Interactions of nifedipine and diltiazem with muscle relaxants and reversal of neuromuscular blockade with edrophonium and neostigmine.

Abstract

The effects and interactions of nifedipine and diltiazem with tubocurarine, gallamine and pancuronium and their reversal by edrophonium and neostigmine were studied on isolated skeletal muscle of the chick. The nerve-muscle preparation of the chick biventer cervicis was set up in an organ bath containing Krebs-Henseleit solution and the mechanical responses produced either by motor nerve stimulation or by drug application were recorded isometrically. The results showed that nifedipine (29-1015 microM) and diltiazem (22-572 microM) reduced, in a dose-dependent manner, the amplitude of indirectly-elicited twitch tension, evoked at 0.2 Hz with 5-10 V and 0.2 msec pulse duration, and increased the neuromuscular blockade produced by d-tubocurarine (1-254 microM), gallamine (0.01-2.0 microM) and pancuronium (0.01-7.0 microM). Edrophonium (250 nM) and neostigmine (150 nM) completely reversed the neuromuscular blockade produced by the muscle relaxants, alone and in combination with nifedipine or diltiazem. The mean IC50 values (concentrations to produce 50% of maximum inhibition) of nifedipine and diltiazem-induced depression of twitch response were 324 +/- 16 microM and 143 +/- 11 microM respectively (means +/- S.E., n = 6). Nifedipine, in high concentrations, produced small contractions (0.4 +/- 0.1 g of tension, n = 6), in the chick muscle. In contrast, diltiazem produced no such contractions in the muscle. However, in concentrations which had little effect on twitch response, diltiazem (20 microM) and nifedipine (50 microM) both increased the neuromuscular blockade produced by tubocurarine, gallamine and pancuronium by about 2-fold. Increasing the external calcium concentration, by a 2-fold, did not reverse or antagonize the inhibitory effects of diltiazem or nifedipine. It was concluded that diltiazem and nifedipine inhibit indirectly-elicited twitch tension and intensify neuromuscular blockade produced by muscle relaxants. These effects of nifedipine and diltiazem may be due to blocking influx of calcium and on release of acetylcholine from presynaptic nerve terminals.