Involvement of nitric oxide in nicotinic receptor-mediated myopathy.
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.
El-Dada
M D
MD
Department of Pharmacology, McGill University, Montreal, Quebec, Canada.
Quik
M
M
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006331:Heart Diseases / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects*
D011978:Receptors, Nicotinic; D009569:Nitric Oxide; D009538:Nicotine