Effects Of Acute Intermittent Hypoxia Research Articles

Effects of acute intermittent hypoxia on muscle strength in individuals with spinal cord injury: A systematic review of randomized trials

Effects of acute intermittent hypoxia on muscle strength in individuals with spinal cord injury: A systematic review of randomized trials

Efficacy of acute intermittent hypoxia in improving the motor and respiratory functions of individuals with spinal cord injury: a systematic review of randomised controlled trials

Background/Aims Spinal cord injury affects individuals’ mobility, balance and respiratory functions. Acute intermittent hypoxia is a novel intervention that is reported to have positive effects on neuroplasticity and synaptic transmission in individuals with spinal cord injury, which may result in positive effects on motor functions of individuals with spinal cord injury. The aim of this systematic review was to examine the evidence of the safety and efficacy of acute intermittent hypoxia on spinal plasticity, walking performance, balance, breathing function and hand use in individuals with spinal cord injury. Methods Five databases were searched from inception until 7 February 2024 for randomised trials investigating the effects of acute intermittent hypoxia on motor functions in spinal cord injuries. After checking the retrieved trials against the eligibility criteria, a risk of bias assessment using the Risk of Bias 2.0 tool was conducted by two authors independently. In addition, data extraction was conducted by two authors independently, which included the study design, participants’ characteristics, intervention characteristics, outcome measures and results. Results The systematic search retrieved 1120 records, of which only 11 studies were included in the analysis. Nine of the included studies were randomised crossover trials, while two were randomised controlled trials. Acute intermittent hypoxia may have a significant effect on walking performance (ie speed and endurance, ankle strength, dynamic balance, hand strength and function, breathing functions and corticospinal function), but not on intralimb motor coordination, static balance and muscle activity. Conclusions Despite the high risk of bias, small sample sizes, high heterogeneity and inconsistency of the results across the included studies, acute intermittent hypoxia may be a valuable intervention in addressing spinal cord injury motor deficiencies. Larger and well-designed randomised controlled trials are required to reach a definitive conclusion regarding its efficacy. Implications for practice Acute intermittent hypoxia could be considered with caution for inclusion in the management plan for individuals with spinal cord injuries who are aiming for immediate and short-term motor improvement.

Intermittent hypoxia enhances voluntary activation and reduces performance fatigability during repeated lower limb contractions.

Prior research has highlighted the therapeutic benefits of acute intermittent hypoxia (AIH) in enhancing motor performance after motor incomplete spinal cord injury and in able-bodied individuals. Although studies in rodents and humans indicate that AIH may facilitate motor excitability, the relationship between excitability changes and functional performance remains unclear. In addition, discrepancies in the effects of AIH on excitability in able-bodied individuals merit further investigation. Understanding the concurrent impact of repetitive AIH on voluntary activation and spinal reflex excitability may clarify the functional implications of AIH for muscle force production. High voluntary activation is vital for sustaining torque production during activities that require repeated muscle contractions. We hypothesized that repetitive AIH would attenuate decreases in both voluntary activation and maximum torque production typically observed during fatiguing contractions. To test this hypothesis, we examined the effects of four consecutive days of AIH on voluntary activation and torque generation during repeated maximal plantar flexion contractions. We assessed changes in voluntary activation using the central activation ratio by calculating the ratio of voluntary torque to the torque produced with supramaximal electrical stimulation. Consistent with our hypothesis, we show that repetitive AIH significantly increases both voluntary activation and peak torque during fatiguing contractions. We did not observe any changes in resting spinal reflex excitability or antagonist muscle coactivation during fatiguing contractions post-AIH. Together, these findings suggest that repetitive AIH reduces performance fatigability through enhanced descending neural drive. Optimizing voluntary activation is critical for facilitating the recovery of functional walking skills after neurological injury.NEW & NOTEWORTHY This study shows that repetitive acute intermittent hypoxia (AIH) significantly increases both voluntary activation and peak torque during fatiguing lower limb contractions. However, resting spinal reflex excitability and antagonist muscle coactivation during fatiguing contractions did not change following repetitive AIH. Together, these observations indicate that repetitive AIH reduces performance fatigability through enhanced descending neural drive. These findings underscore the therapeutic potential of AIH for promoting motor recovery after neurological injury.

A randomized controlled crossover trial of acute intermittent and continuous hypoxia exposure in mild-moderate obstructive sleep apnea: A feasibility study.

