Competitive interactions between Bay K 8644 and nifedipine in K+ depolarized smooth muscle: a passive role for Ca2+?
The kinetics of the interactions between Bay K 8644, a calcium channel activator, and the "calcium-antagonists" nifedipine, verapamil and diltiazem have been investigated. Nifedipine shifted cumulative concentration-response curves for Ca2+ to the right in K+ depolarized taenia preparations from the guinea-pig caecum. The apparent pA2 was 9.3 +/- 0.2 (slope 1.44; 95% confidence limits 0.99-1.88). Bay K 8644 (10-1,000 nmol/l) reduced the inhibitory effects of nifedipine, shifting the Schild plots to the right, without affecting the slope of the nifedipine:Ca2+ interaction. Thus, the interaction between the dihydropyridines was independent of external Ca2+. The parallel shifts of the Schild plots allow a novel interpretation of the "agonist" potency of Bay K 8644 because the compound had an apparent pA2 of 8.8 (slope 0.92) as an "antagonist" of the inhibitory effects of nifedipine. In contrast, Bay K 8644 was a non-competitive antagonist of the inhibitory effects of verapamil and diltiazem on Ca2+-induced contractions. These findings emphasize the differences between the various classes of "calcium-antagonists" and show that Bay K 8644 is a powerful tool discriminating between them.
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects; D004347:Drug Interactions; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011188:Potassium / Q000502:physiology
D002121:Calcium Channel Blockers; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009543:Nifedipine; D011188:Potassium; D002118:Calcium