Abstract
Moderate acute intermittent hypoxia (mAIH) elicits a progressive increase in phrenic motor output lasting hours post-mAIH, a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). mAIH-induced pLTF is initiated by activation of spinally-projecting raphe serotonergic neurons during hypoxia and subsequent serotonin release near phrenic motor neurons. Since raphe serotonergic neurons are also sensitive to pH and CO2, the prevailing arterial CO2 pressure (PaCO2) may modulate their activity (and serotonin release) during hypoxic episodes. Thus, we hypothesized that changes in background PaCO2 directly influence the magnitude of mAIH-induced pLTF. mAIH-induced pLTF was evaluated in anesthetized, vagotomized, paralyzed and ventilated rats, with end-tidal CO2 (i.e., a PaCO2 surrogate) maintained at: (1) ≤39 mmHg (hypocapnia); (2) ∼41 mmHg (normocapnia); or (3) ≥48 mmHg (hypercapnia) throughout experimental protocols. Although baseline phrenic nerve activity tended to be lower in hypocapnia, short-term hypoxic phrenic response, i.e., burst amplitude (Δ = 5.1 ± 1.1 μV) and frequency responses (Δ = 21 ± 4 bpm), was greater than in normocapnic (Δ = 3.6 ± 0.6 μV and 8 ± 4, respectively) or hypercapnic rats (Δ = 2.0 ± 0.6 μV and −2 ± 2, respectively), followed by a progressive increase in phrenic burst amplitude (i.e., pLTF) for at least 60 min post mAIH. pLTF in the hypocapnic group (Δ = 4.9 ± 0.6 μV) was significantly greater than in normocapnic (Δ = 2.8 ± 0.7 μV) or hypercapnic rats (Δ = 1.7 ± 0.4 μV). In contrast, although hypercapnic rats also exhibited significant pLTF, it was attenuated versus hypocapnic rats. When pLTF was expressed as percent change from maximal chemoreflex stimulation, all pairwise comparisons were found to be statistically significant (p < 0.05). We conclude that elevated PaCO2 undermines mAIH-induced pLTF in anesthetized rats. These findings contrast with well-documented effects of PaCO2 on ventilatory LTF in awake humans.
Highlights
One of the most well-studied forms of respiratory motor plasticity is phrenic long-term facilitation, characterized by a progressive increase in phrenic burst amplitude following moderate acute intermittent hypoxia
We report that moderate acute intermittent hypoxia (mAIH)-induced phrenic long-term facilitation (pLTF) is inversely correlated with baseline PaCO2 in rats, unlike humans (Harris et al, 2006; Syed et al, 2013; Tester et al, 2014)
For example: (1) all groups reached similar absolute phrenic burst amplitudes 60 min post-mAIH, despite different background respiratory drive; (2) the hypercapnic group had a blunted burst frequency response during hypoxia, which remained below baseline levels following mAIH
Summary
One of the most well-studied forms of respiratory motor plasticity is phrenic long-term facilitation (pLTF), characterized by a progressive increase in phrenic burst amplitude following moderate acute intermittent hypoxia (mAIH; Hayashi et al, 1993; Baker-Herman and Mitchell, 2002; Baker-Herman et al, 2004). Carotid body neural network are activated, including brainstem neurons of the caudal, spinallyprojecting raphe nuclei (Holtman et al, 1986; Pilowsky et al, 1990; Erickson and Millhorn, 1991, 1994; Morris et al, 1996) These raphe neurons release serotonin in the ventral spinal cord, including the phrenic motor nucleus (Kinkead et al, 2001), thereby activating spinal serotonin type 2 receptors that initiate an intracellular signaling cascade giving rise to pLTF (MacFarlane and Mitchell, 2009; Tadjalli and Mitchell, 2019). One might predict greater activation and serotonin-release from raphe neurons during hypoxia with a background of hypercapnia versus hypocapnia Since both hypoxia (indirect) and CO2 (direct and indirect) modulate raphe serotonergic neuron activity, mAIH-induced pLTF expression may depend, at least in part, on the prevailing arterial CO2 pressure (PaCO2). The impact of background PaCO2 on pLTF has never been systematically investigated in anesthetized rats, it’s impact on ventilatory LTF has been investigated extensively in humans (Harris et al, 2006; Syed et al, 2013; Tester et al, 2014)
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