almokalant and Arrhythmias--Cardiac

The rapid component of the delayed rectifying potassium ion current (IKr), plays an important role in cardiac repolarization. In rats, potent IKr channel blocking drugs cause similar stage-specific malformations (such as orofacial clefts and digital reductions) on gestational days (GDs) 10-14 as after periods of embryonic oxygen deprivation (hypoxia). The idea of a hypoxia-related teratogenic mechanism is supported by studies using rat embryos cultured in vitro. These studies show that the embryonic heart reacts with concentration-dependent bradycardia, arrhythmia, and cardiac arrest when exposed to IKr blockers on GDs 10-14. The main purpose of this study was to investigate whether previously shown teratogenic doses on GD 11 and 13 of the selective IKr blocker almokalant (ALM) induce hypoxia in rat embryos in vivo by using the hypoxia marker pimonidazole hydrochloride (PIM). Rats were orally dosed with almokalant or tap water on GD 11 (150 micromol/kg), 13 (50 micromol/kg), or 16 (800 micromol/kg), followed by PIM intravenously 30 min later. Two hours after the PIM dose, the embryonic heart activity was videotaped and analysed, and the embryos were fixed, sectioned, and immunostained. Computer-assisted image analysis showed a two- and threefold increase in hypoxia staining in embryos exposed to teratogenic doses of ALM on GDs 11 and 13. Embryonic arrhythmia was observed in almokalant groups on these GDs, but not in controls. In contrast, dosing on GD 16, with a much higher dose (800 micromol/kg), caused neither hypoxia nor any effects on heart rhythm. The results support the IKr-related arrhythmia-hypoxia hypothesis, by showing that the potent IKr-blocking drug, almokalant, (1) causes severe embryonic hypoxia and arrhythmia at stages (GDs 11 and 13) when developmental toxicity could be induced and IKr is functional and (2) does not cause hypoxia or affect heart rhythm at a developmental stage when IKr is suppressed (GD 16) and potent IKr blockers do not induce developmental toxicity.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Arrhythmias, Cardiac; Cation Transport Proteins; Dose-Response Relationship, Drug; Ether-A-Go-Go Potassium Channels; Female; Fetal Hypoxia; Image Processing, Computer-Assisted; Injections, Intravenous; Nitroimidazoles; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Pregnancy; Propanolamines; Rats; Rats, Sprague-Dawley; Teratogens; Videotape Recording

The proarrhythmic effects of four antiarrhythmic agents were examined during alpha1-adrenoceptor stimulation in chloralose-anesthetized rabbits. Each dose of almokalant (26, 88, and 260 microg/kg), D-sotalol, quinidine, or amiodarone (each 3, 10, and 30 mg/kg) was infused i.v. over 5 min and there was a 20-min interval between each infusion. D-sotalol and almokalant evoked torsade de pointes (TdP) and other arrhythmics, frequently. The incidences of TdP were 0, 50, and 40% after administering the first, second, and third doses of the nonselective I(Kr) inhibitor D-sotalol, respectively. Similarly, these values were 20, 40, and 33% after administering the first, second, and third doses, respectively, of the selective I(Kr) inhibitor almokalant. Quinidine elicited only a few arrhythmics, but not TdP. Quinidine, D-sotalol, and almokalant evoked conduction blocks in a dose-related manner (p < 0.05) and prolonged QT and QT(c) intervals (p < 0.05). Amiodarone neither prolonged QT and QT(c) nor evoked ventricular tachyarrhythmias, blocks, or other proarrhythmias. In conclusion, these results show no direct correlation between the occurrence of TdP and the infusion rate or dose of anti-arrhythmics. Furthermore, the lack of TdP with quinidine warns of false-negative results in the applied model.

Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-Agonists; Amiodarone; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Electrocardiography; Heart Rate; Infusions, Intravenous; Male; Phenylephrine; Propanolamines; Quinidine; Rabbits; Sotalol; Torsades de Pointes

To evaluate whether prolongation of the plateau of the action potential duration, in the absence of instability and triangulation, can reverse the proarrhythmia elicited by a class III antiarrhythmic agent.. The effects of almokalant, erythromycin and their combination, on cardiac electrophysiological parameters (action potential duration (APD), instability, triangulation and ectopics) were evaluated in isolated hearts from female albino rabbits. In this study, proarrhythmia was estimated quantitatively by number of ectopic beats.. Erythromycin lengthened the APD primarily by a prolongation of the plateau, while having only minor effects upon phase 3 repolarization. The prolongation did not induce much instability, triangulation or reverse use dependence and, as expected, erythromycin did not induce significant proarrhythmia. Almokalant also lengthened APD, but it did not lengthen the plateau; instead, it prolonged phase 3 repolarization. The prolongation markedly triangulated the action potential, elicited much instability and marked reverse use dependence. This combination of effects induced very marked proarrhythmia. When almokalant and erythromycin were combined, their effects upon APD appeared additive: both the plateau and the repolarization phase were prolonged. However, the larger prolongation of APD did not lead to more proarrhythmia; this suggests that a prolongation of APD is not proarrhythmic per se. On the contrary, proarrhythmia as a function of APD prolongation was reduced in the presence of erythromycin (P<0.05).. Instability plus triangulation consistently lead to serious proarrhythmia especially when combined with reverse use dependence, but prolongation of APD in itself is not necessarily proarrhythmic. In fact, APD prolongation in the absence of instability and triangulation can be antiarrhythmic.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Interactions; Electrocardiography; Electrophysiology; Erythromycin; Female; Organ Culture Techniques; Propanolamines; Rabbits

Almokalant (ALM, CAS 123955-10-2), a class III antiarrhythmic drug, has been shown to be embryotoxic in rats. In the absence of human pregnancy outcome data, the human relevance of these findings in rats is unknown, and results from other species would indicate if these findings are of more universal interest. Therefore, this study was initiated to evaluate the potential effects in mice. ALM was given to three groups of pregnant mice (approximately 20 mice/group) during gestation days 6-15 at dose levels of 50, 125 and 300 mumol/kg. A fourth group served as a control. In addition, whole embryo culture was performed on gestation day 10 with doses of ALM ranging from 325-5200 nmol/l (approximately 17 embryos/group) in order to study if ALM had the potential to induce dysrhythmia in the embryonic mouse heart. ALM induced total embryonic death in the high dose group, and in the intermediate group the level of embryonic death was elevated and the mean foetal weights decreased. A slight increase in minor skeletal defects was observed, mainly consisting of reduced calcification of elements in the vertebral column and among the phalanges. ALM caused bradycardia in a concentration dependent manner (13-42% at 650-5200 nmol/l). Irregular heart rhythm and/or episodes of cardiac arrest were observed in one embryo at 2600 and in seven embryos at 5200 nmol/l. In conclusion, ALM caused embryotoxicity in the mouse, most likely secondary to adverse effects on the embryonic heart. The results may suggest that class III antiarrhythmics are embryotoxic also in humans.

Topics: Abnormalities, Drug-Induced; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Eating; Embryo, Mammalian; Female; Fetal Heart; Mice; Pregnancy; Propanolamines; Teratogens; Weight Gain

In this study the antiarrhythmic and the proarrhythmic activities of almokalant, a selective class III antiarrhythmic agent, were compared. The antiarrhythmic effect of the drug was tested in pentobarbital-anaesthetised rabbits. Arrhythmia was evoked by occluding and releasing the left circumflex coronary artery. Almokalant in a dose of 250 nmol/kg i.v., significantly decreased the incidence of reperfusion induced ventricular fibrillation (21% vs. 75% in the control group) and increased the proportion of surviving animals during reperfusion (86% vs. 42%). The proarrhythmic effect of almokalant was examined during alpha1-adrenoceptor stimulation in chloralose-anaesthetised rabbits. Almokalant (75 nmol/kg per min) triggered torsade de pointes arrhythmias in 8 animals out of 11. The dose of almokalant (mean+/-S.E.M.) required to produce this effect was 1181+/-519 nmol/kg. It is concluded that, although almokalant is an effective antiarrhythmic agent against ischaemia-reperfusion induced arrhythmias, it has marked proarrhythmic activity during alpha1-adrenoceptor stimulation.

