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 inhibitorl-5N-iminoethyl ornithine andl-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-α-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.
Footnotes
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Send reprint requests to: Dr. M. Quik, Parkinson’s Institute, 1170 Morse Ave, Sunnyvale, CA 94089.
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↵1 The authors gratefully acknowledge support from the Medical Research Council, Canada, and the Muscular Dystrophy Association, United States.
- Abbreviations:
- α-BGT
- α-bungarotoxin
- BSA
- bovine serum albumin
- cytosar
- cytosine arabinoside
- DMEM
- Dulbecco’s modified Eagle’s medium
- d-NAME
- d-nitroarginine methyl ester
- l-NAME
- l-nitroarginine methyl ester
- NIO
- l-5N-iminoethyl ornithine
- NO
- nitric oxide
- NOS
- nitric oxide synthase
- SNP
- sodium nitroprusside
- Received October 3, 1996.
- Accepted February 4, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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