In a prospective, randomized, controlled crossover study, we explored the effects of acute intermittent hypoxia and acute continuous hypoxia on patients with mild-moderate obstructive sleep apnea. Over three single-night sessions, subjects were alternately exposed to normoxia, acute continuous hypoxia and acute intermittent hypoxia before sleep. The apnea-hypopnea index and oxygen desaturation index were used to diagnose obstructive sleep apnea and evaluate efficacy. A responder was defined as a participant with a ≥ 50% reduction in apnea-hypopnea index between normoxia and hypoxia exposure. Sixteen participants with mild-moderate obstructive sleep apnea completed the study. Compared with normoxia, the mean apnea-hypopnea index decreased by 8.9 events per hr (95% confidence interval, 4.2-13.6, p = 0.001) with acute intermittent hypoxia and by 4.1 events per hr (95% confidence interval, 0.5-8.8, p = 0.082) with acute continuous hypoxia, equating to a mean decrease in apnea-hypopnea index of 4.8 events per hr (95% confidence interval, 0.1-9.5, p = 0.046) with acute intermittent hypoxia compared with acute continuous hypoxia. Compared with normoxia, the mean oxygen desaturation index decreased by 9.8 events per hr (95% confidence interval, 4.4-15.1, p = 0.001) with acute intermittent hypoxia but did not significantly decrease with acute continuous hypoxia; the mean oxygen desaturation index decreased by 7.2 events per hr (95% confidence interval, 1.8-12.6, p = 0.010) with acute intermittent hypoxia compared with acute continuous hypoxia. Of the 16 participants, 11 responded to acute intermittent hypoxia and four responded to acute continuous hypoxia (p = 0.032), of whom eight of 11 cases and all four cases had oxygen desaturation indexes <5 events per hr, respectively (p = 0.273). All participants tolerated acute intermittent hypoxia and there were no obvious adverse events during acute intermittent hypoxia exposure. In conclusion, acute intermittent hypoxia exposure improved apnea-hypopnea index and oxygen desaturation index in patients with mild-moderate obstructive sleep apnea, suggesting that further prospective validation of intermittent hypoxia exposure in patients with obstructive sleep apnea is needed to establish its clinical feasibility as a therapeutic modality.

Effects of acute intermittent hypoxia on P0.1 in humans with spinal cord injury

Spinal cord injury (SCI) disrupts neural pathways to respiratory motor neurons, diminishing respiratory drive and breathing function. Breathing impairment remains a leading cause of illness and death after SCI. Therapeutic acute intermittent hypoxia (tAIH; 15, 1-minute episodes of 9% inspired O 2 , 1.5 min normoxic intervals), a promising strategy to restore breathing function after SCI, promotes spinal neuroplasticity in rodent models. However, in humans, respiratory drive is unchanged after a single tAIH session; thus we tested the hypothesis that tAIH on five successive days increases neuromechanical respiratory drive in humans living with chronic SCI. Sixteen participants with chronic SCI (1 female; 33.5 + 15.3 years of age; 1-28 years post-SCI; 11 cervical, 5 thoracic; C1-T6 AIS A-D) were studied; their respiratory function was 52% ± 19% of age predicted expiratory pressure generation, and 123% ± 32% for inspiratory pressure. Five days of tAIH or Sham treatment were delivered in a randomized, cross-over design (minimum 3 weeks apart). Airway occlusion pressure in the first 0.1s of inspiration (P0.1), a surrogate for neuromechanical respiratory drive prior to within-breath sensory feedback, was collected at baseline and at 1, 3, and 7-days post-treatment. Repeated measures ANOVA revealed no significant effect of time (F(3)=.49; P=.69) or group (F(3)=1.33; P=.27). Despite the lack of significant differences in this preliminary analysis, P0.1 increased by 25% on day 3 versus 0.8% after Sham. Because of this change, pairwise comparisons were conducted, revealing a near significant increase in P0.1, 3 days post tAIH (MD=-.17; P =.06). Thus, although P0.1, a surrogate for neuromechanical respiratory drive, did not significantly increase after 5 days of AIH in people with SCI, the marginally significant change at day 3 suggests further investigation is warranted. Next steps include assessment in a larger sample, investigation of biomarkers for treatment effects, and examination of combinatorial interventions including task specific training and/or mild CO 2 elevations to enhance AIH-induced neuroplasticity in the drive to breathe. DoD SCIRP Clinical Trial Award W81XWH-17-SCIRP-CTA; The Craig H. Neilsen Foundation (JW); NIH T32 HL134621 (MM); and the UF McKnight Brain Institute. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ventilatory Effects of Acute Intermittent Hypoxia in Conscious Dystrophic Mice.

