Stereospecific action of diltiazem on the mitochondrial Na-Ca exchange system and on sarcolemmal Ca-channels.

The benzothiazepine diltiazem is a potent Ca-channel blocker, which also inhibits the Na-dependent Ca-efflux from heart mitochondria. In this study, the action of the 4 stereoisomers of diltiazem has been investigated using guinea-pig heart and liver mitochondria. The rate of the Na-dependent Ca-efflux from liver mitochondria has been found to be 10 times smaller than in heart mitochondria. Otherwise, the exchange systems from the two tissues have been found to be pharmacologically indistinguishable. Both the (+)-optical isomers of the cis- and trans-forms of diltiazem inhibit Na-Ca exchange activity with comparable potency (IC50 of 10-20 microM), while the (-)-optical isomers are ineffective (IC50 greater than 200 microM). Radioligand binding experiments have revealed that only one stereoisomer of diltiazem, the (+)-cis form, interacts with high affinity with the Ca-channel receptors of guinea-pig heart sarcolemma preparations (KD = 120 nM). The results have shown that the Ca-channel of plasma membranes and the mitochondrial Na-Ca exchanger have different stereospecific requirements for the binding of diltiazem.