Effects of 4'-chlorodiazepam on cellular excitation-contraction coupling and ischaemia-reperfusion injury in rabbit heart

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Abstract
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. 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. 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.

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