Abstract â–¡ 94

In mammals, exposure to asphyxic or anoxic conditions elicits a pattern of respiratory responses characterized by an initial hyperpnea, followed by primary apnea, and within a variable period of time (gasp latency), gasping respiratory efforts emerge and finally stop (terminal apnea). In the developing rat, the gasping period is not a homogeneous monophasic phenomenon but rather consistently demonstrates three recognizable phases (P1-P3) and two types of gasps. Type I gasps consist of an inspiratory effort which is preceded and followed by expiratory excursions, while in type II gasps the initial expiratory effort is absent. The first phase (P1) consists of frequent type I gasps while P2 is a relatively quiescent period in which type I or type II gasps occur a frequencies < 2 gasps.min-1. Finally, P3 may be recognized by the onset of frequent type II gasps of progressively diminishing amplitude until all gasping activity ceases, i.e. terminal apnea occurs. In addition to the well established tolerance to anoxia exhibited by younger rat pups, significant maturation occurs in each of the 3 phases such that at 25 days postnatally, the triphasic gasping pattern virtually disappears, and is replaced by the adult gasping response. The lateral tegmental field of the medulla (LTF), located immediately ventromedial to the nucleus ambiguus is the putative neural site underlying gasp formation. However, the neurotransmitters involved in the phasic characteristics of gasp generation are unknown. When the NMDA receptor blocker MK-801 was administered to developing rat pups. prolongation of the overall gasping phase duration in rat pups occurred irrespective of their degree of maturation. However, type I gasps were eliminated and increases in type II gasping frequencies occurred with MK801 only in the younger animals, suggesting that during this period of development, important changes in the role of NMDA emerge in relation to the neurogenesis of gasping. Since NMDA receptor activation induces intracellular calcium influxes and activation of nitric oxide synthase (NOS), the effects of L-arginine (NOS substrate) and of NOS inhibitors (L-NAME and 7-nitroindazole) on anoxia-induced gasping were examined in rat pups. Tissue nitric oxide (NO) levels were highly correlated to particular gasping characteristics across postnatal ages and immunocytochemical assessment of NOS expression within the LTF further confirmed the developmental regulation of NOS expression. These experiments suggest that increased NOS brainstem expression and resultant higher NO concentrations may favor early autoresuscitation but be detrimental to overall survival during prolonged asphyxia.

Supported by NIH HD-01072, MCJ-229163, and the American Lung Association CI-002-N.