothesis that an enhancement of I Ks may play a pivotal role in ventricular proarrhythmia under high sympathetic activity. A 2-dimensional ventricular muscle layer was prepared in rabbit hearts, and action potential signals were analyzed by optical mapping. During constant stimulation, isoproterenol (ISP, 0.1 μM) significantly shortened action potential duration (APD); chromanol 293B (30 μM), a selective I Ks -blocker, reversed the APD shortening. VTs induced in the presence of ISP lasted longer than in the control, and this was reversed by 293B. E-4031 (0.1 μM), a selective I Kr -blocker, did not cause such reversal. Spiral-wave (SW) reentry with ISP was characterized by more stable rotation around a shorter functional block line (FBL) than in the control. After application of 293B, SW reentry was destabilized, and rotation around a longer FBL with prominent drift reappeared. The APD abbreviation by ISP close to the rotation center was more pronounced than in the periphery, leading to an opposite APD gradient (center < periphery) compared with controls. This effect was also reversed by 293B. In conclusion, β-adrenergic stimulation stabilizes SW reentry most likely though an enhancement of I Ks . Blockade of I Ks may be a promising therapeutic modality in prevention of ventricular tachyarrhythmias under high sympathetic activity.

Inhibitory Effect of Vascular Endothelial Growth Factor on the Slowly Activating Delayed Rectifier Potassium Current in Guinea Pig Ventricular Myocytes

“…Studies show that high sympathetic nerve activity easily facilitates malignant ventricular tachyarrhythmias . Blocking I Ks can prevent proarrhythmic effects under the condition of high sympathetic tone, suggesting that enhancement of I Ks may play a pivotal role in ventricular proarrhythmia under high sympathetic activity …”

Selective activation of adrenoceptors potentiates IKs current in pulmonary vein cardiomyocytes through the protein kinase A and C signaling pathways

“…There is increasing evidence showing that abnormal activity and modification of the sympathetic and parasympathetic functions are involved in the pathogenesis of AF (Khan et al, 2019 ). An interesting recent study reported by Kato (Kato et al, 2012 ) showed that, in rabbit ventricular myocardium, the spiral-wave reentry is maintained by β-adrenergic stimulation, likely through enhancement ofI Ks . Because this effect was reversed byI Ks inhibitor, the authors suggested that blockade of I Ks channels might be a promising therapeutic modality under conditions of high sympathetic activity.…”