Lack of renoprotective effects by long-term PCSK9 and SGLT2 inhibition using alirocumab and empagliflozin in obese ZSF1 rats.

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). Despite the entry of sodium glucose cotransporter 2 (SGLT2) inhibitors, CKD persists as a medical challenge. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces low-density lipoprotein (LDL)-cholesterol, a major risk factor of CVD.

The K2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs.

Aims: To describe the effects of the K2 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.

The K2 Channel Inhibitor AP14145, But Not Dofetilide or Ondansetron, Provides Functional Atrial Selectivity in Guinea Pig Hearts.

Prolongation of cardiac action potentials is considered antiarrhythmic in the atria but can be proarrhythmic in ventricles if the current carried by Kv11.1-channels (I) is inhibited. The current mediated by K2-channels, I, is considered a promising new target for treatment of atrial fibrillation (AF).

Antiarrhythmic effect of the Ca-activated K (SK) channel inhibitor ICA combined with either amiodarone or dofetilide in an isolated heart model of atrial fibrillation.

Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics dofetilide and amiodarone have documented anti-AF effects. While dofetilide has dose-related ventricular side effects, amiodarone primarily has adverse non-cardiac effects.

Synergistic antiarrhythmic effect of combining inhibition of Ca²⁺-activated K⁺ (SK) channels and voltage-gated Na⁺ channels in an isolated heart model of atrial fibrillation.

Background: Application of antiarrhythmic compounds is limited by both proarrhythmic and extracardiac toxicities, as well as incomplete antiarrhythmic efficacy. An improved antiarrhythmic potential may be obtained by combining antiarrhythmic drugs with different modes of action, and a reduction of the adverse effect profile could be an additional advantage if compound concentrations could be reduced.

Objective: The purpose of this study was to test the hypothesis that combined inhibition of Ca(2+)-activated K(+) channels (SK channels) and voltage-gated Na(+) channels, in concentrations that would be subefficacious as monotherapy, may prevent atrial fibrillation (AF) and have reduced proarrhythmic potential in the ventricles.