The interaction of verapamil and other phenylalkylamine calcium channel blockers with the 1,4-dihydropyridine receptor was examined. Studies characterizing the interaction and relationship between calcium channel blocking potency and binding affinity were performed in rat myocardium. The 1,4-dihydropyridines, nifedipine and nitrendipine, interacted competitively. The apparent Kd and Bmax of nitrendipine were 270 +/- 140 pM and 390 +/- 76 fmol/mg protein, respectively. In contrast, the interaction of the phenylalkylamines with the 1,4-dihydropyridine receptor was not competitive. At a 3H-nitrendipine concentration of 0.12 nM, verapamil displaced only 60% of specifically bound radioactivity and progressively less as the concentration of 3H-nitrendipine increased. Kinetic data indicated that the interaction of both D600 and verapamil with the 1,4-dihydropyridine receptor was not cooperative. At infinite dilution the dissociation rate constant (k-1) was not altered in the presence of 10(-5) M D600. We examined the hypothesis that 3H-nitrendipine interacts at several sites with similar affinities and that the phenylalkylamines interact at one of these sites. Although D600 could not further displace 3H-nitrendipine in the presence of a maximally displacing concentration of nifedipine (10(-6) M), nifedipine could further displace 3H-nitrendipine in the presence of a maximally displacing concentration of D600 (10(-5) M). These results are consistent with competitive interactions at multiple sites but do not explain the diminished ability of the phenylalkylamines to displace progressively less radioactivity at increasing 3H-nitrendipine concentrations. No relationship between binding affinity and pharmacologic potency of the phenylalkylamines was found suggesting that the interaction of the phenylalkylamines with the 1,4-dihydropyridine receptor is not responsible for their calcium channel blocking effects.