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This Article Full Text Full Text (PDF) All Versions of this Article: 572/2/335    most recent jphysiol.2005.100776v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bucchi, A. Articles by DiFrancesco, D. Search for Related Content PubMed PubMed Citation Articles by Bucchi, A. Articles by DiFrancesco, D. Related Collections Molecular and Genomic

¹ Laboratory of Molecular Physiology and Neurobiology, Department of Biomolecular Sciences and Biotechnology, University of Milano, via Celoria 26, 20133 Milan, Italy

Ivabradine is a ‘heart rate-reducing’ agent able to slow heart rate, without complicating side-effects. Its action results from a selective and specific block of pacemaker f-channels of the cardiac sinoatrial node (SAN). Investigation has shown that block by ivabradine requires open f-channels, is use dependent, and is affected by the direction of current flow. The constitutive elements of native pacemaker channels are the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, of which four isoforms (HCN1–4) are known; in rabbit SAN tissue HCN4 is expressed strongly, and HCN1 weakly. In this study we have investigated the blocking action of ivabradine on mouse (m) HCN1 and human (h) HCN4 channels heterologously expressed in HEK 293 cells. Ivabradine blocked both channels in a dose-dependent way with half-block concentrations of 0.94 µM for mHCN1 and 2.0 µM for hHCN4. Properties of block changed substantially for the two channels. Block of hHCN4 required open channels, was strengthened by depolarization and was relieved by hyperpolarization. Block of mHCN1 did not occur, nor was it relieved, when channels were in the open state during hyperpolarization; block required channels to be either closed, or in a transitional state between open and closed configurations. The dependence of block upon current flow was limited for hHCN4, and not significant for mHCN1 channels. In summary our results indicate that ivabradine is an ‘open-channel’ blocker of hHCN4, and a ‘closed-channel’ blocker of mHCN1 channels. The mode of action of ivabradine on the two channels is discussed by implementing a simplified version of a previously developed model of f-channel kinetics.

(Received 26 October 2005; accepted after revision 9 February 2006; first published online 16 February 2006)
Corresponding author D. DiFrancesco: Laboratory of Molecular Physiology and Neurobiology, Department of Biomolecular Sciences and Biotechnology, University of Milano, via Celoria 26, 20133 Milan, Italy. Email: dario.difrancesco{at}unimi.it

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