flunarizine and almokalant

The present study examined how Ca++ entry and intracellular Ca++ overload may contribute to the appearance of torsades de pointes in the setting of delayed repolarization. In anesthetized rabbits, the infusion of methoxamine and the selective I kappa s blocker almokalant (8.8 micrograms/kg.min) was associated with a lengthening of the QTU interval (37 +/- 2.6 ms, P < .001) and the appearance of torsades de pointes in 9/10 rabbits. In rabbits pretreated with nisoldipine (7.7 or 37 micrograms/kg i.v.), the incidence of almokalant-induced torsades de pointes was reduced to 7/10 (P = .5820 vs. vehicle) and 1/10 (P = .0006) rabbits, respectively. This occurred without attenuating the QTU-prolonging effect of almokalant (47 +/- 7.0 ms and 56 +/- 8.6 ms, respectively). Likewise, pretreatment with flunarizine (0.5 or 3.0 mg/kg i.v.) reduced the incidence to 1/6 (P = .0076) and 0/6 animals (P = .0009), respectively. In 10 of the rabbits that were given nisoldipine or flunarizine and did not experience torsades de pointes with almokalant, BAY K 8644 (0.11 mg/kg) was injected. In six of these rabbits, BAY K 8644 promptly induced torsades de pointes. In four vehicle-pretreated rabbits that experienced torsades de pointes with almokalant, acute injection of nisoldipine (37 micrograms/kg) abruptly suppressed the proarrhythmia. In separate experiments, rabbits were treated with ryanodine or BAPTA-AM and were subsequently administered almokalant. Compared with the vehicle-pretreated rabbits, these interventions did not significantly reduce the incidence of torsades de pointes (from 6/5 rabbits to 3/8 and 3/8 rabbits, respectively, P = .1776). The results demonstrate that Ca++ entry through the L-type Ca++ channel may be of crucial importance for the induction of torsades de pointes in the acquired long QT syndrome.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Action Potentials; Animals; Calcium; Electrocardiography; Flunarizine; Male; Nisoldipine; Propanolamines; Rabbits; Ryanodine; Sarcolemma; Torsades de Pointes

Ryanodine, a specific blocker of the Ca2+ release channel of the sarcoplasmic reticulum, and flunarizine, a [Ca2+]i overload blocker, possess antiarrhythmic effects against delayed afterdepolarizations (DADs) and DAD-dependent arrhythmias. In vitro controversy exists about their effect on early after-depolarizations (EADs): no effect was reported on cesium-induced EADs, while ryanodine did prevent EADs induced by isoproterenol. To study the possible role of intracellular Ca2+ overload in acquired EAD-dependent torsades de pointes (TdP) arrhythmias, we tested the effects of flunarizine and ryanodine in our animal model of TdP.. Anaesthetized dogs with chronic AV block received d-sotalol or almokalant followed by pacing. A subset of dogs with reproducible TdP (> or = 3 times) were selected to receive flunarizine (2 mg/kg per 2 min) or ryanodine (10 micrograms/kg per 10 min). After d-sotalol, TdP was induced at a mean cycle length of the idioventricular rhythm (CL-IVR) of 2070 +/- 635 msec and a QT(U) interval of 535 +/- 65 msec. Induction of TdP was prevented by flunarizine in all experiments (8/8): electrophysiologically this was associated with a decrease in CL-IVR, QT(U), and QTc interval (390 +/- 100 to 320 +/- 45, P < 0.05). Ryanodine prevented TdP induction in 4 of 5 experiments and decreased the CL-IVR, QT(U), and the QTc interval from 385 +/- 75 to 320 +/- 20 msec (P < 0.05). Both drugs also suppressed the almokalant-induced EADs and related ectopic activity. This antiarrhythmic action corresponded with the inability to reinduce TdP by pacing.. Blockade of the Ca2+ release channel of the sarcoplasmic reticulum by ryanodine or the reduction of [Ca2+]i overload by flunarizine prevents induction of EAD-dependent acquired TdP arrhythmias, suggesting a role for [Ca2+]i overload in acquired TdP.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Calcium Channels; Disease Models, Animal; Dogs; Female; Flunarizine; Heart; Isoproterenol; Male; Propanolamines; Ryanodine; Sarcoplasmic Reticulum; Sotalol; Time Factors; Torsades de Pointes