Time domains of the sympatho-respiratory response to hypoxia: plasticity in phrenic and sympathetic nerve activities

Powell et al. defined short- and long-term time domains in the respiratory response to both single and repetitive hypoxic exposures [1]. Aspects of these time domains reflect a neural 'plasticity' in the network generating the respiratory pattern and are evident in both the timing and amplitude of the cycle. Studies from our laboratory have focused on the plasticity evoked by hypoxia, in particular, the role of the lateral pons in modulating the cycle's timing [2,3]. Because of respiratory modulation of sympathetic nerve activity (SNA), we hypothesized that comparable time domains are also evident in SNA's response to hypoxia and that the lateral pons also modulates plasticity in SNA.

We recorded phrenic nerve activity (PNA) and splanchnic SNA in anesthetized (Equithesin), paralyzed, vagotomized, thoracotomized, adult male rats (Sprague-Dawley, Zivic Miller). We generated cycle-triggered averages of PNA and sSNA before, during and after hypoxic exposures (8% O₂/92% N₂, 45 s duration). In a series of experiments, we have analyzed the hypoxic-evoked plasticity before and after ventrolateral (vl) pontine interventions as well as before and after multiple exposures to hypoxia.

Before hypoxic exposures, SNA was modulated weakly by respiration with a tendency for activity to increase just after the phase transition from inspiration (I) to expiration (E). During the 1^st brief hypoxic exposure, SNA increased during stage-IIE. Immediately after hypoxia, sSNA became quiescent during the prolonged E associated with short-term depression of respiration. Following vl pontine interventions, baseline respiratory modulation of SNA was attenuated, the shift or increase in stage-II "expiratory" sSNA did not occur during hypoxia but the post-hypoxic decrease of sSNA remained. After the 10th hypoxic exposure, both SNA and PNA increased their activity; in particular, respiratory-modulated SNA coincident with expiration remained increased after hypoxia. This increase in activity was sustained for more than 60 min. The increase in SNA was reflected by a greater response to injected cyanide compared to the baseline response prior hypoxia. We conclude that long-term facilitation (LTF) is elicited in SNA after repetitive hypoxic exposures and, thus, the interaction between the sympatho-respiratory control systems may be a mechanism for the increased SNA associated with sleep apnea. Further, we interpret the results of these studies as supporting an 'activity-dependent' plasticity not only in respiratory but also sympathetic networks [4].