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CARDIOVASCULAR

Effects of Sodium-Calcium Exchange Inhibitors, KB-R7943 and SEA0400, on Aconitine-Induced Arrhythmias in Guinea Pigs in Vivo, in Vitro, and in Computer Simulation Studies

Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan

The sodium-calcium exchange (NCX) plays a pivotal role in regulating contractility and electrical activity in the heart. However, the effects of NCX blockers on ventricular arrhythmias are still controversial. We examined the effects of KB-R7943 (KBR) and SEA0400 (SEA), two NCX blockers, on aconitine-induced arrhythmias in guinea pigs using the ECG recordings and the current-clamp method. Using Luo's and Rudy's computer model (1991 Circ Res 68:1501–1526) for ventricular myocytes, we simulated abnormal membrane activity produced by NCX inhibition. In the whole-animal model, KBR in a dose range of 1 to 30 mg/kg (intravenous) suppressed aconitine-induced arrhythmias dose-dependently, but 10 mg/kg of SEA did not suppress these arrhythmias. There was a difference in isolated ventricular myocytes also. KBR (10 µM) suppressed abnormal electrical activity induced by aconitine, but SEA (100 µM) did not show such effects. KBR (10 µM) significantly changed the shape of the action potential configurations (action potential duration at 50% repolarization), but SEA (1–100 µM) did not change these configurations. In the computer simulation study, the aconitine-induced abnormal electrical activity was mimicked by a negative shift of the kinetics of Na⁺ channels, and this was followed by additional suppression of NCX activity by 90% (mimicking the effect of NCX inhibitors), which enhanced abnormal membrane activity. Our results indicate that the inhibition of aconitine-induced arrhythmias by KBR, not by SEA, might result from a mechanism other than the inhibition of NCX, and thus the involvement of the NCX system plays an insignificant role in the aconitine-induced arrhythmias.

Address correspondence to: Dr. Nobuo Homma, Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato 1110, Tamaho, Nakakoma, Yamanashi 409-3898, Japan. E-mail: nhomma{at}res.yamanashi-med.ac.jp

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				S.-S. Zhou, J. Yang, Y.-Q. Li, L.-Y. Zhao, M. Xu, and Y.-F. Ding Effect of Cl- channel blockers on aconitine-induced arrhythmias in rat heart Exp Physiol, November 1, 2005; 90(6): 865 - 872. [Abstract] [Full Text] [PDF]