Interactions between a ?calcium channel agonist?, Bay K 8644, and calcium antagonists differentiate calcium antagonist subgroups in K+-depolarized smooth muscle

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Abstract
The proposal that calcium antagonists have different sites of action has been tested by attempting to reverse their inhibitory effects with a dihydropyridine which augments Ca2+ entry into cells, Bay K 8644. Bay K 8644 (1–1000 nmol/l) increased the sensitivity to Ca2+ of K+-depolarized taenia preparations from the guinea-pig caecum. Thus Bay K 8644 augmented established submaximal Ca2+-induced contractions and also shifted cumulative concentration-response curves to Ca2+ to the left, even in the presence of an optimal K+-depolarization. The inhibitory effects of nifedipine (10 nmol/l), verapamil (0.2 μmol/l), diltiazem (1 μmol/l) and diclofurime (1 μmol/l) on Ca2+-induced contractions were reversed by Bay K 8644 (1–100 nmol/l). In contrast, Bay K 8644 did not reverse the effects of cinnarizine (1 μmol/l), flunzrizine (1 μmol/l), fendiline (3 μmol/l), prenylamine (3 μmol/l), pimozide (1 μmol/l), bepridil (3 μmol/l), perhexiline (10 μmol/l) or the calmodulin antagonist W-7 (200 μmol/l). Bay K 8644 (1–100 nmol/l) was less effective at reversing the effects of nisoldipine (10 nmol/l), a slowly dissociating dihydropyridine, than the effects of nifedipine. However, preincubation with Bay K 8644 (1 μmol/l) protected the taenia from the inhibitory effects of nisoldipine (10 nmol/l). These findings are compatible with interactions of nisoldipine and Bay K 8644 at a common site. Taenia preparations incubated with Bay K 8644 (1 μmol/l) were protected from the inhibitory effects of nifedipine (10 nmol/l), nisoldipine (10 nmol/l) and to a lesser extent verapamil (0.2 μmol/l) and diltiazem (1 μmol/l). However, there was no protection against the inhibitory effects of cinnarizine (1 μmol/l), flunarizine (1 μmol/l), pimozide (1 μmol/l), fendiline (3 μmol/l), prenylamine (3 μmol/l) or W-7 (200 μmol/l). Thus, the lack of protection indicates that there is no interaction between the dihydropyridine site and the site for the latter drugs. These experiments show that Bay K 8644 defines subgroups of calcium antagonists which are the same as those previously reported from functional studies.