Cardiovascular Research Advance Access originally published online on February 26, 2008
Cardiovascular Research 2008 79(1):141-149; doi:10.1093/cvr/cvn053
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Effects of 4'-chlorodiazepam on cellular excitation–contraction coupling and ischaemia–reperfusion injury in rabbit heart
Department of Medicine, Division of Cardiology, Institute of Molecular Cardiobiology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, 1059 Ross Building, Baltimore, MD 21205, USA
* Corresponding author. Tel: +1 410 614 0034; fax: +1 410 955 7953. E-mail address: 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 ischaemia–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 and results: 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 ischaemia/reperfusion in order to determine how 4-ClDzp influenced the susceptibility to arrhythmias and contractile dysfunction. 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 ischaemia and 30 min of reperfusion were protected against reperfusion arrhythmias and post-ischaemic 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.
Conclusion: The findings indicate that the effects of 4-ClDzp on both mitochondrial and sarcolemmal ion channels contribute to protection against post-ischaemic cardiac dysfunction. Of clinical relevance, the compound is effective when given upon reperfusion, unlike other pre-conditioning agents.
KEYWORDS Arrhythmia; Mitochondrial ion channels; Ischaemia; Reperfusion; Peripheral benzodiazepine receptor
Time for primary review: 20 days