NITRIC-OXIDE AND VENTILATORY RESPONSE TO HYPOXIA

It is believed that hypoxia results in the release of neurotransmitter s in the central nervous system, which can excite or inhibit breathing . Recent evidence indicates that nitric oxide (NO) is a physiological messenger molecule that may serve as a neurotransmitter in the CNS. In this study we examined (1) the localization of nitric oxide synthase (NOS) within the nucleus tractus solitarius, and (2) the role of the N O-cGMP pathway in the respiratory response to oxygen deprivation. Nico tinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemis try was used to determine the distribution of neurons that express NOS , an enzyme involved in NO formation. The NOS inhibitor N-omega-nitro- L-arginine was used as tool to assess the NOS activity in the medulla, and to define the role of NO in the respiratory response to acute oxy gen deprivation. In the rat and the cat brainstem, histochemical studi es showed the presence of NADPH-diaphorase reactive neurons within sub nuclei of the nucleus tractus solitarius which receive peripheral chem oreceptor inputs. Chronic pretreatment of rats with N-omega-nitro-L-ar ginine (75 mg/kg, ip, twice daily for 7 days) caused a significant dec rease in cGMP, and attenuated the ventilatory response to hypoxia. In anesthetized, paralyzed, vagotomized and artificially ventilated cats with intact carotid sinus nerves (n = 8), administration of N-omega-ni tro-L-arginine (30-100 mg/kg) attenuated the response to hypoxia, and caused the hypoxia induced roll-off of phrenic nerve activity to occur significantly earlier than when NOS activity was not inhibited. In si noaortic denervated cats (n = 9) blockage of NOS potentiated the decli ne of the phrenic nerve output. The data suggest that oxygen deprivati on leads to activation of NO-cGMP pathway in the central nervous syste m, which contributes to the induction and maintenance of hypoxia-induc ed increase in respiratory output. In addition, these findings indicat e that NO may inhibit inhibitory synaptic transmission that is trigger ed by CNS hypoxia, and this is not directly related to peripheral chem oreceptor inputs.