Md. Eldada et M. Quik, INVOLVEMENT OF NITRIC-OXIDE IN NICOTINIC RECEPTOR-MEDIATED MYOPATHY, The Journal of pharmacology and experimental therapeutics, 281(3), 1997, pp. 1463-1470
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.