Modulation of intracellular Ca(2+) concentration by tedisamil, a class III antiarrhythmic agent, in isolated heart preparation.
New class III antiarrhythmic/defibrillating compound tedisamil was shown to facilitate termination of atrial and ventricular fibrillation in experimental as well as clinical conditions. However, class III-related inhibition of K(+) current associated with prolongation of repolarization can not solely explain its defibrillating ability. Following recent findings it was hypothesized that defibrillating effect of tedisamil is likely due to its sympathomimetic feature linked with modulation of intracellular calcium. Results of this study obtained in isolated heart preparation showed that elevated intracellular Ca(2+) free concentration was decreased by administration of tedisamil in concentration that did not induce Q-T interval prolongation. Due to species differences the effective concentration was in rat 10(-7) M, while in guinea pig 10(-5) M. On the contrary, further dramatic increase of elevated Ca(2+) was detected upon administration of tedisamil in concentration that markedly prolonged Q-T interval (10(-5) M in rat). It is concluded that defibrillating ability of tedisamil is most likely associated with attenuation of abnormal and harmful intracellular Ca(2+) elevation (that is highly arrhythmogenic) than with prolongation of APD or Q-T interval.
Seki
S
S
Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
Tribulova
N
N
Manoach
M
M
Mochizuki
S
S
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D003521:Cyclopropanes / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; C059921:tedisamil; D002118:Calcium