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First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
1. We examined the role of nitric oxide (NO) in respiratory regulation in the nucleus tractus solitarii (NTS), where L-glutamate release associated with peripheral chemoreceptor activation modulates the hypoxic ventilatory response. 2. Experiments were performed in unanaesthetized freely moving rats. First, the effects on the hypoxic ventilatory response of sodium nitroprusside (SNP, a NO donor) or NG-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor), microinjected into the NTS, were investigated. Second, using in vivo microdialysis, changes in extracellular L-glutamate during hypoxia were examined in the presence of L-NMMA. Third, the effect of L-NMMA on ventilatory augmentation by exogenous L-glutamate was examined. Furthermore, we measured extracellular L-citrulline concentration changes during hypoxia in the NTS to assess NO formation indirectly and also examined the effect of MK-801 (an 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 significantly 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 evidence that, in the NTS, NO works as a retrograde messenger in an L-glutamate-releasing positive feedback system contributing to the augmentation of ventilation during hypoxia.
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