The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs

Abstract

Aims: To describe the effects of the K Ca 2 channel inhibitor AP30663 in pigs regarding tolerability, cardiac electrophysiology, pharmacokinetics, atrial functional selectivity, effectiveness in cardioversion of tachy-pacing induced vernakalant-resistant atrial fibrillation (AF), and prevention of reinduction of AF. Methods and Results: Six healthy pigs with implanted pacemakers and equipped with a Holter monitor were used to compare the effects of increasing doses (0, 5, 10, 15, 20, and 25 mg/kg) of AP30663 on the right atrial effective refractory period (AERP) and on various ECG parameters, including the QT interval. Ten pigs with implanted neurostimulators were long-term atrially tachypaced (A-TP) until sustained vernakalant-resistant AF was present. 20 mg/kg AP30663 was tested to discover if it could successfully convert vernakalantresistant AF to sinus rhythm (SR) and protect against reinduction of AF. Seven anesthetized pigs were used for pharmacokinetic experiments. Two pigs received an infusion of 20 mg/kg AP30663 over 60 min while five pigs received 5 mg/kg AP30663 over 30 min. Blood samples were collected before, during, and after infusion on AP30663. AP30663 was well-tolerated and prominently increased the AERP in pigs with little effect on ventricular repolarization. Furthermore, it converted A-TP induced AF that had become unresponsive to vernakalant, and it prevented reinduction of AF in pigs. Both a >30 ms increase of the AERP and conversion of AF occurred in different pigs at a free plasma concentration level of around 1.0-1.4 µM of AP30663, which was achieved at a dose level of 5 mg/kg. Conclusion: AP30663 has shown properties in animals that would be of clinical interest in man.

Inhibition of KCa2 Channels Decreased the Risk of Ventricular Arrhythmia in the Guinea Pig Heart During Induced Hypokalemia

“…However, the effect of K Ca 2 channel inhibition on atrial refractoriness has consistently been found to be greater than the ventricular effects and hence K Ca 2 channels seem to show functional atrial selectivity (Diness et al, 2010;Qi et al, 2014;Diness et al, 2017;Kirchhoff et al, 2019;Bentzen et al, 2020;Diness et al, 2020). Our data during hypokalemia are different from the findings by Chan et al who suggested that K Ca 2 channel inhibition by the toxin apamin facilitated VF induction (Chan et al, 2015) in rabbits.…”

Modulation of SK Channels: Insight Into Therapeutics of Atrial Fibrillation

“…AP30663 played a vital role in prolongation of the atrial refractory period, with a small effect on ventricular repolarisation. The model was established by long-term atrial tachypacing [78]. The anti-AF properties shown in pigs would be of clinical interest in humans.…”

Small Conductance Ca2 +-Activated K+ (SK) Channel mRNA Expression in Human Atrial and Ventricular Tissue: Comparison Between Donor, Atrial Fibrillation and Heart Failure Tissue

“…A clinical trial regarding the efficacy and safety of a (non-selective) TASK-1 channel inhibitor is still ongoing [Doxapram conversion to sinus rhythm (SR) “DOCTOS” study, EudraCT No: 2018-002979-17, Protocol-Code: K620]. For SK-channel inhibition, preclinical research is ongoing ( Saljic et al, 2019 ; Shamsaldeen et al, 2019 ; Diness et al, 2020 ), and this atria-selective antiarrhythmic drug target appears to be the only one not yet investigated in patients ( Heijman and Dobrev, 2017 ).…”