In Vitro and In Vivo Effects of the Atrial Selective Antiarrhythmic Compound AVE1231

Abstract

The novel compound AVE1231 was investigated in order to elucidate its potential against atrial fibrillation. In CHO cells, the current generated by hKv1.5 or hKv4.3 + KChIP2.2b channels was blocked with IC50 values of 3.6 microM and 5.9 microM, respectively. In pig left atrial myocytes, a voltage-dependent outward current was blocked with an IC50 of 1.1 microM, mainly by accelerating the time constant of decay. Carbachol-activated IKACh was blocked by AVE1231 with an IC50 of 8.4 microM. Other ionic currents, like the IKr, IKs, IKATP, ICa, and INa were only mildly affected by 10 microM AVE1231. In guinea pig papillary muscle the APD90 and the upstroke velocity were not significantly altered by 30 microM AVE1231. In anesthetized pigs, oral doses of 0.3, 1, and 3 mg/kg AVE1231 caused a dose-dependent increase in left atrial refractoriness (LAERP), associated by inhibition of left atrial vulnerability to arrhythmia. There were no effects on the ECG intervals, ventricular monophasic action potentials, or ventricular refractory periods at 3 mg/kg AVE1231 applied intravenously. In conscious goats, both AVE1231 (3 mg/kg/h iv) and dofetilide (10 microg/kg/h iv) significantly prolonged LAERP. After 72 hours of tachypacing, when LAERP was shortened significantly (electrical remodelling), the prolongation of LAERP induced by AVE1231 was even more pronounced than in sinus rhythm. In contrast, the effect of dofetilide was strongly decreased. The present data demonstrate that AVE1231 blocks early atrial K channels and prolongs atrial refractoriness with no effects on ECG intervals and ventricular repolarisation, suggesting that it is suited for the prevention of atrial fibrillation in patients.

Effects of a novel amiodarone-like compound SAR114646A on the pig atrium and susceptibility to ventricular fibrillation in dogs and pigs

“…Inhibition of the "early K + channels" I sus and I to may explain the prolongation of AERP in pigs as reported in the present study and the previously reported prolongation of the action potential in rabbit left atrial tissue . It has been clearly demonstrated that inhibition of the early K + channels potently suppresses AF in a pig and goat model of AF (Blaauw et al 2004;Blaauw et al 2007;Wirth et al 2003;Wirth et al 2007).…”

“…Atrial effective refractory period (AERP) was measured in anesthetized pentobarbital thoracotomized pigs with the S1-S2 method at 400, 300, and 240 ms basic cycle lengths (BCLs) as previously described (Wirth et al 2003(Wirth et al , 2007. Briefly, atrial responses to the pacing procedure were measured in the left atrium using a monophasic action potential (MAP) pacing catheter (combined MAP and stimulation catheter, 7 F; Foehr Medical Instruments GmbH, Seeheim, Germany).…”

Kv1.5 blockers preferentially inhibit TASK-1 channels: TASK-1 as a target against atrial fibrillation and obstructive sleep apnea?

“…Due to our observation that these blockers have a strong preference for TASK-1 channels and as the structures of S20951 and AVE1231 were not yet released by Sanofi-Aventis, we published these compound as TASK-1 blockers using the synonyms A1899 [30] for S20951 [16,17] and A293 [27] for AVE1231 [27]. Both compounds were previously described as being effective in animal models against atrial fibrillation [16,17,37], and AVE1231 (A293) had entered clinical development (phase I trial) against atrial fibrillation.…”

Breathing Stimulant Compounds Inhibit TASK-3 Potassium Channel Function Likely by Binding at a Common Site in the Channel Pore

“…TASK-1 expression in human and pig hearts, unlike that in rodents, is limited to the atria and promotes action potential recovery (Limberg et al, 2011;Schmidt et al, 2014). TASK-1-inhibiting compounds increase cardiac atrial tissue refractoriness and may prevent and/or treat atrial fibrillation (Wirth et al, 2003(Wirth et al, , 2007Kiper et al, 2015). Other TASK-inhibiting drugs with known cardiac pro-or antiarrhythmic properties include lidocaine, bupivacaine, amiodarone, and carvedilol (Kindler et al, 1999;Gierten et al, 2010;Staudacher et al, 2011).…”