生物活性

• 描述E-4031 is a class III antiarrhythmic agent which selectively blocks hERG potassium channel. Dofetilide and E-4031 induced EADs (early afterdepolarizations) or TdP (Torsade de Pointes) in all assays (50-83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization^[3]. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (n = 4), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5 ng/mL at 10 min after their start of administration, respectively^[4]. In single sinoatrial nodal cells, E-4031 (0.1 mumol/L) significantly prolonged cycle length and action potential duration, depolarized maximum diastolic potential, and reduced both the upstroke velocity of the action potential and the diastolic depolarization rate. E-4031 blocked part of the outward current during depolarizing steps as well as the tail current upon subsequent repolarization (ITD) in a dose-dependent manner. E-4031 (10 mumol/L) depressed ITD (88 +/- 4%), reduced peak ICa,L at 0 mV (29 +/- 15%), but did not affect I(f)^[5]. E-4031 in doses of 0.01 and 0.1 mg/kg that can provide the plasma concentrations effectively to inhibit IKrin vitro significantly delayed the repolarization beyond the initiation of diastole, resulting in the inversion of electro-mechanical coupling, which provides an ideal proarrhythmic substrate, while the durations of left ventricular systole and diastole remained the same^[6].