Novel approaches for developing new antiarrythmic agents

Abstract

Arrhythmias are a major public health concern. The most common forms of arrhythmias leading to a high risk of cardiac morbidity and mortality are atrial fibrillation (AF) and ventricular tachycardia/ventricular fibrillation (VT/VF). We focus on ion-channel activation and blockade and the role of intracellular Ca2+ as key elements in generating arrhythmias. The aims of the present study were: i) To analyze the effect of the two optical enantiomers of the benzodiazepine R-L3 (ZS_1270B and ZS_1271B) on IKs current in rabbit isolated ventricular myocytes. ii) To investigate and to compare the properties (including amplitudes, current-voltage relationships, activation and deactivation kinetics) of the rapid and slow components of the delayed rectifier potassium current (IKr and IKs) in ventricular preparations isolated from dog, rabbit and guinea pig hearts and from undiseased human cardiac muscle. iii) To investigate the electrophysiological effects of ORM-10103, a newly synthetised specific sodium/calcium exchanger (NCX) inhibitor, on the NCX and L-type Ca2+ currents and on the triggered arrhythmias (formation of early and delayed afterdepolarizations). Our results demonstrate: i) The two optical enantiomers of R-L3 (ZS_1270B and ZS_1271B) have adverse modulating effects on IKs in the same concentration range. ZS_1270B is a potent activator of IKs, therefore, this substance is adequate to test whether IKs activators are indeed ideal tools to suppress ventricular arrhythmias originating from prolongation of action potentials. ii) The human cardiac delayed rectifier potassium currents best resemble those measured in the dog ventricle and rabbit heart, but are dissimilar to the kinetic properties of IKr and IKs found in guinea pig. Based also on our studies the IKr current plays the most important role in cardiac repolarization, and our findings suggest that the dog and the rabbit are suitable species for preclinical evaluation of new drugs believed to affect cardiac repolarisation. iii) ORM-10103 possesses strong NCX-inhibitory activity and it is able to suppress elementary arrhythmogenic phenomena, such as EAD and DAD.

Related Papers

• → Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG(2012)137 cited
• → Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death(2001)180 cited
• → Facilitation of I Kr current by some hERG channel blockers suppresses early afterdepolarizations(2019)21 cited
• → Optical Mapping of Cardiomyocytes in Monolayer Derived from Induced Pluripotent Stem Cells(2023)10 cited
• → The processing of cardiac image based on optical mapping(2010)