Bradycardic and Proarrhythmic Properties of Sinus Node Inhibitors

Abstract

Sinus node inhibitors reduce the heart rate presumably by blocking the pacemaker current I f in the cardiac conduction system. This pacemaker current is carried by four hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. We tested the potential subtype-specificity of the sinus node inhibitors cilobradine, ivabradine, and zatebradine using cloned HCN channels. All three substances blocked the slow inward current through human HCN1, HCN2, HCN3, and HCN4 channels. There was no subtype-specificity for the steady-state block, with mean IC 50 values of 0.99, 2.25, and 1.96 M for cilobradine, ivabradine, and zatebradine, respectively. Native I f , recorded from mouse sinoatrial node cells, was slightly more efficiently blocked by cilobradine (IC 50 value of 0.62 M) than were the HCN currents. The block of I f in sinoatrial node cells resulted in slower and dysrhythmic spontaneous action potentials. The in vivo action of these blockers was analyzed using telemetric ECG recordings in mice. Each compound reduced the heart rate dose-dependently from 600 to 200 bpm with ED 50 values of 1.2, 4.7, and 1.8 mg/kg for cilobradine, ivabradine, and zatebradine, respectively. ␤-Adrenergic stimulation or forced physical activity only partly reversed this bradycardia. In addition to bradycardia, all three drugs induced increasing arrhythmia at concentrations greater than 5 mg/kg for cilobradine, greater than 10 mg/kg for zatebradine, or greater than 15 mg/kg for ivabradine. This dysrhythmic heart rate is characterized by periodic fluctuations of the duration between the T and P wave, resembling a form of sick sinus syndrome in humans. Hence, all available sinus node inhibitors possess an as-yetunrecognized proarrhythmic potential.

Hyperpolarization-Activated Cation Channels: From Genes to Function

“…Interestingly, all patients suffering from these mutations have in common that they display a more or less severe bradycardia, a clinical phenotype that is not observed in HCN channel-deficient mouse models. Another issue that is difficult to explain at this moment is the effect of bradycardic agents, such as cilobradine, ivabradine, and zatebradine (373), as well as of clonidine (208). It was proposed that these agents lower heart rate by blocking I h channels and reducing the firing frequency of SA node cells.…”

“…Low micromolar concentrations of both blockers (IC 50 between 0.5 and 2 M) inhibit sinoatrial I h as well as heterologously expressed HCN channels in a use-dependent fashion (373,401). Like with ivabradine, zatebradine block results from drug molecules entering the channel pore from the intracellular site (115).…”

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

“…Single myocytes from the sinus node were isolated and prepared for electrophysiological recordings as described previously (66,67). If was recorded with the whole-cell patchclamp recording in the presence or absence of 8-Br-cAMP.…”

Genetics and Sinus Node Dysfunction

“…The basis for association of a prolonged QTc with a decrease in HCN4 current amplitude is unclear, since a loss of function of If is not expected to prolong the QT interval, other than through a reduction in heart rate. Studies in both humans 34,35 and mice 36 have not observed prolongation of the QTc in response to If blockers.…”