Felodipine is unique among the dihydropyridine calcium antagonists in that it is the most potent in relaxing porcine coronary arteries (IC50 = 1.5 X 10(-10) M); it is not as sensitive to photoinactivation as nifedipine and nisoldipine, and it is fluorescent. The fluorescence of felodipine has allowed us to study many aspects of its interaction with various calcium-binding proteins in muscle, including calmodulin, skeletal troponin C, and cardiac troponin C. Calcium binding to the calcium-specific regulatory sites on these proteins exposes allosterically related felodipine-binding sites. The binding of other calmodulin antagonists and calcium antagonists, including prenylamine, R24571, and diltiazem, to these calcium-binding proteins abolishes the cooperativity between two felodipine-binding sites, resulting in felodipine binding to the remaining site with a 20-25-fold greater affinity. In addition, the binding of high-affinity drugs to these calcium-dependent hydrophobic sites on these calcium-binding proteins produces dramatic increases (40-50-fold) in their affinity for calcium. The affinity of felodipine for these calcium-binding proteins is 100-1,000 times lower than felodipine's IC50 for relaxing tension in coronary arteries, indicating that these calcium-binding proteins are probably not the primary receptors for felodipine. Similarities between the binding of dihydropyridines to the calcium channel and to these calcium-binding proteins have led us to suggest that a "calmodulin-like" calcium-binding protein on the calcium channel is the actual pharmacological receptor for dihydropyridine calcium channel antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)