Inhibition of KACh channels by the bee venom peptide tertiapin-Q rescues inherited cardiac conduction defects and sino-atrial bradycardia and atrioventricular block in models of congenital dysfunction

Introduction Pacemaker activity of the sino-atrial node (SAN) generates the heart rate. SAN dysfunction leads to sick sinus syndrome (SSS) characterized by abnormally low heart rate (HR). The only currently available therapy for SSS is electronic pacemaker implantation. Mice lacking SAN L-type Ca v 1.3 Ca 2+ channels (Ca v 1.3 −/− ) present symptoms similar to those observed of SSS in humans especially SAN bradycardia and atrioventricular (AV) block. Cardiac voltage-gated Na+ channels (Nav) are essential for SAN impulse conduction through the AV node and the working myocardium. Mutations in the α-subunit of the cardiac Nav1.5 channel isoform are associated with inherited dysfunction of heart impulse conduction. We recently showed that genetic ablation of muscarinic-gated K + channels (I KAch ) rescues bradycardia of Ca v 1.3 −/− mice. Purpose We tested pharmacologic inhibition of I KAch by the peptide tertiapine-Q to rescue SSS and conduction dysfunction in Ca v 1.3 −/− mice having concurrent ablation of Ca v 1.3 and T-type Ca v 3.1 channels (Ca v 1.3 −/− /Ca v 3.1 −/− ) and Nav1.5 ± mice, which present ECG profiles similar to individuals carrying congenital bradycardia and conduction defects. Methods We employed telemetric ECG recordings of SAN activity, HR and AV dysfunction in mice before and after administration of different doses of tertiapin-Q. Results Tertiapin-Q significantly improves the HR of Ca v 1.3 −/− (19%), Ca v 1.3 −/− /Ca v 3.1 −/− (23%) from doses of 0.1 to 5 mg/kg. HRs of tertiapine-Q-treated mice were similar to those recorded in untreated wild-type mice. Tertiapin-Q also improved cardiac conduction of Nav1.5 ± mice by 24%. Conclusion Pharmacological inhibition of I KAch by tertiapin-Q prevents SAN dysfunction and improves conduction in three models of congenital bradycardia and impulse conduction defects suggesting the possibility of I KACh pharmacologic targeting to manage SAN and conduction disease.