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Paradoxical Effects of Sodium-Calcium Exchanger Inhibition on Torsade De Pointes and Early Afterdepolarization in a Heart Failure Rabbit Model

Paradoxical Effects of Sodium-Calcium Exchanger Inhibition on Torsade De Pointes and Early Afterdepolarization in a Heart Failure Rabbit Model

Po-Cheng Chang, Yu-Ying Lu, Hui-Ling Lee, Shien-Fong Lin, Yen Chu, Ming-Shien Wen, Chung-Chuan Chou

J Cardiovasc Pharmacol. 2018 Aug;72(2):97-105.

PMID: 29738372

Abstract:

Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium-calcium exchanger (NCX) inhibition in genesis of secondary Ca rise and EAD-TdP is still debated. Dual voltage and intracellular Ca optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development. E4031 enhanced secondary Ca rise, EADs development, and TdP inducibility in both control and failing hearts. The results showed that ORM-10103 reduced premature ventricular beats but was unable to suppress the inducibility of TdP or EADs. The electrophysiological effects of ORM-10103 included prolongation of action potential duration (APD) and increased APD heterogeneity in failing hearts. ORM-10103 had a neutral effect on the amplitude of secondary Cai rise in control and heart failure groups. In this model, most EADs generated from long-short APD junction area. In conclusion, highly selective NCX inhibition with ORM-10103 reduced premature ventricular beat burden but was unable to suppress secondary Ca rise, EADs development, or inducibility of TdP. The possible electrophysiological mechanisms include APD prolongation and increased APD heterogeneity.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP488847285	ORM-10103		488847-28-5	Price

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