Episodic hypoxia enhances late hypoxic ventilation in developing rat: putative role of neuronal NO synthase

Nitric oxide (NO) is an excitatory neurotransmitter in the hypoxic ventilatory response (HVR). Furthermore, neuronal NO synthase (nNOS) activity in the developing rat correlates with the magnitude of late hypoxic ventilatory depression. To test the hypothesis that repeated short exposures to hypoxia may modify late HVR characteristics in young rats, we conducted 30-min hypoxic challenges in 2- to S-day-old rat pups, before (Pre) and 6 h after (Post) they completed a series of eight cycles consisting of 5 min of hypoxia and 10 min of normoxia (Hyp-Norm) or normoxia throughout (Norm-Norm). In an additional group, similar challenges were performed after administration of either intraperitoneal vehicle or 25 mg/kg 7-nitroindazole (7-NI). Ventilation ((V) over dot(E)) was measured using whole body plethysmography. Although no changes in peak (V) over dot(E) responses occurred with episodic hypoxia (Pre vs. Post, P = not significant), late (V) over dot(E) reductions were markedly attenuated in Post (Delta(V) over dot(E) from early to late: 7.2 +/- 1.5 ml/min in Pre vs. 4.5 +/- 1.1 ml/min in Post; P < 0.002). Furthermore 7-NI treatment of Post animals was associated with late (V) over dot(E) reductions to Pre levels in Hyp-Norm-exposed animals. Western blots of protein equivalents from the caudal brain stem revealed increased nNOS expression in Hyp-Norm compared with Norm-Norm (P < 0.01). Current findings suggest that repeated short hypoxic exposures improve the ability to sustain (V) over dot(E), which appears to be mediated by increased nNOS expression and activity in brain stem respiratory regions. We postulate that changes in nNOS may play a role in respiratory control plasticity.