Current-dependent Block of Rabbit Sino-Atrial Node If Channels by Ivabradine

Abstract

“Funny” (f-) channels have a key role in generation of spontaneous activity of pacemaker cells and mediate autonomic control of cardiac rate; f-channels and the related neuronal h-channels are composed of hyperpolarization-activated, cyclic nucleotide–gated (HCN) channel subunits. We have investigated the block of f-channels of rabbit cardiac sino-atrial node cells by ivabradine, a novel heart rate-reducing agent. Ivabradine is an open-channel blocker; however, block is exerted preferentially when channels deactivate on depolarization, and is relieved by long hyperpolarizing steps. These features give rise to use-dependent behavior. In this, the action of ivabradine on f-channels is similar to that reported of other rate-reducing agents such as UL-FS49 and ZD7288. However, other features of ivabradine-induced block are peculiar and do not comply with the hypothesis that the voltage-dependence of block is entirely attributable to either the sensitivity of ivabradine-charged molecules to the electrical field in the channel pore, or to differential affinity to different channel states, as has been proposed for UL-FS49 (DiFrancesco, D. 1994. Pflugers Arch. 427:64–70) and ZD7288 (Shin, S.K., B.S. Rotheberg, and G. Yellen. 2001. J. Gen. Physiol. 117:91–101), respectively. Experiments where current flows through channels is modified without changing membrane voltage reveal that the ivabradine block depends on the current driving force, rather than voltage alone, a feature typical of block induced in inwardly rectifying K+ channels by intracellular cations. Bound drug molecules do not detach from the binding site in the absence of inward current through channels, even if channels are open and the drug is therefore not “trapped” by closed gates. Our data suggest that permeation through f-channel pores occurs according to a multiion, single-file mechanism, and that block/unblock by ivabradine is coupled to ionic flow. The use-dependence resulting from specific features of If block by ivabradine amplifies its rate-reducing ability at high spontaneous rates and may be useful to clinical applications.

If channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities

“…It is interesting to observe that in the mice treated orally with ivabradine for 1 week, reduction in HR was detectable with ivabradine plasma level in the range of 0.01-0.04 mM. In vitro patch-clamp studies showed that the IC 50 for the I f blockade by ivabradine is 1.5-2.2 mM (Bois et al, 1996;Thollon et al, 1997;Bucchi et al, 2002).…”

“…It has been shown that I f current of sinoatrial node pacemaker cells is affected by adrenergic stimulation (DiFrancesco & Tortora, 1991) and that ivabradine is a usedependent I f current blocker (Bois et al, 1996;Bucchi et al, 2002). Therefore, it is expected that the efficacy of ivabradine on HR would be modulated by alterations in the sympathetic activity.…”

“…Ivabradine (S16257) is a novel pharmacological agent specifically inhibiting the hyperpolarization-activated pacemaker I f current that underlies the rate of spontaneous diastolic depolarization in sinoatrial pacemaker cells (Thollon et al, 1994;Bucchi et al, 2002). Previous studies have established the selective HR-reducing activity of ivabradine devoid of negative inotropic effect in various species, including the rat, pig, dog and human, when given intravenously (Thollon et al, 1994;Simon et al, 1995;Monnet et al, 2001;Colin et al, 2002;Camm & Lau, 2003) or orally (Borer et al, 2003).…”

Ivabradine: Current and Future Treatment of Heart Failure

“…Ivabradine binds to the subfamily of hyperpolarization-activated, cyclic nucleotide 4 (HCN4) channels, which creates the I(f) current. It diffuses across the cellular membrane and binds intracellularly to the HCN4 channel when it is in its open state [25].…”

Ligand-gated Ion Channels

“…A standardised nomenclature for HCN channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels (see Hofmann et al, 2005). et al, 1993) and ivabradine (Bucchi et al, 2002) have proven useful in identifying and studying functional HCN channels in native cells. Zatebradine and cilobradine are also useful blocking agents.…”