Electropharmacology of dofetilide, a new class III agent, in anaesthetised dogs

Gwilt, Michael; Blackburn, K J; Burges, Roger A.; Higgins, Alan J.; Milne, Aileen A; Solca, Anne M.

doi:10.1016/0014-2999(92)90021-u

Cited by 34 publications

(20 citation statements)

References 20 publications

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“…9,10 Dofetilide is more potent in isolated Purkinje fibers, where the EC 50 is 10-fold lower than in ventricle. 10,11 Similar prolongations of action potential duration (or QT interval) and effective refractory period have been reported in intact animals [12][13][14][15] and in humans. 16,17 In isolated atrial myocardium, the action of dofetilide to prolong action potential duration and effective refractory period was more than double that of ventricle.…”

Section: Effects Of Dofetilide On Action Potential Durationsupporting

confidence: 58%

Dofetilide

2000

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Dofetilide is a new antiarrhythmic drug that recently was recommended for approval by an advisory committee to the Food and Drug Administration (FDA) for treatment of patients with persistent atrial fibrillation. Dofetilide is a specific blocker of the rapid component of the outward delayed rectifier potassium current I Kr and will represent the first drug with relatively pure class III antiarrhythmic properties to be widely released. Basic ElectrophysiologyCardiac depolarization results principally from the flow of inward Na ϩ and Ca 2ϩ ions as the rapid and slow inward currents. Repolarization results from a balance between inactivation of the slow inward current and activation of repolarizing predominantly K ϩ currents. Early repolarization results from a transient outward current, I TO , which is activated rapidly by membrane depolarization. Terminal repolarization is mediated by outward delayed rectifier K ϩ currents, I K , which are activated slowly (over a period of 200 to 300 ms) on membrane depolarization and turn off, or deactivate, relatively slowly on membrane repolarization.I K can be separated pharmacologically into 2 components: a rapidly activating component, I Kr , and a slower component, I Ks , each carried by a separate ion channel molecule. 1,2 HERG channels are responsible for I Kr , whereas I Ks flows through KvLQT1 channels. Specific blockers of I Kr are therefore classified as pure class III antiarrhythmic agents because they produce only prolongation of action potential duration (and hence of QT interval). These actions may result in arrhythmia termination or suppression but can also lead to excess QT prolongation and polymorphic ventricular tachycardia. Examples of specific I Kr blockers include the methanesulfonanilide agents dofetilide, E4031, almokalant, and D-sotalol. Effects of Dofetilide on I krDofetilide blocks I Kr in all myocardial tissues with high potency (50% effective concentration [EC 50 ] in the nanomolar range). Block is voltage dependent and most prominent at depolarized potentials. 1,3,4 It does not occur in resting muscle but rather develops on depolarization. 1,5 Recovery from block is also potential dependent and is very slow at hyperpolarized potentials close to the resting potential. 1 Steady-state block at any dose is constant and does not change with increasing heart rate 1,3 because the recovery time is much greater than the diastolic interval. 1 Dofetilide block of I Kr increases as extracellular potassium concentration ([K]o) is reduced. 6 This sensitivity of dofetilide block to [K]o is of obvious clinical importance. Even moderate hypokalemia would be expected to disproportionately increase action potential prolongation induced by dofetilide, and correction of hypokalemia is of crucial importance in treating QT prolongation and torsade de pointes caused by I Kr blockade. Conversely, hyperkalemia blunts the effect of dofetilide, 7 suggesting the possibility of reduced efficacy after acute coronary occlusion or during rapid heart rates, when local cardiac tis...

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Section: Effects Of Dofetilide On Action Potential Durationsupporting

confidence: 58%

Dofetilide

2000

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“…Both compounds decreased HR in a dose‐dependent manner, and it is a well‐established fact that blockers of I Kr current can reduce HR [Tande et al., ; Gwilt et al., ; Andersen et al., ], and this effect was clearly evident for both E‐7229 and GLG‐V‐13 in the present study.…”

Section: Discussionsupporting

confidence: 75%

In Vivo Preclinical Evaluation of a Promising Antiarrhythmic Agent, EGIS‐7229

Drimba

Németh

Sári

et al. 2012

Drug Development Research

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Preclinical Research The basic hemodynamic, electrophysiological, and pharmacological effects of EGIS‐7229 (E‐7229) were evaluated and compared with those of a pure “Class III“ antiarrhythmic drug (GLG‐V‐13) in conscious rabbits. Both compounds decreased heart rate dose‐dependently. Mean arterial blood pressure was not influenced by E‐7229; however, GLG‐V‐13 produced a significant elevation on this parameter. Left ventricular end‐diastolic pressure was gradually increased by E‐7229, while GLG‐V‐13 induced more considerable elevation on that at intermediate doses. QT and QTcb were lengthened by both compounds; however, higher doses of E‐7229 resulted in shortening of the prolonged QT and QTcb. Ventricular effective refractory period (VERP) was significantly prolonged by either drug studied. Threshold doses to produce QT50%, QTmax, VERP50%, and VERPmax were significantly higher for E‐7229 compared with GLG‐V‐13. Significantly higher doses were required for E‐7229 to induce arrhythmias. The safety ratio was comparable for both of the compounds. E‐7229 can exert multiple actions on cardiac ion channels with minimal influence on hemodynamic parameters and reduced proarrhytmic profile in our preclinical model.

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“…It is also reported that class III agents exhibit negative chronotropic activity in experimental situations (2)(3)(4), but the mechanism behind this effect has not been fully investigated.…”

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confidence: 99%

Effects of Dofetilide on Membrane Currents in Sinoatrial Node Cells of Rabbit

Tohse

Kanno

1995

Japanese Journal of Pharmacology

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ABSTRACT-The effects of dofetilide (UK 68798) on membrane currents were examined in isolated sinoatrial node cells of rabbits by using patch clamping. At a concentration of 1 pM, dofetilide decreased the delayed rectifier K+ current (IK) (50.2±10.2 o, mean±S.E.). The Ca 21 current was slightly decreased during the application of dofetilide. However, the decrease in the current may be attributed to the "run down" phenomenon. The drug did not affect the hyperpolarization-activated inward current. Therefore, dofetilide exhibited class III antiarrhythmic activity in rabbit sinoatrial node cells. Similarly, E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonylaminobenzoyl)pireridine)(1 pM), a standard class III agent, also showed specific inhibition of IK. Furthermore, dofetilide depolarized the maximum diastolic potentials, reduced the slope of the pacemaker potential and then abolished spontaneously firing action potentials in the nodal cells. The results demonstrate that dofetilide may produce negative chronotropic effects as a result of its class III activity.

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Electropharmacology of dofetilide, a new class III agent, in anaesthetised dogs

Cited by 34 publications

References 20 publications

Dofetilide

Dofetilide

In Vivo Preclinical Evaluation of a Promising Antiarrhythmic Agent, EGIS‐7229

Effects of Dofetilide on Membrane Currents in Sinoatrial Node Cells of Rabbit

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