Topics: Adrenergic alpha-Agonists; Anesthesia; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Female; Heart; Heart Rate; Male; Myocardial Reperfusion Injury; Phenylephrine; Propanolamines; Rabbits; Torsades de Pointes

Ventricular arrhythmias remain a major problem, in particular in patients with left ventricular dysfunction or heart failure. In this group of patients, Class I drugs were shown to be ineffective, and they even increased mortality during chronic treatment. New antiarrhythmic agents should preferably not only have pure antiarrhythmic effects, but should also be free from adverse autonomic properties. In the present study, the electrophysiological, rate dependent and autonomic effects of intravenously administered almokalant, a new Class III antiarrhythmic drug, were investigated in nine pigs surviving a myocardial infarction. The ventricular effective refractory period (VERP) increased after almokalant (loading dose: 0.05 mumol.kg-1.min-1, continuous infusion: 0.0025 mumol.kg-1.min-1) from 292 +/- 25 to 308 +/- 13 ms (pacing cycle length [PCL] 500 ms + 1 extrasystole [ES]), from 249 +/- 19 to 261 +/- 16 ms (PCL 400 ms +1ES), and from 209 +/- 18 to 219 +/- 18 ms (PCL 300 ms +1ES). The VERPs increased most after three ES at PCL 400 ms: from 167 +/- 27 to 186 +/- 29 ms (P < 0.05) and at PCL 300 ms: from 150 +/- 29 to 174 +/- 27 ms (P < 0.05). The ventricular monophasic action potential durations (MAPD) were similarly prolonged and the ratio VERP/MAPD did not change. Prolongation of MAPD after almokalant remained present at short pacing cycle lengths. Before almokalant infusion, sustained monomorphic ventricular tachycardia (VT) was inducible in two pigs, and nonsustained VT in a third animal. After almokalant, only one pig remained inducible. Two weeks after myocardial infarction, heart rate variability and baroreflex sensitivity were reduced. Furthermore, subsequent electrophysiological testing transiently reduced these parameters of autonomic activity. During almokalant however, no changes in autonomic functions were observed after programmed stimulation. Heart rate variability decreased after myocardial infarction from 6.3 +/- 2.5 ms to 5.4 +/- 4.2 ms (P = NS). After programmed stimulation, it further decreased to 2.8 +/- 2.0 ms (P = 0.028). Almokalant infusion prevented autonomic deterioration: 3.3 +/- 2.2 ms before stimulation and 3.3 +/- 1.3 after stimulation (P = NS). In postinfarct pigs, almokalant prolongs VERP and MAPD at shorter pacing cycle lengths. The results indicate absence of reverse rate dependence and of adverse autonomic changes.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Baroreflex; Cardiac Complexes, Premature; Cardiac Pacing, Artificial; Electrocardiography; Heart Rate; Infusions, Intravenous; Myocardial Infarction; Propanolamines; Refractory Period, Electrophysiological; Signal Processing, Computer-Assisted; Swine; Tachycardia, Ventricular; Ventricular Function

The antiarrhythmic effect of almokalant, a new type III antiarrhythmic agent, was examined by occluding and releasing the left circumflex coronary artery for 10 min, respectively, in openchest, pentobarbital-anaesthetized albino rabbits. Almokalant pretreatment increased the number of animals developing no arrythmias (5/9 vs. 1/12 in controls), and decreased the incidence of ventricular fibrillation (1/9 vs. 9/12) during reperfusion. According to our results almokalant can protect the heart against arrhythmias induced by ischaemia and reperfusion.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electric Conductivity; Female; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium; Propanolamines; Rabbits