Organic calcium channel antagonists provoke acetylcholine receptor autodesensitization on train stimulation of motor nerve.

The effects of nicardipine and other organic Ca2(+)-channel antagonists on the responses induced by indirect train stimulation (3 s, 50-100 Hz) were studied in mouse phrenic nerve diaphragm preparations. Nicardipine at 1-10 microM, which alone did not affect single or tetanic contractions or the amplitude of evoked endplate potentials and spontaneous miniature endplate potentials, caused tetanic contraction to fade completely in the presence of 0.3 microM neostigmine or 50 microM diisopropylfluorophosphate. In combination with these anticholinesterases, nicardipine caused a severe run-down and shortening of endplate potentials in 1-2 s. This effect on endplate potentials was dependent on stimulus frequency and on extracellular Ca2+. The effect was accelerated by intracellular injection of Ca2+, but retarded by injection of EGTA. The amplitudes of miniature endplate potentials and the evoked endplate depolarization were also depressed during repetitive stimulation. On termination of repetitive stimulation, all postsynaptic responses, including evoked endplate potentials, miniature endplate potentials and single twitches, recovered to pre-train level in 3-10 s. These results suggest that the postsynaptic nicotinic receptors had lost the functional activity during repetitive stimulation. The time-courses of the aforementioned changes initiated by repetitive stimulation were similar to the fast phase of desensitization induced by acetylcholine. The irreversible action of alpha-bungarotoxin on acetylcholine receptor was attenuated in the presence of nicardipine and neostigmine if repetitive stimulation was applied. The same effects were observed with other organic Ca2(+)-channel antagonists (diltiazem, verapamil and nifedipine) as well as agonist (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyr idine- 5-carboxylate, BAY K8644), but not with Mn2+, theophylline or caffeine. It is inferred that organic Ca2(+)-channel antagonists interact directly with acetylcholine receptor ion channel, enhance its autodesensitization liability and thus cause extinction of endplate potentials on repetitive stimulation.