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
- 17 March 2004
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 310 (1), 83-89
- https://doi.org/10.1124/jpet.104.066951
Abstract
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.Keywords
This publication has 34 references indexed in Scilit:
- Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivoCardiovascular Research, 2004
- Successful treatment of aconitine induced life threatening ventricular tachyarrhythmia with amiodaroneHeart, 2000
- From Ionic Currents to Molecular Mechanisms: The Structure and Function of Voltage-Gated Sodium ChannelsNeuron, 2000
- Both α1A- and α1B-adrenergic receptor subtypes couple to the transient outward current (ITo) in rat ventricular myocytesBritish Journal of Pharmacology, 2000
- Direction‐independent block of bi‐directional Na+/Ca2+ exchange current by KB‐R7943 in guinea‐pig cardiac myocytesBritish Journal of Pharmacology, 1999
- Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivoBritish Journal of Pharmacology, 1999
- A Novel Isothiourea Derivative Selectively Inhibits the Reverse Mode of Na+/Ca2+ Exchange in Cells Expressing NCX1Published by Elsevier BV ,1996
- Effects of Magnesium on Polymorphic Ventricular Tachycardias Induced by AconitineJournal of Cardiovascular Pharmacology, 1994
- R 56 865, a Na+/Ca2+-Overload Inhibitor, Protects Against Aconitine-Induced Cardiac Arrhythmias In VivoJournal of Cardiovascular Pharmacology, 1993
- A statistical approach to the analysis of phenomena of frequency potentiation of isolated myocardial stripsBasic Research in Cardiology, 1983