OBJECTIVETo investigate the mechanism of drug-induced torsade de pointes (Tdp) in dogs.

METHODSIn arterially perfused canine left ventricular wedge preparations, the action potential duration (APD) of the endocardial (Endo), midmyocardial (M) and epicardial (Epi) myocytes, and transmural electrocardiogram (ECG) were recorded simultaneously. The effects of different concentrations of D-Sotalol on APD, transmural dispersion of repolarization (TDR), early after depolarization (EAD) and Tdp were observed.

RESULTSD-Sotalol prolonged APD of the Endo, M and Epi cells in a concentration-dependent manner from 0-100 µmol/L, and increased TDR due to a preferential APD prolongation of the M cells relative to Epi and Endo cells. The application of D-Sotalol elicited EAD, R on T ventricular premature beats, transmural reentry and Tdp in the M cells.

CONCLUSIONEAD and R on T ventricular premature beats induced by D-Sotalol in M cells triggers Tdp, which is maintained by TDR increment and transmural reentry.

Animals ; Dogs ; Electrocardiography ; Heart Conduction System ; Torsades de Pointes ; chemically induced ; physiopathology

The current difference between male and female rabbit ventricular myocytes was investigated for elucidating the mechanism of longer QT interval and higher incidence of drug-associated torsade de pointes in female rabbits than in male rabbits. Whole cell patch clamp technique was used to record APD, Ito, IK,tail, IK1 and ICa,L of myocytes from left ventricular apex. There was no difference in the membrane capacitance between male and female rabbit myocytes. APD90 was longer in female rabbits (560.4+/-26.5 ms, n=15) than in male ones (489.0+/-20.7 ms, n = 14), P<0. 05. In female rabbit myocytes, IKtail, Ito, IK1 and ICa,L were 0.71+/-0.05 pA/pF (n=17), 8.28+/-1.03 pA/pF (n=18), 24.5+/-3.6 pA/pF (n=12) and 9.0+/-2.3 pA/pF (n=15) respectively. In male rabbit myocytes, they were 0.84+/-0.07 pA/pF (n=18), 8.60+/-1.20 pA/pF (n=18), 25.9+/-4.5 pA/pF (n=14) and 9.3+2.6 pA/pF (n=16) respectively. IK,tail in female rabbits was significantly lower than that of male rabbits (P<0.05), but there was no difference in Ito,IK1 and ICa.L between male rabbits and female rabbits (P>0.05). The lower IK.tail of female rabbit myocytes may contribute to the longer repolarization and the higher incidence of drug-associated torsade de pointes.
Action Potentials/physiology ; Heart Ventricles/*physiology ; Myocytes, Cardiac/*physiology ; Patch-Clamp Techniques ; Potassium Channels/physiology ; Sex Characteristics ; Torsades de Pointes/chemically induced

OBJECTIVETo 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.

METHODSTdP 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.

RESULTSTreatment 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.

CONCLUSIONSIn 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.

Animals ; Calmodulin ; antagonists & inhibitors ; Enzyme Inhibitors ; therapeutic use ; Female ; In Vitro Techniques ; Rabbits ; Sotalol ; adverse effects ; Sulfonamides ; therapeutic use ; Torsades de Pointes ; chemically induced ; prevention & control

Aged ; Anemia, Diamond-Blackfan ; complications ; Aza Compounds ; adverse effects ; Female ; Fluoroquinolones ; Humans ; Quinolines ; adverse effects ; Torsades de Pointes ; chemically induced ; complications