The respiratory system expresses multiple forms of plasticity, defined as alterations in the breathing pattern that persist or develop after a stimulus. Stimulation of breathing with intermittent hypoxia (IH) elicits long-term facilitation (LTF), a type of plasticity in which respiratory motor activity progressively increases in anaesthetized animals, even after the stimuli have ceased and blood gases have normalized. It is unknown whether the sympathetic nervous system similarly expresses IH-induced plasticity, but we predicted that IH would evoke LTF in sympathetic nerve activity (SNA) because respiratory and sympathetic control systems are coupled. To test this idea, we recorded splanchnic (sSNA) and phrenic nerve activities (PNA) in equithesin-anaesthetized rats. Animals were exposed to 10 45 s episodes of 8% O 2 -92% N 2 , separated by 5 min intervals of 100% O 2 , and recordings were continued for 60 min following the last hypoxic exposure. Cycle-triggered averages of integrated PNA and sSNA from periods preceding, and 5 and 60 min following the hypoxic stimuli were compared. Intermittent hypoxia significantly increased both sSNA and PNA. Treatment with methysergide (3 mg kg −1 , I.V.) 20 min before the intermittent hypoxic exposures prevented the increases in integrated PNA and sSNA 60 min after IH, indicating a role of serotonergic pathways in this form of plasticity. No increases in PNA and sSNA occurred at comparable times (60 and 120 min) in rats not exposed to hypoxia. The increased sSNA was not simply tonic, but was correlated with respiratory bursts, and occurred predominantly during the first half of expiration. These findings support the hypothesis that sympathorespiratory coupling may underlie the sustained increase in SNA associated with the IH that occurs during sleep apnoea.

Sympathetic and respiratory motor activities are entrained centrally. We hypothesize that this coupling may partially underlie changes in sympathetic activity evoked by hypoxia due to activity-dependent changes in the respiratory pattern. Specifically, we tested the hypothesis that sympathetic nerve activity (SNA) expresses a short-term potentiation in activity after hypoxia similar to that expressed in phrenic nerve activity (PNA). Adult male, Sprague-Dawley (Zivic Miller) rats (n = 19) were anesthetized (Equithesin), vagotomized, paralyzed, ventilated, and pneumothoracotomized. We recorded PNA and splanchnic SNA (sSNA) and generated cycle-triggered averages (CTAs) of rectified and integrated sSNA before, during, and after exposures to hypoxia (8% O(2) and 92% N(2) for 45 s). Inspiration (I) and expiration (E) were divided in half, and the average and area of integrated sSNA were calculated and compared at the following time points: before hypoxia, at the peak breathing frequency during hypoxia, immediately before the end of hypoxia, immediately after hypoxia, and 60 s after hypoxia. In our animal model, sSNA bursts consistently followed the I-E phase transition. With hypoxia, sSNA increased in both halves of E, but preferentially in the second rather than the first half of E, and decreased in I. After hypoxia, sSNA decreased abruptly, but the coefficient of variation in respiratory modulation of sSNA was significantly less than that at baseline. The hypoxic-evoked changes in sympathetic activity and respiratory pattern resulted in sSNA in the first half of E being correlated negatively to that in the second half of E (r = -0.65, P < 0.05) and positively to Te (r = 0.40, P < 0.05). Short-term potentiation in sSNA appeared not as an increase in the magnitude of activity but as an increased consistency of its respiratory modulation. By 60 s after hypoxia, the variability in the entrainment pattern had returned to baseline. The preferential recruitment of late expiratory sSNA during hypoxia results from either activation by expiratory-modulated neurons or by non-modulated neurons whose excitatory drive is not gated during late E.

Cardiorespiratory coupling is an encompassing term describing more than the well-recognized influences of respiration on heart rate and blood pressure. Our data indicate that cardiorespiratory coupling reflects a reciprocal interaction between autonomic and respiratory control systems, and the cardiovascular system modulates the ventilatory pattern as well. For example, cardioventilatory coupling refers to the influence of heart beats and arterial pulse pressure on respiration and is the tendency for the next inspiration to start at a preferred latency after the last heart beat in expiration. Multiple complementary, well-described mechanisms mediate respiration’s influence on cardiovascular function, whereas mechanisms mediating the cardiovascular system’s influence on respiration may only be through the baroreceptors but are just being identified. Our review will describe a differential effect of conditioning rats with either chronic intermittent or sustained hypoxia on sympathetic nerve activity but also on ventilatory pattern variability. Both intermittent and sustained hypoxia increase sympathetic nerve activity after 2 weeks but affect sympatho-respiratory coupling differentially. Intermittent hypoxia enhances sympatho-respiratory coupling, which is associated with low variability in the ventilatory pattern. In contrast, after constant hypobaric hypoxia, 1-to-1 coupling between bursts of sympathetic and phrenic nerve activity is replaced by 2-to-3 coupling. This change in coupling pattern is associated with increased variability of the ventilatory pattern. After baro-denervating hypobaric hypoxic-conditioned rats, splanchnic sympathetic nerve activity becomes tonic (distinct bursts are absent) with decreases during phrenic nerve bursts and ventilatory pattern becomes regular. Thus, conditioning rats to either intermittent or sustained hypoxia accentuates the reciprocal nature of cardiorespiratory coupling. Finally, identifying a compelling physiologic purpose for cardiorespiratory coupling is the biggest barrier for recognizing its significance. Cardiorespiratory coupling has only a small effect on the efficiency of gas exchange; rather, we propose that cardiorespiratory control system may act as weakly coupled oscillator to maintain rhythms within a bounded variability.

Slow deep breathing (SDB) has a therapeutic effect on autonomic tone. Our previous studies suggested that coupling of the cardiovascular to the respiratory system mediates plasticity expressed in sympathetic nerve activity. We hypothesized that SDB evokes short-term plasticity of cardiorespiratory coupling (CRC). We analyzed respiratory frequency (fr), heart rate and its variability (HR&HRV), the power spectral density (PSD) of blood pressure (BP) and the ventilatory pattern before, during, and after a 20-min epoch of SDB. During SDB, CRC and the relative PSD of BP at fr increased; mean arterial pressure decreased; but HR varied; increasing (n=3), or decreasing (n=2) or remaining the same (n=5). After SDB, short-term plasticity was not apparent for the group but for individuals differences existed between baseline and recovery periods. We conclude that a repeated practice, like pranayama, may strengthen CRC and evoke short-term plasticity effectively in a subset of individuals.

Acute lung injury evokes a pulmonary inflammatory response and changes in the breathing pattern. The inflammatory response has a centrally mediated component which depends on the vagi. We hypothesize that the central inflammatory response, complimentary to the pulmonary inflammatory response, is expressed in the nuclei tractus solitarii (nTS) and that the expression of cytokines in the nTS is associated with breathing pattern changes. Adult, male Sprague-Dawley rats (n=12) received intratracheal instillation of either bleomycin (3U in 120 µl of saline) or saline (120 µl). Respiratory pattern changed by 24h. At 48 h, bronchoalveolar lavage fluid and lung tissue had increased IL-1β and TNF-α levels, but not IL-6. No changes in these cytokines were noted in serum. Immunocytochemical analysis of the brainstem indicated increased expression of IL-1β in the nTS commissural subnucleus that was localized to neurons. We conclude that breathing pattern changes in acute lung injury were associated with increased levels of IL-1β in brainstem, areas which integrate cardio-respiratory sensory input.