Exposure to acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). Interest has grown in developing AIH interventions to treat ventilatory insufficiency, with promising results in spinal cord injury and amyotrophic lateral sclerosis. Therapeutic AIH may have application in neuromuscular disorders including muscular dystrophies. We sought to establish hypoxic ventilatory responsiveness and the expression of ventilatory LTF in X-linked muscular dystrophy (mdx) mice.Experiments were performed in 15 male wild-type (BL10) and 15 male mdx mice at 4 months of age. Ventilation was assessed using whole-body plethysmography. Baseline measures of ventilation and metabolism were established. Mice were exposed to 10 successive bouts of hypoxia, each lasting 5min, interspersed with 5-min bouts of normoxia. Measurements were taken for 60 min following termination of AIH.In mdx mice, ventilation was significantly increased 60 min post-AIH compared to baseline. However, metabolic CO2 production was also increased. Therefore, ventilatory equivalent was unaffected by AIH exposure, i.e., no ventilatory LTF manifestation. In wild-type mice, ventilation and metabolism were not affected by AIH.Eliciting ventilatory LTF is dependent on many factors and may require concomitant isocapnia or hypercapnia during AIH exposures and/or repeated daily AIH exposures, which is worthy of further pursuit.

Effects of acute intermittent hypoxia on corticospinal excitability within the primary motor cortex

PurposeAcute intermittent hypoxia (AIH) is a safe and non-invasive treatment approach that uses brief, repetitive periods of breathing reduced oxygen air alternated with normoxia. While AIH is known to affect spinal circuit excitability, the effects of AIH on cortical excitability remain largely unknown. We investigated the effects of AIH on cortical excitability within the primary motor cortex.MethodsEleven healthy, right-handed participants completed two testing sessions: (1) AIH (comprising 3 min in hypoxia [fraction of inspired oxygen ~ 10%] and 2 min in normoxia repeated over five cycles) and (2) normoxia (NOR) (equivalent duration to AIH). Single- and paired-pulse transcranial magnetic stimulations were delivered to the primary motor cortex, before and 0, 25, and 50 min after AIH and normoxia.ResultsThe mean nadir in arterial oxygen saturation was lower (p < 0.001) during the cycles of AIH (82.5 ± 4.9%) than NOR (97.8 ± 0.6%). There was no significant difference in corticospinal excitability, intracortical facilitation, or intracortical inhibition between AIH and normoxia conditions at any time point (all p > 0.05). There was no association between arterial oxygen saturation and changes in corticospinal excitability after AIH (r = 0.05, p = 0.87).ConclusionOverall, AIH did not modify either corticospinal excitability or excitability of intracortical facilitatory and inhibitory circuits within the primary motor cortex. Future research should explore whether a more severe or individualised AIH dose would induce consistent, measurable changes in corticospinal excitability.

New insights into the effects of acute intermittent hypoxia on neural plasticity in the human motor system.

New insights into the effects of acute intermittent hypoxia on neural plasticity in the human motor system.

The effect of acute intermittent hypoxia on human limb motoneurone output.

What is the central question of this study? Does a single session of repeated bouts of acute intermittent hypoxic breathing enhance the motoneuronal output of the limb muscles of healthy able-bodied participants? What is the main finding and its importance? Compared to breathing room air, there were some increases in motoneuronal output following acute intermittent hypoxia, but the increases were variable across participants and in time after the intervention and depended on which neurophysiological measure was checked. Acute intermittent hypoxia (AIH) induces persistent increases in output from rat phrenic motoneurones. Studies in people with spinal cord injury (SCI) suggest that AIH improves limb performance, perhaps via postsynaptic changes at cortico-motoneuronal synapses. We assessed whether limb motoneurone output in response to reflex and descending synaptic activation is facilitated after one session of AIH in healthy able-bodied volunteers. Fourteen participants completed two experimental days, with either AIH or a sham intervention (randomised crossover design). We measured H-reflex recruitment curves and homosynaptic post-activation depression (HPAD) of the H-reflex in soleus, and motor evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS) and their recruitment curves in first dorsal interosseous. All measurements were performed at rest and occurred at baseline, 0, 20, 40 and 60min post-intervention. The intervention was 30min of either normoxia (sham, ≈0.21) or AIH (alternate 1-min hypoxia [ ≈0.09], 1-min normoxia). After AIH, the H-reflex recruitment curve shifted leftward. Lower stimulation intensities were needed to evoke 5%, 50% and 99% of the maximal H-reflex at 40 and 60min after AIH (P<0.04). The maximal H-reflex, recruitment slope and HPAD were unchanged after AIH. MEPs evoked by constant intensity TMS were larger 40min after AIH (P=0.027). There was no change in MEP recruitment or the maximal MEP. In conclusion, some measures of the evoked responses from limb motoneurones increased after a single AIH session, but only at discrete time points. It is unclear to what extent these changes alter functional performance.

