Selectivity of Inhibition of Na+-Ca2+ Exchange of Heart... : Journal of Cardiovascular Pharmacology (original) (raw)

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Selectivity of Inhibition of Na+-Ca2+ Exchange of Heart Mitochondria by Benzothiazepine CGP-37157

Cox, David A.; Conforti, Laura*; Sperelakis, Nicholas; Matlib, Mohammed A.

Departments of Pharmacology and Cell Biophysics and *Physiology and Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.

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Abstract

The objective was to determine if the benzothiazepine compound CGP-37157 selectively inhibits the Na + -Ca2+ exchanger of cardiac mitochondria without affecting the L-type voltage-dependent calcium channel, the Na+-Ca2+ exchanger, or the Na +-K +-ATPase of the cardiac sarcolemma, or the Ca2+ -ATPase of the cardiac sarcoplasmic reticulum. Mitochondrial Na + -Ca2+ exchange activity was determined by monitoring intramitochondrial free [Ca2+ ] in isolated heart mitochondria loaded with the Ca2+-sensitive fluorophore fura-2. CGP-37157 inhibited the activity of mitochondrial Na+-Ca2+ exchange in a dose-dependent manner (IC50 0.36 μ_M_). Calcium currents were recorded by whole-cell voltage clamp in isolated neonatal ventricular myocytes. Diltiazem was able to block the recorded current completely, thus confirming the current to be exclusively L-type. CGP-37157 had no effect on the calcium current recorded under identical conditions. CGP-37157, at concentrations ≤ 10 μ_M_, had no effect on the activities of the Na + -Ca2+ exchanger and Na + -K+-ATPase in isolated cardiac sarcolemmal vesicles or on activity of the Ca2+ -ATPase in isolated cardiac sarcoplasmic reticulum vesicles. The data suggest that CGP-37157 is a potent, selective, and specific inhibitor of mitochondrial Na+-Ca2+ exchange at concentrations ≤ 10 μ_M_.