The protective effect of class III antiarrhythmic agents against calcium overload in cultured myocytes.
Calcium ions have been implicated in the mechanisms of ventricular arrhythmias. Impairment of intercellular coupling by calcium overload is considered to facilitate ventricular fibrillation (VF) and to sup-press its self termination. According to our hypothesis, any compound that decreases intracellular calcium concentration [Ca2+]i during VF can serve as defibrillating drug. In this study, we examined the effect of d-sotalol and tedisamil on calcium overload in cultured, spontaneously beating rat cardiomyocytes. The changes of [Ca2+]i were measured by indo-1 method and the intercellular synchronization by image analysis. The results showed that increase in [Ca2+]o from 1.9 mM to 3.9 mM increased [Ca2+]i from 100 nM to 320 nM and transformed the synchronized cell movement to an asynchronous one. Administration of 5 x 10(-6) M d-sotalol or 10(-6) M tedisamil, decreased the [Ca2+]i to its basic level and restored the synchronized activity. In summary: Our results showed that increase in [Ca2+]i known to cause inhibition of intercellular coupling, that could lead to arrhythmia and fibrillation while d-sotalol or tedisamil prevented this effect. These results support our hypothesis, that class III antiarrhythmic compounds with positive inotropic effect, increase intercellular synchronization, by decreasing free [Ca2+]i, most probably by increasing the Ca2+ uptake by the sarcoplasmic reticulum, and therefore act as a defibrillating compound.
Manoach
M
M
Department of Physiology, Tel Aviv Medical School, Israel.
Varon
D
D
Shainberg
A
A
Zinman
T
T
Isaack
A
A
Rutman
I H
IH
Kaplan
D
D
Tribulova
N
N
D000818:Animals; D000831:Animals, Newborn; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002118:Calcium / Q000009:adverse effects / Q000378:metabolism*; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D013015:Sotalol / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; C059921:tedisamil; D013015:Sotalol; D002118:Calcium