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.