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Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity

C Thollon1, S Bedut, N Villeneuve

  • 1Division Pathologies Cardiaques et Vasculaires, Institut de Recherches Servier, 11 rue des Moulineaux, Suresnes 92150, France. catherine.thollon@fr.netgrs.com

British Journal of Pharmacology
|November 28, 2006
PubMed

Insights

Ivabradine selectively inhibits the HCN4 channel, the primary heart rate regulator in human sino-atrial nodes. This use-dependent action explains its slow onset and effectiveness in rapid heart rhythms.

Area of Science:

  • Cardiovascular Pharmacology
  • Ion Channel Physiology
  • Cardiac Electrophysiology

Background:

  • Ivabradine is a specific I(f) inhibitor that reduces heart rate.
  • The sino-atrial node (SAN) is the primary pacemaker of the heart.
  • HCN channels, particularly HCN4, are crucial for cardiac rhythm generation.

Purpose of the Study:

  • To characterize ivabradine's effect on the predominant HCN channel isoform in human SAN (hHCN4).
  • To determine the kinetics and rate-dependency of ivabradine's action on HCN channels.
  • To elucidate the mechanism of ivabradine's anti-ischaemic activity.

Main Methods:

  • RT-PCR analysis of HCN channel isoforms in hSAN.
  • Patch-clamp recordings from CHO cells expressing hHCN4.
  • Intracellular recordings from isolated SAN and beating rate measurements of rat atria.

Main Results:

  • hHCN4 mRNA is predominant in hSAN.
  • Ivabradine demonstrated time-dependent inhibition of hHCN4 (IC50 = 0.5 microM).
  • Ivabradine progressively reduced action potential frequency in rabbit SAN and rat atria, with use-dependent kinetics.

Conclusions:

  • Ivabradine's use-dependent inhibition of hHCN4 current contributes to its slow onset.
  • The drug's effectiveness is enhanced in species with rapid SAN activity.
  • Ivabradine's mechanism involves direct modulation of cardiac pacemaker channels.
Abstract

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