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CELLULAR AND MOLECULAR

Competitive and Cooperative Effects of Bay K8644 on the L-Type Calcium Channel Current Inhibition by Calcium Channel Antagonists

Alexandra Zahradníková, Igor Minarovi, and Ivan Zahradník

Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic

Phenylalkylamines, benzothiazepines, and dihydropyridines bind noncompetitively to the L-type calcium channel. The molecular mechanisms of this interaction were investigated in enzymatically isolated rat ventricular myocytes using the whole-cell patch-clamp technique. When applied alone, felodipine, verapamil, and diltiazem inhibited the L-type calcium current with values of inhibitory constant (K_B) of 11, 246, and 512 nM, respectively, whereas 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl]phenyl)-3-pyridine carboxylic acid methyl ester (Bay K8644) activated I_Ca with activation constant (K_A) of 33 nM. Maximal activation of I_Ca by 300 nM Bay K8644 strongly reduced the inhibitory potency of felodipine (apparent K_B of 165 nM), significantly reduced the inhibitory potency of verapamil (apparent K_B of 737 nM), but significantly increased the inhibitory potency of diltiazem (apparent K_B of 310 nM). In terms of a new pseudoequilibrium two-drug binding model, the interaction between the dihydropyridine agonist Bay K8644 and the antagonist felodipine was found purely competitive. The interaction between Bay K8644 and verapamil or diltiazem was found noncompetitive, and it could be described only by inclusion of a negative interaction factor = –0.60 for verapamil and a positive interaction factor = +0.24 for diltiazem. These results suggest that at physiological membrane potentials, the L-type calcium channel cannot be simultaneously occupied by a dihydropyridine agonist and antagonist, whereas it can simultaneously bind a dihydropyridine agonist and a nondihydropyridine antagonist. Generally, the effects of the drugs on the L-type calcium channel support a concept of a channel domain responsible for binding of calcium channel antagonists and agonists changing dynamically with the membrane voltage and occupancy of individual binding sites.

Address correspondence to: Dr. Ivan Zahradník, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava, Slovak Republic. E-mail: ivan.zahradnik{at}savba.sk

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