The role of sarcoplasmic reticulum in the protective effect of class III drugs against Ca2+ overload.
Various studies on humans and experimental mammals showed that d-sotalol and tedisamil (class III antiarrhythmic drugs with positive inotropic effect) facilitate spontaneous ventricular defibrillation. Following our previous results, we summarized that spontaneous ventricular defibrillation requires high level of intercellular coupling and synchronization, both of which depends on intracellular free Ca2+ concentration. We hypothesized that any antiarrhythmic compound that facilitates spontaneous defibrillation, including d-sotalol and tedisamil, should prevent intracellular free Ca2+ overload most likely by elevating cAMP level and enhancing cAMP-related Ca2+ uptake of the sarcoplasmic reticulum (SR). The aim of the present study was to examine the role of the SR uptake function in their effect against Ca2+ overload.


METHODS
The effect of d-sotalol, tedisamil and dbcAMP on increased intracellular Ca2+ level were examined in cultured rat cardiomyocytes during blockade of SR Ca2+ uptake by administration of thapsigargin (TG), a selective inhibitor of Ca2+-ATPase.


RESULTS
Administration of 3 x 10(-6) mol/l TG, prior to d-sotalol, tedisamil and dbcAMP, significantly increased intracellular free Ca2+ concentration and prevented the effect of d-sotalol, tedisamil or dbcAMP to decrease intracellular Ca2+ level to its beseline, while 10(-6) mol/l TG prevented it only partially. Administration of either d-sotalol or tedisamil (at concentration of 10(-5) mol/l) before the administration of 10(-6) mol/l TG prevent the TG induced elevation of [Ca2+]i.


CONCLUSIONS
These results support our hypothesis that d-sotalol and tedisamil prevent Ca2+ overload by the cAMP dependent SR Ca2+ uptake.
Manoach
M
M
Department of Physiology, Tel Aviv Medical School, Israel. manoach@post.tau.ac.il
Varon
D
D
Tribulova
N
N
Zinman
T
T
Kaplan
D
D
Khananshvili
D
D
Shainberg
A
A
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000145:classification / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D013015:Sotalol / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D003994:Bucladesine; D019284:Thapsigargin; C059921:tedisamil; D013015:Sotalol; D002118:Calcium