Physiological and Anatomical Correlates of Prolonged Hypercapnia in A Developing Swine Model

Abstract □ 104

The sequence of events leading to sudden infant death involves a failure of central cardiorespiratory controllers to respond appropriately to signals over many different afferent pathways. Clearly, such victims lacked adequate responses to chemoreceptor activation (i.e., hypoxia, hypercapnia, asphyxia). Such a failure to respond would necessarily involve an alteration of activity in brainstem neurons which play a critical role in the regulation of breathing and cardiovascular function. The present investigation was designed to evaluate whether prolonged CO₂ exposure elicited age-related changes of: (a) mean arterial pressure (MAP) and heart rate (HR); (b) neuronal activation in the nucleus of the solitary tract (NTS) and the circumventricular organ, the area postrema (AP), as indicated by expression of the c-fos protooncogene product, fos. We studied swine at: a) 5-8 d old, b) 13-15 d old, c) 26-34 d old. In each experiment, two animals, matched the age and weight, were prepared simultaneously, and received similar levels of anesthesia, paralysis, and artificial ventilation (100% O₂). MAP, HR, and arterial blood gases-pH were monitored during experiments, and did not differ at baseline. One animal of each pair was exposed to 10% CO₂ for 1 hr while the other breathed 100% O₂. Following exposure, ventilation with 100% O₂ was 4% phosphate-buffered paraformaldehyde. Tissues were incubated in human fos antibody and processed immunohistochemically. NTS and AP neurons in hypercapnic-exposed animals expressed markedly more fos than control animals regardless of age (p<0.05). However, only NTS neurons of exposed 13-15 d old animals expressed significantly more fos than the other two age groups (p<0.05); no such age relationship was observed for AP neurons. Surprisingly, changes of MAP and HR were not noted in 13-15 d old exposed animals. Increased MAP and HR were exhibited only by 5-8 d old animals; 26-34 d old animals exhibited a depression of MAP and HR. These results indicated that the degree of neuronal excitation may not be linearly related to age, and that, depending upon stage of development, functionally appropriate reflex changes may not be expressed. Such an absence of responsivity may play an important role in the development of cardiorespiratory pathophysiology. (Supported by NIH Grants HL-20864 and HD-28931)