Title
Use-dependent block of the pacemaker current i(f) in rabbit sinoatrial node cells by zatebradine (ul-fs-49) - on the mode of action of sinus node inhibitors Use-dependent block of the pacemaker current i(f) in rabbit sinoatrial node cells by zatebradine (ul-fs-49) - on the mode of action of sinus node inhibitors
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
New York, N.Y. ,
Subject
Human medicine
Source (journal)
Circulation / American Heart Association. - New York, N.Y.
Volume/pages
88(1993) :5Part 1 , p. 2389-2401
ISSN
0009-7322
ISI
A1993ME83300045
Carrier
E
Target language
English (eng)
Abstract
Background. Zatebradine (UL-FS 49) is a drug with a specific bradycardiac electrophysiological profile. It reduces heart rate by lengthening the duration of diastolic depolarization in the sinoatrial (SA) node. The ionic basis of this action, however, is not clarified. Methods and Results. We used the whole-cell patch-clamp technique to study the effects of zatebradine on ionic currents underlying diastolic depolarization of isolated rabbit SA node cells. Low concentrations of zatebradine simultaneously reduced diastolic depolarization rate and the pacemaker current I(f). The drug blocked the pacemaker current, I(f), in a use-dependent manner without causing a shift of its activation curve. At hyperpolarized potentials, unblock of I(f) occurred. Clinically relevant concentrations of the drug have little effect on the L-type calcium current or delayed rectifier potassium current. Conclusions. This use-dependent block of the I(f) channel can account for most of the pharmacological characteristics of zatebradine and is probably the mechanism of heart rate reduction caused by this agent. Thus, the sinus node inhibitor zatebradine belongs to a new class of ''I(f) blockers'' with possible advantages over currently available drugs for the treatment of ischemic heart disease.
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