Kurt Eichenberger

Stereospecific action of diltiazem on the mitochondrial NaCa 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.

Hydralazine and its metabolites: in vitro and in vivo activity in the rat

Summary: The vasodilator, hypotensive, and antihypertensive effects of hydralazine and its known and putative metabolites were compared in vitro, in the isolated, perfused mesenteric arterial bed of the rat, and in vivo, in the urethane-anesthetized normotensive rat (NR) and in the conscious renal hypertensive rat (RHR). In the mesenteric bed, hydralazine produced inhibition of noradrenaline (NA)-induced vasoconstriction (IC50–NA = 0.4 μg/ml). All the metabolites were five to >250 times less potent than the parent compound. Hydralazine inhibited potassium-induced vasoconstriction at concentrations (IC50–K+ = 700 μg/ml) above those required to inhibit NA. Two metabolites, 9-hydroxy-3-methyl-s-triazolo-(3.4-a)phthalazine and the acetone hydrazone (HP-AH), were more potent (five- and 10-fold, respectively) than hydralazine in inhibiting potassium-induced vasoconstriction. The other metabolites produced <50% inhibition at the highest concentration tested. In in vivo studies, blood pressure in NR or RHR was reduced by hydralazine, following doses of 0.1 or 0.25 mg/kg i.v. and above. HP-AH was sixfold less active than hydralazine in NR and 10-fold less active in RHR, while the pyruvic acid hydrazone was 33- and 14-fold less active, respectively. The other metabolites tested were practically inactive in concentrations up to the limits of solubility. Although several hydralazine metabolites show some vasodilator and blood pressure–lowering activity, it seems unlikely that the formation of metabolites is a major factor in the antihypertensive effect of hydralazine or is responsible for its long duration of action.