The effect of acute intermittent hypoxia on postprandial triglyceride levels in humans: a randomized crossover trial

BackgroundObstructive sleep apnea (OSA), a sleep disorder frequently observed in individuals living with obesity, consists of repeated involuntary breathing obstructions during sleep, leading to intermittent hypoxia (IH). In humans, acute continuous hypoxia slightly increases plasma triglycerides (TG). However, no study yet compared the postprandial TG response of individuals with or without OSA under intermittent hypoxia.MethodsUsing a randomized crossover design, seven individuals diagnosed with moderate OSA and eight healthy individuals without OSA were given a meal after which they were exposed for 6 h to normoxia or intermittent hypoxia (e.g., 15 hypoxic events per hour). Blood lipid levels were measured hourly during each session.ResultsPeak postprandial TG concentrations tended to be 22% higher under IH irrespective of group (IH × time interaction, p = 0.068). This trend toward higher total plasma TG was attributable to increased levels of denser TG-rich lipoproteins such as very low-density lipoproteins (VLDL) and chylomicrons (CM) remnants. Irrespective of group, the postprandial TG concentrations in denser TG-rich lipoproteins was 20% higher under IH (IH × time interaction, p = 0.036), although IH had virtually no impact on denser TG-rich lipoprotein concentrations in the OSA group.ConclusionAcute intermittent hypoxia tends to negatively affect postprandial TG levels in healthy individuals, which is attributable to an increase in denser TG-carrying lipoprotein levels such as VLDL and CM remnants. This altered postprandial TG response to acute intermittent hypoxia was not observed in individuals with OSA.

Single-session effects of acute intermittent hypoxia on breathing function after human spinal cord injury

After spinal cord injury (SCI) respiratory complications are a leading cause of morbidity and mortality. Acute intermittent hypoxia (AIH) triggers spinal respiratory motor plasticity in rodent models, and repetitive AIH may have the potential to restore breathing capacity in those with SCI. As an initial approach to provide proof of principle for such effects, we tested single-session AIH effects on breathing function in adults with chronic SCI. 17 adults (13 males; 34.1±14.5years old; 13 motor complete SCI; >6months post injury) completed two randomly ordered sessions, AIH versus sham. AIH consisted of 15, 1-min episodes (hypoxia: 10.3% O2; sham: 21% O2) interspersed with room air breathing (1.5min, 21% oxygen); no attempt was made to regulate arterial CO2 levels. Blood oxygen saturation (SpO2), maximal inspiratory and expiratory pressures (MIP; MEP), forced vital capacity (FVC), and mouth occlusion pressure within 0.1s (P0.1) were assessed. Outcomes were compared using nonparametric Wilcoxon's tests, or a 2×2 ANOVA. Baseline SpO2 was 97.2±1.3% and was unchanged during sham experiments. During hypoxic episodes, SpO2 decreased to 84.7±0.9%, and returned to baseline levels during normoxic intervals. Outcomes were unchanged from baseline post-sham. Greater increases in MIP were evident post AIH vs. sham (median values; +10.8 cmH2O vs. -2.6 cmH2O respectively, 95% confidence interval (-18.7) - (-4.3), p=.006) with a moderate Cohen's effect size (0.68). P0.1, MEP and FVC did not change post-AIH. A single AIH session increased maximal inspiratory pressure generation, but not other breathing functions in adults with SCI. Reasons may include greater spared innervation to inspiratory versus expiratory muscles or differences in the capacity for AIH-induced plasticity in inspiratory motor neuron pools. Based on our findings, the therapeutic potential of AIH on breathing capacity in people with SCI warrants further investigation.

