Female gender is a risk factor for drug-induced long QT and cardiac arrhythmias in an in vivo rabbit model.

INTRODUCTION: Clinical observations and in vitro experimental data indicate that females have a longer QT interval than males, which is associated with a higher risk of drug-induced cardiac arrhythmias. Little is known about this gender difference in anesthetized animals, which may affect the outcome of in vivo drug tests. METHODS AND RESULTS: We evaluated potential gender differences in ventricular repolarization (QT, QTc, JT, and JTc interval) and its dispersion, as well as in its response to dofetilide, an IKr blocker, in anesthetized rabbits challenged with the alpha1-adrenoceptor agonist methoxamine. A 12-lead ECG was recorded during the experiments. At baseline, there were no significant gender differences in ventricular repolarization values in male and female rabbits under anesthesia. Dofetilide (0.04 mg/kg/min IV for 60 min; n = 10 per gender) produced marked prolongation of the ventricular repolarization time and its dispersion, associated with a high incidence of polymorphic ventricular tachycardia (PVT; 100% in females vs 80% in males) and ventricular fibrillation (VF; 80% in females vs 50% in males; P > 0.05). QT and JT interval at 2 minutes as well as QT and JT dispersion at 10 and 30 minutes during dofetilide infusion were significantly higher in female than in male rabbits. After 30 minutes of dofetilide infusion, 10 of 10 female rabbits had severe cardiac arrhythmias (complete AV block, PVT, or VF), so ECG parameters were impossible to assess (vs 3/10 males with severe cardiac arrhythmias; P < 0.05). During dofetilide infusion, female rabbits developed complete AV block, PVT, or VF at doses about 50% lower than those given to males. CONCLUSION: The present study indicates that female rabbits are more susceptible to drug-induced long QT and cardiac arrhythmias than are male rabbits; therefore, female rabbits are more appropriate for testing drug-induced cardiac arrhythmias.

Species plays an important role in drug-induced prolongation of action potential duration and early afterdepolarizations in isolated Purkinje fibers.

INTRODUCTION: Although isolated Purkinje fibers (PFs) often are used to evaluate the electrophysiologic effects of new drugs in terms of prolongation of action potential duration (APD) and induction of early afterdepolarizations (EADs), species differences in this respect remain elusive. We evaluated potential species-specific differences in drug-induced prolongation of APD and EADs in isolated PF from various species. METHODS AND RESULTS: Using a microelectrode technique, PFs (n = 7 to 11 per species) were isolated from hearts of rabbits, guinea pigs, dogs, swine, goats, or sheep, superperfused in Tyrode's solution with dofetilide (1 x 10(-8) M) or quinidine (1 x 10(-5) M) for 25 minutes, and stimulated at 1 Hz for 20 minutes and at 0.2 Hz for another 5 minutes. Dofetilide increased APD at 90% repolarization (APD90) at 1 Hz by 83% (rabbit), 24% (guinea pig), 65% (dogs), 18% (swine), 61% (goat), and 30% (sheep), and prolonged APD90 at 0.2 Hz by 187% (rabbit), 31% (guinea pig), 154% (dog), 17% (swine), 61% (goat), and 8% (sheep). Similarly, quinidine changed APD90 by 93% (rabbit), 0% (guinea pig), 16% (dog), -3% (swine), 0% (goat), and -24% (sheep) at 1 Hz, and by 124% (rabbit), 15% (guinea pig), 53% (dog), 17% (swine), 11% (goat), and -39% (sheep) at 0.2 Hz in PF. During superfusion of dofetilide or quinidine, EADs occurred in most preparations in rabbit PFs at 0.2 Hz, but not in any of the PFs from other species at 0.2 Hz. CONCLUSION: Our study demonstrates that species plays an important role in the response of PF to drug-induced prolongation of APD and EADs. Rabbit PFs constitute the most sensitive model for detecting drug-induced, potential long APD and proarrhythmogenic effects in vitro.

Are there sex-specific differences in ventricular repolarization or in drug-induced early afterdepolarizations in isolated rabbit purkinje fibers?

Women are known to have a longer QT interval than men and a greater propensity toward drug-induced "torsades de pointes" (TdPs). However, little is known about these sex differences in isolated cardiac tissues. We evaluated potential sex differences in repolarization in isolated rabbit Purkinje fibers using a microelectrode technique. Isolated male or female Purkinje fibers were perfused in a Tyrode's solution with solvent, dofetilide (1 x 10(-8) M) or quinidine (1 x 10(-5) M), and stimulated at 1 or 0.2 Hz. Female Purkinje fibers with solvent (n = 11) tended to have a longer duration of the action potential at 90% repolarization (APD90) than male fibers with solvent (n = 10): 331 (median) vs. 272 ms at 1 Hz (p > 0.05); 473 vs. 367 ms at 0.2 Hz (p < 0.05). Dofetilide (1 x 10(-8) M) significantly increased APD90 more in female Purkinje fibers (n = 11) than in male fibers (n = 10): 670 vs. 385 ms at 1 Hz, at 20 min after the infusion (p < 0.05), and 1,000 vs. 937 ms at 0.2 Hz at the end of the 25-min infusion (p < 0.05), respectively. Quinidine (1 x 10(-5) M) tended to increase APD90 more in female Purkinje fibers (n = 11) than in male fibers (n = 10): 705 vs. 500 ms at 1 Hz, at 20 min after the infusion (p > 0.05). Furthermore, dofetilide (1 x 10(-8) M) and quinidine (1 x 10(-5) M) elicited a higher incidence of early afterdepolarizations in female Purkinje fibers than in male fibers at 0.2 Hz (100 vs. 60%, p < 0.05; and 91 vs. 50%, p > 0.05). Our data indicate that female Purkinje fibers tend to have longer ventricular repolarization and are at higher risk of drug-induced early afterdepolarizations at a slow stimulation rate than male fibers. This may contribute to a sex difference in QT interval and to a greater tendency on the part of women to the development of drug-induced TdPs.

Ischemia/reperfusion-induced arrhythmias in anaesthetized rats: a role of Na+ and Ca2+ influx.

We hypothesized that by limiting the Na+ and Ca2+ loading by a blocker/inhibitor of the Na+ channel (lidocaine), Na+ overload (R56865: N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazo lamine), Ca2+ channel (verapamil), Na+ -H+ exchange (ethylisobutyl amiloride) or of Na+ -Ca2+ exchange (No. 7943: 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate), it should be possible to reduce ischemia/reperfusion-induced arrhythmias. To test this hypothesis, we used anaesthetized rats subjected to 5 min of coronary artery occlusion followed by 10 min of reperfusion to study antiarrhythmic effects of above compounds on reperfusion-induced ventricular premature beats, ventricular tachycardia, and reversible and irreversible ventricular fibrillation. Compound or saline was administered as an intravenous bolus injection at 5 min before ischemia. Pretreatment with lidocaine (5 mg/kg), verapamil (0.63 mg/kg), R56865 (0.63 mg/kg) or ethylisobutyl amiloride (1.25 mg/kg) significantly reduced or abolished all types of ventricular arrhythmias. However, pretreatment with verapamil was associated with second or third degree heart block in 3 out of 12 animals. Pretreatment with No. 7943 did not significantly influence the ischemia/reperfusion-induced ventricular arrhythmias. The present results suggest that both intracellular Na+ -and Ca2+ -loading play important roles in reperfusion-induced ventricular arrhythmias and the inhibition of Na+ -Ca2+ exchange to limit Ca2+ loading probably does not play any important role in ischemia/reperfusion-induced arrhythmias in anaesthetized rats.