Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 668, Issue 3, Pages 419-426Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2011.07.025
Keywords
Ivabradine; Purkinje fiber; Diastolic depolarization; V-max; Repolarization; Human heart
Categories
Funding
- Hungarian Scientific Research Fund [OTKA CNK-77855, OTKA K-82079]
- Hungarian Ministry of Health [ETT 302-03/2009, ETT 306-03/2009]
- National Office for Research and Technology [TECH_08_A1_CARDIO08]
- National Development Agency [TAMOP-4.2.2-08/1-2008-0013]
- European Community (EU) [ICT-2008-224381]
- European Union (NORMACOR)
- Hungarian Academy of Sciences
- Janos Bolyai Research Scholarship
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Ivabradine is a novel antianginal agent which inhibits the pacemaker current. The effects of ivabradine on maximum rate of depolarization (V-max), repolarization and spontaneous depolarization have not yet been reported in human isolated cardiac preparations. The same applies to large animals close to human in heart size and spontaneous frequency. Using microelectrode technique action potential characteristics and by applying patch-clamp technique ionic currents were studied. Ivabradine exerted concentration-dependent (0.1-10 mu M) decrease in the amplitude of spontaneous diastolic depolarization and reduction in spontaneous rate of firing of action potentials and produced a concentration- and frequency-dependent V-max block in dog Purkinje fibers while action potential duration measured at 50% of repolarization was shortened. In the presence of ivabradine, at 400 ms cycle length, V-max block developed with an onset kinetic rate constant of 13.9 +/- 3.2 beat(-1) in dog ventricular muscle. In addition to a fast recovery of V-max from inactivation (tau = 41-46 ms) observed in control, a second slow component for recovery of V-max was expressed (offset kinetics of V-max block) having a time constant of 8.76 +/- 1.34 s. In dog after attenuation of the repolarization reserve ivabradine moderately but significantly lengthened the repolarization. In human, significant prolongation of repolarization was only observed at 10 mu M ivabradine. Ivabradine in addition to the Class V antiarrhythmic effect also has Class I/C and Class Ill antiarrhythmic properties, which can be advantageous in the treatment of patients with ischemic heart disease liable to disturbances of cardiac rhythm. (C) 2011 Elsevier B.V. All rights reserved.
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