Assessment of "Ca2+ -antagonist" effects of drugs in K+ -depolarized smooth muscle. Differentiation of antagonist subgroups.

1. Taenia preparations from the guinea-pig caecum yielded reproducible concentration-response curves to Ca2+ (EC50 134 +/- 8 mumol/1) when maintained in depolarizing Tyrode solution containing K+ (40 mmol/1). Drugs which are claimed to be "Ca2+ -antagonists" displaced the curves to the right without depression of the maximum response. In this test nifedipine, verapamil, diltiazem, pimozide, cinnarizine, flunarizine and fendiline appeared qualitatively similar but had different potencies. 2. The antagonist effects of nifedipine, verapamil and diltiazem were readily reversed by washout of the drugs from the bathing fluid, but the effects of the other drugs were not. 3. Cinnarizine, flunarizine, pimozide and fendiline were only weakly active as relaxants of Ca2+ (100 mumol/1)-induced contractions, when compared with their antagonist activity when applied initially in Ca2+ -free media. As the presence of Ca2+ (100 mumol/1) in the K+ -Tyrode reduced the antagonist effects of cinnarizine and pimozide, but not that of verapamil and diltiazem, the weak activity of some of the antagonists as relaxants of Ca2+ -induced contractions can be attributed to a protective effect of Ca2+ during the incubation period with the antagonist. 4. The problems associated with the assessment of the potency of drugs as "Ca2+ -antagonists" are discussed and it is proposed that three subgroups of drugs may exist within the overall classification.