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. T he present experiments test whether nitric oxide (NO) may play such a role. Both the irreversible nitric oxide synthase inhibitor L-N-5-imin oethyl ornithine and L-nitroarginine methyl ester, a reversible inhibi tor, protected the muscle cells from the myopathic effects of nicotine . These results may suggest that nicotinic receptor stimulation produc es an increase in NO that results in muscle cell degeneration. In line with this interpretation, exposure of the muscle cultures to the NO d onor sodium nitroprusside resulted in a dose-dependent decline in myot ube branch points. Neither L-N-5-iminoethyl ornithine nor nitroprussid e altered the binding of the nicotinic receptor agonist (125)-I-alpha- bungarotoxin to muscle cells in culture, which indicates that the effe ct of these agents was not mediated through an interaction at the nico tinic receptor recognition site. The results with agents that inhibit guanylate cyclase or modify extracellular levels of cGMP suggest an in volvement of this cyclic nucleotide in the nicotinic receptor-mediated myopathy. To conclude, the present results suggest that nicotinic rec eptor activation causes skeletal muscle degeneration through an increa se in NO production and a possible involvement of cGMP.