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Organic calcium channel antagonists provoke acetylcholine receptor autodesensitization on train stimulation of motor
C C Chang1, C Y Huang, S J Hong
1Department of Pharmacology, College of Medicine, National Taiwan University, Taipei.
Abstract:
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.
Insights
Organic calcium channel blockers like nicardipine, when combined with anticholinesterases, cause nerve-muscle junction responses to fade during repetitive stimulation. This suggests these blockers interact with acetylcholine receptors, impacting their function.
Area of Science:
- Neuropharmacology
- Muscle Physiology
- Ion Channel Research
Background:
- Calcium channel antagonists are used clinically, but their effects on neuromuscular transmission under specific conditions are not fully understood.
- Anticholinesterases potentiate neuromuscular responses, and their interaction with other drugs warrants investigation.
Purpose of the Study:
- To investigate the effects of nicardipine and other organic calcium channel antagonists on neuromuscular responses during repetitive nerve stimulation.
- To elucidate the mechanism by which these antagonists affect endplate potentials and receptor function.
Main Methods:
- Experiments were conducted on mouse phrenic nerve-diaphragm preparations.
- Responses to indirect train stimulation were recorded in the presence and absence of nicardipine, anticholinesterases, and varying extracellular calcium concentrations.
- Effects on endplate potentials, miniature endplate potentials, and muscle contractions were analyzed.
Main Results:
- Nicardipine alone did not affect basal neuromuscular transmission but caused a complete fade of tetanic contractions when combined with anticholinesterases.
- This fade was characterized by a rapid rundown and shortening of endplate potentials, dependent on stimulus frequency and extracellular calcium.
- Nicardipine also attenuated the irreversible blockade of acetylcholine receptors by alpha-bungarotoxin during repetitive stimulation.
Conclusions:
- Organic calcium channel antagonists, including nicardipine, interact directly with the acetylcholine receptor ion channel.
- These interactions enhance the receptor's autodesensitization, leading to the extinction of endplate potentials during repetitive nerve stimulation.
- The findings suggest a novel mechanism for calcium channel antagonist action at the neuromuscular junction.