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Cardiovascular Research Advance Access first published online on February 26, 2008
This version [Accepted Manuscript] published online on February 28, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn053
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Effects of 4'-Chlorodiazepam on Cellular Excitation-Contraction Coupling and Ischemia-Rreperfusion Injury in Rabbit Heart

David A. Brown, Miguel A. Aon, Fadi G. Akar, Ting Liu, Nicolas Sorarrain and Brian O'Rourke

Institute of Molecular Cardiobiology, Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore MD 21205

Corresponding Author Brian O'Rourke, Ph.D. Professor of Medicine Johns Hopkins University School of Medicine Institute of Molecular Cardiobiology 720 Rutland Ave. 1059 Ross Bldg. Baltimore, MD 21205-2195 tel: 410-614-0034 fax: 410-955-7953 e-mail: bor{at}jhmi.edu

Aims: Recent evidence indicates that the activity of energy-dissipating ion channels in the mitochondria can influence the susceptibility of the heart to ischemia-reperfusion injury. In this study, we describe the effects of 4'-chlorodiazepam (4-ClDzp), a well-known ligand of the mitochondrial benzodiazepine receptor, on the physiology of both isolated cardiomyocytes and intact hearts.

Methods: We used current- and voltage-clamp methods to determine the effects of 4-ClDzp on excitation-contraction coupling in isolated rabbit heart cells. At the level of the whole heart, we subjected rabbit hearts to ischemia/reperfusion in order to determine how 4-ClDzp influenced the susceptibility to arrhythmias and contractile dysfunction.

Results: In isolated rabbit cardiomyocytes, 4-ClDzp evoked a significant reduction in the cardiac action potential that was associated with a decrease in calcium currents and peak intracellular calcium transients. In intact perfused normoxic rabbit hearts, 4-ClDzp mediated a dose-dependent negative inotropic response, consistent with the observation that 4-ClDzp was reducing calcium influx. Hearts that underwent 30 min of global ischemia and 30 min of reperfusion were protected against reperfusion arrhythmias and post-ischemic contractile impairment when 4-ClDzp (24 µM) was administered throughout the protocol or as a single bolus dose given at the onset of reperfusion. In contrast, hearts treated with cyclosporin-A, a classical blocker of the mitochondrial permeability transition pore, were not protected against reperfusion arrhythmias.

Conclusions: The findings indicate that the effects on 4-ClDzp on both mitochondrial and sarcolemmal ion channels contribute to protection against post-ischemic cardiac dysfunction. Of clinical relevance, the compound is effective when given upon reperfusion, unlike other preconditioning agents.

KEYWORDS arrhythmia; mitochondrial ion channels; ischemia; reperfusion

Time for primary review: 20


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