NITRIC-OXIDE AS A RETROGRADE MESSENGER IN THE NUCLEUS-TRACTUS-SOLITARII OF RATS DURING HYPOXIA

1. We examined the role of nitric oxide (NO) in respiratory regulation in the nucleus tractus solitarii (NTS), where L-glutamate release ass ociated with peripheral chemoreceptor activation modulates the hypoxic ventilatory response. 2. Experiments were performed in unanaesthetize d freely moving rats. First, the effects on the hypoxic ventilatory re sponse of sodium nitroprusside (SNP, a NO donor) or N-G-monomethyl-L-a rginine (L-NMMA, a NO synthase inhibitor), microinjected into the NTS, were investigated. Second, using in vivo microdialysis, changes in ex tracellular L-glutamate during hypoxia were examined in the presence o f L-NMMA. Third, the effect of L-NMMA on ventilatory augmentation by e xogenous L-glutamate was examined. Furthermore, we measured extracellu lar L-citrulline concentration changes during hypoxia in the NTS to as sess NO formation indirectly and also examined the effect of MK-801 (a n NMDA receptor antagonist) on L-citrulline levels during hypoxia. 3. SNP increased ventilation during both normoxia and hypoxia. L-NMMA did not alter ventilation or L-glutamate levels during normoxia but signi ficantly attenuated the hypoxic ventilatory response and the increase in L-glutamate during hypoxia. The inhibition by L-NMMA was blocked by L-arginine. The ventilatory augmentation by exogenous L-glutamate was attenuated by L-NMMA. L-Citrulline increased during hypoxia, and this increase was inhibited by MK-801. 4. We provide the first in vivo evi dence that, in the NTS, NO works as a retrograde messenger in an L-glu tamate-releasing positive feedback system contributing to the augmenta tion of ventilation during hypoxia.