Effect of varying chemoreflex stress on sympathetic neural recruitment strategies during apnea

Abstract

PURPOSE Sympathetic nervous system responses to voluntary apnea are increased by hypoxia and attenuated by hyperoxia. However, whether neural firing and recruitment strategies in response to apnea can be modified by hypoxia and/or hyperoxia were previously unknown. We examined the influence of chemoreceptor stimuli on sympathetic neural firing and recruitment strategies during voluntary end‐expiratory apnea. We hypothesized increases in the firing frequency and probability of low‐threshold axons during apnea would be exaggerated during hypoxia and attenuated during hyperoxia. METHODS Multi‐unit muscle sympathetic nerve activity (MSNA, microneurography) was measured in 10 young, healthy men (31±2 yrs, 25±1 kg/m2). Data were collected at baseline and during maximal voluntary end‐expiratory apnea under normoxic (SpO2: 98±1%), hypoxic (FiO2: 0.17±0.01; SpO2: 82±1%), and hyperoxic (FiO2: 0.92±0.03; SpO2: 100±0%) conditions. Condition order was randomized and trials were separated by a minimum of 15‐min quiet normoxic rest. Action potential (AP) patterns were studied from the filtered raw signal using wavelet‐based methodology. Data are reported from the last 2‐min of baseline and during the second half of apnea, reflecting the time of highest MSNA. RESULTS There was an increase in multi‐unit MSNA (24±3 to 35±3 bursts/min, p=0.04) during normoxic apnea, which was due to an increase in the frequency and incidence of AP spikes (243±75 to 519±134 AP/min, p=0.048; 412±133 to 773±185 AP/100 heart beats, p=0.04). An increase in the probability of AP firing more than once per burst was also observed (p=0.01). There was an increase in multi‐unit MSNA (20±4 to 46±7 bursts/min, p<0.01) during hypoxic apnea that was due to an increase in the frequency and incidence of AP spikes (192±59 to 952±266 AP/min, p<0.01; 326±89 to 1212±327 AP/100 heart beats, p<0.01). Hypoxic apnea also resulted in an increase in the probability of AP firing more than once per burst (p<0.01). Hyperoxia attenuated any increase in MSNA with apnea, such that no changes in multi‐unit MSNA (24±4 to 28±5 bursts/min, p=0.14) nor frequency or incidence of AP spikes (155±35 to 253±71 AP/min, p=0.12; 249±61 to 502±188 AP/100 heart beats, p=0.28) were observed. Hyperoxia also attenuated any increase in the probability of AP firing more than once per burst (p=0.47). CONCLUSION These data are the first to show neural firing and recruitment strategies in response to voluntary end‐expiratory apnea are modified by hypoxia and hyperoxia. Our results demonstrate that hypoxic apnea increases the frequency and incidence of action potential spikes, as well as the probability of multiple within‐burst firing; whereas this response was suppressed when individuals were hyperoxic. These data may have important implications for neural control of the circulation in recreational activities (i.e. diving) and/or clinical conditions prone to apnea (i.e. sleep apnea). Support or Funding Information FUNDING: AHA #15SDG25080095, NIH HL130339, Natural Sciences and Engineering Research Counc...

Action potential amplitude and baroreflex resetting of action potential clusters mediate hypoxia‐induced sympathetic long‐term facilitation

“…Compared to sympathetic stress elicited during orthostatic challenges (Badrov et al., 2015; Klassen et al., 2019, 2020) and chemical stimuli via end expiratory apnoea or intermittent hypercapnic hypoxia (Badrov et al., 2015; Klassen et al., 2019; Ott et al., 2020), acute isocapnic hypoxia produced a less robust sympathetic response. Indeed, acute (≥5 min) poikilocapnic hypoxia has been shown to have little effect on total AP cluster activity (Ott et al., 2019), supporting the notion that the type of neural reflex manoeuvre and intensity of sympathoexcitation influences the degree of sympathetic postganglionic neuronal recruitment (Charkoudian & Wallin, 2014).…”

“…Smaller-sized APs are not only under weak baroreflex control (Klassen et al, 2020), but also express greater asynchronous firing patterns between bursts during periods previously considered 'neurally silent' (Klassen et al, 2019). Sympathetic activation during severe orthostatic (Badrov et al, 2015;Klassen et al, 2019Klassen et al, , 2020Salmanpour et al, 2011) and chemical (Badrov et al, 2015;Ott et al, 2019Ott et al, , 2020Steinback et al, 2010) stressors appears to be facilitated by both enhanced neural recruitment of previously latent, larger-diameter sympathetic axons and resetting of the arterial baroreflex to permit increased firing frequency of medium sized AP subpopulations (Klassen et al, 2020), in addition to reduced incidence of asynchronous AP activity (Klassen et al, 2019). However, the baroreflex governing strategies over varying-sized sympathetic axons that permit sLTF following hypoxia-induced chemoreflex activation is unknown.…”

A comprehensive review of respiratory, autonomic and cardiovascular responses to intermittent hypoxia in humans

“…In addition, if transient hyperoxia had a direct effect on central mechanisms, then reductions in baseline muscle sympathetic nerve activity might be expected. Several investigations have shown that this is not the case ( Morgan et al, 1995 ; Ott et al, 2019 ; Querido et al, 2010 ).…”

Sympathetic neural recruitment strategies following acute intermittent hypoxia in humans

“…AP patterns were detected and extracted using wavelet-based methodology on the raw, band-pass-filtered neurogram using techniques developed in the laboratory of Dr. J. Kevin Shoemaker (60). As described previously (30,46), a continuous wavelet transform using a "mother wavelet" with the same morphology as a physiological postganglionic sympathetic AP was used for AP detection. APs were only extracted if they occurred within an integrated burst (i.e., 0.8 s around the peak of the burst).…”

“…The probability of 100% indicates clusters within the bin fired more than once in every integrated burst, whereas a probability less than 100% indicates the cluster did not fire multiple times in every burst. Because the number of total clusters varies by individual, normalization procedures were completed using methods published previously (5,30,46). Briefly, APs were normalized to the largest detected cluster (given a value of 100%).…”