PHARMACOLOGICAL AND RADIOLIGAND BINDING-STUDIES OF 1,4-DIHYDROPYRIDINES IN RAT CARDIAC AND VASCULAR PREPARATIONS - STEREOSELECTIVITY AND VOLTAGE DEPENDENCE OF ANTAGONIST AND ACTIVATOR INTERACTIONS

The pharmacologic and radioligand-binding properties of 1,4-dihydropyr idines in an activator (Bay K 8644) and an antagonist (nifedipine) ser ies were studied in rat tail artery, heart membrane, and neonatal rat ventricular myocytes. The S-enantiomers of the activator series contra cted rat tail artery in the presence of 15 mM K+ (EC50 values of 10(-8 ) to 10(-5) M). (S)-Bay K 8644 (I) and its o-difluoromethoxy analog (I II) were the most potent members of the activator series examined. The abilities of the activators to stimulate maximum tension response of the artery differed with structure; thus, the efficacy of (S)-Bay K 86 44 was 70% that of the analog lacking the 3-carbomethoxy group. The R- enantiomers of the activator series and a series of achiral nifedipine analogs were inhibitory in the same tissue. The intact-cell binding a ssay revealed the binding affinities of 1,4-dihydropyridine antagonist s in depolarized cells (50 mM K+) to be higher than those in polarized cells (5 mM K+). The ratio K(D) (polarized)/K(D) (depolarized) was 77 for nifedipine (IC50 = 5.4 x 10(-9) M) but was only 2.9 for the weak 3-methoxy nifedipine analog (IC50 = 4.8 x 10(-6) M); an approximately linear relationship exists between this ratio and the antagonist poten cy. In marked contrast, and in confirmation of previous work [Mol. Pha rmacol. 35:541-552 (1989)], the binding affinities of activators were not significantly affected by membrane potential, regardless of potenc y. We conclude that the S-enantiomers of Bay K 8644 analogs are activa tors with different potency and efficacy and that the R-enantiomers ar e antagonists, that the binding of 1,4-dihydropyridine antagonists is voltage dependent, whereas binding of the activators is not, and that the voltage-dependence of binding of the antagonists is correlated wit h the potency of the antagonist.