Assessment of “Ca²⁺-antagonist” effects of drugs in K⁺-depolarized smooth muscle

Summary

• 1. Taenia preparations from the guinea-pig caecum yielded reproducible concentration-response curves to Ca²⁺ (EC 50 134±8 μmol/l) when maintained in depolarizing Tyrode solution containing K⁺ (40 mmol/l). Drugs which are claimed to be “Ca^2--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 μmol/l)-induced contractions, when compared with their antagonist activity when applied initially in Ca²⁺-free media. As the presence of Ca²⁺ (100 μmol/l) in the K⁺-Tryrode 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.