Antiarrhythmic Activity of NMDA Receptor Antagonists in Humans Versus Animal Models

Abstract

Understanding of cardiac ion channels as well as inventive ways to intend compound screening will allow a novel expectation for imminent discovery of antiarrhythmic remedies. In this regard, N‐methyl D‐aspartate receptor (NMDAR) antagonists, such as memantine, which are clinically approved for the treatment of Alzheimer's disease (AD), Huntington's disease, and dementia have displayed promising protective effects against cardiac arrhythmia in several animal models. However, our current data revealed that maximal ex‐vivo β‐adrenergic stimulation of the right ventricular (RV) papillary muscles, but not in‐vivo ECG analysis of thyroxine‐treated mice, exhibited arrhythmia in undoubtedly higher number (~ 62 %) compared to the control, and this even reached a greater level (~ 73 %) following memantine treatment. Transformation of outcomes acquired in animal models to human pathophysiology is frequently hampered by species‐dependent dissimilarities. Thus, it is critical to keep investigating the ex‐vivo effects of prospective attractive drugs on initiated arrhythmia and contractility in the ventricular human myocardium to confirm data that was exclusively acquired from animal models. Interestingly, our preliminary data illustrate that arrhythmia elicited by 100 nmol/L isoproterenol and 0.5 mmol/L caffeine in isolated RV muscles of non‐failing human hearts is inhibited by memantine in a concentration‐dependent manner with a full reserve at 50 μM. However, the exact IC50, mechanism, possibility of pro‐arrhythmia at a higher concentration as well as its impact on the contractile profile of cardiac muscle, which represents an important complementary safety measure to therapeutic efficacy is currently unknown. We have previously reported that zacopride; a moderate IK1 channel activator shows promising antiarrhythmic effects against generated arrhythmia in human ventricular myocardium using the same protocol. This opens the door for further investigation of the possible correlation between NMDAR‐IK1 channel‐Ca2+ signaling pathways in ventricular tachycardia, which is the leading cause of sudden arrhythmic death in the U.S.Support or Funding InformationThis study was supported by American Heart Association Great Rivers Affiliate Post‐doctoral Fellowship 16POST27760155 to M.T. Elnakish and National Heart, Lung, and Blood Institute Grant R01 HL‐113084 to P. M. L. Janssen.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.