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CARDIOVASCULAR

N,N,N',N'-Tetrakis(2-pyridylmethyl)-ethylenediamine Improves Myocardial Protection against Ischemia by Modulation of Intracellular Ca²+ Homeostasis

Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel (Y.A.S., V.S., A.S.); and D-Pharm Ltd., Rehovot, Israel (R.K., G.O., A.K., Y.J.A.)

N,N,N',N'-Tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN), a transition-metal chelator, was recently found to protect against myocardial ischemia-reperfusion injury. The goals of this study were to investigate the in vivo antiarrhythmic and antifibrillatory potential of TPEN in rats and guinea pigs and to study the in vitro effects of TPEN on calcium homeostasis in cultured newborn rat cardiac cells in normoxia and hypoxia. We demonstrated on an in vivo rat model of ischemia-reperfusion that TPEN abolishes ventricular fibrillation incidence and mortality and decreases the incidence and duration of ventricular tachycardia. To elucidate the mechanism of cardioprotection by TPEN, contraction, synchronization, and intracellular calcium level were examined in vitro. We have shown for the first time that TPEN prevented the increase in intracellular Ca²⁺ levels ([Ca²⁺]_i) caused by hypoxia and abolished [Ca²⁺]_i elevation caused by high extracellular Ca²⁺ levels ([Ca²⁺]_o) or by caffeine. Addition of TPEN returned synchronized beating of cardiomyocytes desynchronized by [Ca²⁺]_o elevation. To discover the mechanism by which TPEN reduces [Ca²⁺]_i in cardiomyocytes, the cells were treated with thapsigargin, which inhibits Ca²⁺ uptake into the sarcoplasmic reticulum (SR). TPEN successfully reduced [Ca²⁺]_i elevated by thapsigargin, indicating that TPEN did not sequester Ca²⁺ in the SR. However, TPEN did not reduce [Ca²⁺]_i in the Na⁺-free medium in which the Na⁺/Ca²⁺ exchanger was inhibited. Taken together, the results show that activation of sarcolemmal Na⁺/Ca²⁺ exchanger by TPEN increases Ca²⁺ extrusion from the cytoplasm of cardiomyocytes, preventing cytosolic Ca²⁺ overload, which explains the beneficial effects of TPEN on postischemic cardiac status.

Address correspondence to: Prof. Asher Shainberg, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel. E-mail: shaina{at}mail.biu.ac.il