[Calmodulin antagonist inhibits torsade de pointes induced by d-sotalol in an isolated rabbit heart model].
OBJECTIVE
To evaluate the effects of W-7, a calmodulin inhibitor, on transmural dispersion of repolarization (TDR), early after depolarization (EAD) and torsade de pointes (TdP) induction after administration of d-sotalol in isolated rabbit heart.


METHODS
TdP was induced by d-sotalol (30 micromol/L), bradycardia, and hypokalemic (1.5 mmol/L)/hypomagnesaemic (0.35 mmol/L) solution in isolated female rabbit hearts. Thirty six rabbit hearts were divided into 4 groups (n = 9 each): d-sotalol alone, d-sotalol + W-7 (20 micromol/L), d-sotalol + W-7 (50 micromol/L), and d-sotalol + W-7 (100 micromol/L). Monophasic action potentials (MAPs) of the left ventricular epimyocardium (Epi), midmyocardium (M), and endomyocardium (Endo) were recorded simultaneously with ECG. The incidence of EAD and TdP were observed as well.


RESULTS
Treatment with d-sotalol alone prolonged ventricular MAP duration and QT interval, increased TDR, and evoked high incidence of EAD (9/9) and spontaneous TdP (7/9) in hypokalemic/hypomagnesaemic solution in female rabbit heart. W-7 concentration-dependently decreased incidence of TdP (4/9 in 20 micromol/L; 2/9 in 50 micromol/L; 1/9 in 100 micromol/L). This effect of W-7 coincided with the decreased incidence of EAD (5/9 in 20 micromol/L; 4/9 in 50 micromol/L; 1/9 in 100 micromol/L). However, the d-sotalol-induced prolongation of QT interval and TDR was not significantly altered by W-7 at the three concentration used.


CONCLUSIONS
In isolated female rabbit hearts, calmodulin antagonist W-7 suppresses d-sotalol-induced TdP without altering TDR but does suppress EAD. The effects observed with W-7 also suggest a possible important role for calmodulin-activated enzymes in the induction of TdP.
Pu
Jun
J
Department of Cardiology, Tongji Hospital, Affiliated of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Zhang
Cun-tai
CT
Bai
Rong
R
Liu
Nian
N
Li
Yang
Y
Wang
Lin
L
D000818:Animals; D002147:Calmodulin / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D066298:In Vitro Techniques; D011817:Rabbits; D013015:Sotalol / Q000009:adverse effects; D013449:Sulfonamides / Q000627:therapeutic use*; D016171:Torsades de Pointes / Q000139:chemically induced / Q000517:prevention & control*
D002147:Calmodulin; D004791:Enzyme Inhibitors; D013449:Sulfonamides; C017967:W 7; D013015:Sotalol