NITRIC-OXIDE MODULATES VENTILATORY RESPONSES TO HYPOXIA IN THE DEVELOPING RAT

Nitric oxide (NO) is an important excitatory neurotransmitter in the c entral nervous system. In the adult rat, both selective and nonselecti ve blockers of constitutive nitric oxide synthase (NOS) induce marked ventilatory reductions during sustained hypoxia, thereby enhancing ven tilatory roll-off. Since hypoxic ventilatory depression is greater in developing mammals during the late phases of hypoxic exposure, we hypo thesized that limited NOS activity may play a role in the late arm of the ventilatory response. To test our hypothesis, 5-d-, 10-d-, and 15- d-old rat pups underwent a 30-min hypoxic challenge (10% O-2) before a nd after administration of 100 mg/kg N-nitro-L-arginine methyl ester ( L-NAME), a competitive NOS inhibitor. Minute ventilation (VE) was meas ured using whole-body plethysmography. In 5-d-old pups, early VE hypox ic responses were enhanced, and late VE were similar after administrat ion of L-NAME. In contrast, in 15-d-old hypoxic pups, L-NAME administr ation was; associated with smaller early VE increments and significant ly larger VE reductions when compared with pretreatment conditions. Th e role of central nervous system NO in the development of these ventil atory changes was further assessed by Western blots of protein equival ents from the nucleus tractus solitarius (NTS), the first central rela y for peripheral chemoreceptor afferent input, which revealed increasi ng neuronal NOS expression with age. Furthermore, NADPH-diaphorase imm unohistochemical staining of neurons in the NTS revealed increased pos itively labeled neuronal populations within subnuclei of this structur e with advancing postnatal age. Current findings suggest that NOS acti vity mediates both excitatory and inhibitory components of the hypoxic ventilatory response. Furthermore, in brainstem respiratory regions, NO may play a role in modulating the prominent second phase of the bip hasic response to hypoxia typically seen in early postnatal life.