Mechanisms of the Synergistic Interactions between Organic Calcium Channel Antagonists and Various Neuromuscular Blocking Agents

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Abstract
The effects of Mn2+, neomycin and four organic Ca2+-channel antagonists (OCA): nicardipine, nifedipine, diltiazem and verapamil on the neuromuscular blocking activities of tubocurarine, succinylcholine (SCh), decamethonium and neomycin were studied in isolated mouse phrenic nerve-diaphragm preparations. The effective concentration of SCh of 50% inhibition (IC50) of single indirect twitch responses were reduced markedly by more than 3-fold when the preparations were pretreated with OCA at 10 .mu.M; the latter alone did not appreciably affect the indirect twitch response or the amplitude of miniature endplate potentials. The neuromuscular blocking effect of decamethonium was also enhanced synergistically by OCA to a similar extent. On the other hand, under the comparable condition, the combined uses of OCA plus tubocurarine or neomycin, neomycin plus tubocurarine or SCh, and Mn2+ plus tubocurarine, SCh or neomycin all resulted in insignificant potentiation. These results suggest that OCA have a specific effect to enhance the agonist effect of depolarizing agents on nicotinic acetylcholine receptors. Nicardipine at 2 .mu.M non-competitively inhibited depolarizations of endplates elicited by SCh and decamethonium and abolished them completely at 10 .mu.M nicardipine. The IC50''s in inhibiting endplate potentials and miniature endplate potentials by SCh and decamethonium were also reduced 2 to 3.5-fold by nicardipine. It is inferred that OCA are endowed with a unique capability to allosterically affect the postsynaptic nicotinic aceytylcholine receptor, promoting its desensitization liability, hence synergistic interaction with depolarizing agents. Presynaptic effects of OCA are probably not involved.