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Involvement of nitric oxide in nicotinic receptor-mediated myopathy
1Department of Pharmacology, McGill University, Montreal, Quebec, Canada.
Abstract:
Previous studies have shown that nicotinic cholinergic agonists induce muscle cell degeneration. Although an involvement of calcium is well documented, subsequent intracellular steps have not been identified. The present experiments test whether nitric oxide (NO) may play such a role. Both the irreversible nitric oxide synthase inhibitor L-5N-iminoethyl ornithine and L-nitroarginine methyl ester, a reversible inhibitor, protected the muscle cells from the myopathic effects of nicotine. These results may suggest that nicotinic receptor stimulation produces an increase in NO that results in muscle cell degeneration. In line with this interpretation, exposure of the muscle cultures to the NO donor sodium nitroprusside resulted in a dose-dependent decline in myotube branch points. Neither L-5N-iminoethyl ornithine nor nitroprusside altered the binding of the nicotinic receptor agonist 125I-alpha-bungarotoxin to muscle cells in culture, which indicates that the effect of these agents was not mediated through an interaction at the nicotinic receptor recognition site. The results with agents that inhibit guanylate cyclase or modify extracellular levels of cGMP suggest an involvement of this cyclic nucleotide in the nicotinic receptor-mediated myopathy. To conclude, the present results suggest that nicotinic receptor activation causes skeletal muscle degeneration through an increase in NO production and a possible involvement of cGMP.
Insights
Nicotine causes muscle cell damage by increasing nitric oxide (NO) production. Inhibiting NO synthesis protects muscle cells, suggesting NO is a key mediator in nicotine-induced myopathy.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Nicotinic cholinergic agonists are known to cause muscle cell degeneration.
- Calcium's role in this process is established, but downstream intracellular events remain unclear.
Purpose of the Study:
- To investigate the potential role of nitric oxide (NO) in nicotine-induced skeletal muscle degeneration.
- To elucidate the intracellular signaling pathway linking nicotinic receptor activation to myopathy.
Main Methods:
- Utilized irreversible and reversible nitric oxide synthase inhibitors (L-5N-iminoethyl ornithine, L-nitroarginine methyl ester) to assess protection against nicotine effects.
- Administered a nitric oxide donor (sodium nitroprusside) to muscle cultures to observe its impact on myotube morphology.
- Assessed the binding of a nicotinic receptor agonist (125I-alpha-bungarotoxin) to evaluate receptor interaction.
- Examined the role of guanylate cyclase inhibitors and cGMP modulators.
Main Results:
- Inhibitors of nitric oxide synthase protected muscle cells from nicotine-induced degeneration.
- Exposure to a nitric oxide donor reduced myotube branching in a dose-dependent manner.
- Neither NO synthase inhibitors nor the NO donor affected nicotinic receptor binding.
- Evidence suggests the involvement of cyclic guanosine monophosphate (cGMP) in the observed myopathy.
Conclusions:
- Nicotinic receptor activation leads to skeletal muscle degeneration.
- This degeneration appears to be mediated by increased nitric oxide (NO) production.
- The signaling pathway likely involves cyclic guanosine monophosphate (cGMP).