NERVE-CONDUCTION BLOCK BY NITRIC-OXIDE THAT IS MEDIATED BY THE AXONALENVIRONMENT

Conduction in rat peripheral nerve has been monitored following the st imulated release of nitric oxide (NO) from diethylamine-NONOate (DEA-N ONOate). Branches of the sciatic nerve were dissected, but left otherw ise intact, and propagating signals recorded externally. At levels con sistent with inflammation, NO exposure resulted in a complete loss of the compound action potential. Conduction was fully restored on remova l of the drug. Most notably, this loss of excitability was dependent o n the axonal environment. Removal of the connective tissue sheaths sur rounding the nerve bundle, a process that normally enhances drug actio n, prevented block of signal propagation by nitric oxide. The epineuri um seemed not to be required, and the decreased susceptibility to NO a ppeared to be correlated with a gradual loss of a component of the end oneurium that surrounds individual fibers. Tested on the rat vagus ner ve, NO eliminated action potentials in both myelinated and unmyelinate d fibers. One chemical mechanism that is consistent with the reversibi lity of block and the observed lack of effect of 8-Br-cGMP on conducti on is the formation of a nitrosothiol through reaction of NO with a su lfhydryl group. In contrast to DEA-NONOate, S-nitrosocysteine, which c an both transfer nitrosonium cation (NO+) to another thiol and also re lease nitric oxide, was effective on both intact and desheathed prepar ations. It has previously been demonstrated that chemical modification of invertebrate axons by sulfhydryl-reactive compounds induces a slow inactivation of Na+ channels. Nitric oxide block of axonal conduction may contribute to clinical deficits in inflammatory diseases of the n ervous system.