Sex Differences in the Effect of Acute Intermittent Hypoxia on Respiratory‐Sympathetic Coupling in Humans

Background Sex-related differences in respiratory-sympathetic coupling have been described in preclinical models of intermittent hypoxia (IH) and have been implicated in the development of neurogenic hypertension. Based on sex disparities in the respiratory and blood pressure response to acute IH in humans as well as changes in respiratory-sympathetic coupling in clinical sleep apnea, we examined sex-related differences in respiratory modulation of muscle sympathetic nerve activity (MSNA) following acute IH in healthy humans. We hypothesized the magnitude of respiratory-sympathetic coupling would increase in both men and women following IH; however, the respiratory patterning of MSNA following IH would be sex-specific. Methods Heart rate, MSNA, and respiration were assessed in 21 healthy young men (30±1 yrs) and 10 healthy young women (28±1 yrs) during normoxic rest prior to and following IH. IH was achieved by alternating between a hypercapnic hypoxic (3% carbon dioxide, 5% oxygen) gas cylinder and room air (21% oxygen) to target 15 hypoxic events over 30-min. Respiratory modulation of MSNA was assessed by fitting polynomials to cross-correlation histograms constructed between sympathetic spikes and respiration. Results MSNA was elevated following IH in both men (34±2 to 41±3 bursts/100 heart beats) and women (30±4 to 35±5 bursts/100 heart beats) (p<0.01). When examining the normalized temporal profile of MSNA, both men and women exhibited changes in respiratory patterning of MSNA following IH; however, the pattern of MSNA differed by sex. Following IH, women exhibited more sympathetic activity during late expiration and less during post-inspiration (interaction of IH and time, p<0.01). In contrast, men exhibited greater sympathetic activity during post-inspiration following IH (interaction of IH and time, p<0.01). Conclusions Both men and women exhibit changes in respiratory patterning of MSNA following acute IH; however, this pattern differs by sex. These data support sex disparities in respiratory-sympathetic coupling and advance our understanding of sex-specific changes in sympathetic activation following IH which may have important implications for the development of neurogenic hypertension.

Effect of acute intermittent hypoxia on cortico-diaphragmatic conduction in healthy humans

Acute intermittent hypoxia (AIH) is a strategy to improve motor output in humans with neuromotor impairment. A single AIH session increases the amplitude of motor evoked potentials (MEP) in a finger muscle (first dorsal interosseous), demonstrating enhanced corticospinal neurotransmission. Since AIH elicits phrenic/diaphragm long-term facilitation (LTF) in rodent models, we tested the hypothesis that AIH augments diaphragm MEPs in humans. Eleven healthy adults (7 males, age=29±6years) were tested. Transcranial and cervical magnetic stimulation were used to induce diaphragm MEPs and compound muscle action potentials (CMAP) recorded by surface EMG, respectively. Stimulus-response curves were generated prior to and 30-60min after AIH. Diaphragm LTF was assessed by measurement of integrated EMG burst amplitude and frequency during eupnoeic breathing before and after AIH. Following baseline measurements, AIH was delivered from an oxygen generator connected to a facemask under poikilocapnic conditions (15 one minute episodes of 9% inspired oxygen with one minute room air intervals). There were no detectable changes in MEP (-1.5±12.1%, p=0.96) or CMAP (+0.1±7.8%, p=0.97) amplitudes across the stimulus-response curve. At stimulation intensities approximating 50% of the difference between minimum and maximum baseline amplitudes, MEP and CMAP amplitudes were also unchanged (p>0.05). Further, no AIH effect was observed on diaphragm EMG activity during eupnoea post-AIH (p>0.05). We conclude that unlike hand muscles, poikilocapnic AIH does not enhance diaphragm MEPs or produce diaphragm LTF in healthy humans.

Sympathetic neural recruitment strategies following acute intermittent hypoxia in humans.

We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing patterns and the role of the carotid chemoreceptors. We hypothesized exposure to acute IH would increase muscle sympathetic nerve activity (MSNA) via an increase in action potential (AP) discharge rates and within-burst firing. We further hypothesized any change in discharge patterns would be attenuated during acute chemoreceptor deactivation (hyperoxia). MSNA (microneurography) was assessed in 17 healthy adults (11 male/6 female; 31 ± 1 yr) during normoxic rest before and after 30 min of experimental IH. Prior to and following IH, participants were exposed to 2 min of 100% oxygen (hyperoxia). AP patterns were studied from the filtered raw MSNA signal using wavelet-based methodology. Compared with baseline, multiunit MSNA burst incidence (P < 0.01), AP incidence (P = 0.01), and AP content per burst (P = 0.01) were increased following IH. There was an increase in the probability of a particular AP cluster firing once (P < 0.01) and more than once (P = 0.03) per burst following IH. There was no effect of hyperoxia on multiunit MSNA at baseline or following IH (P > 0.05); however, hyperoxia following IH attenuated the probability of particular AP clusters firing more than once per burst (P < 0.01). Acute IH increases MSNA by increasing AP discharge rates and within-burst firing. A portion of the increase in within-burst firing following IH can be attributed to the carotid chemoreceptors. These data advance the mechanistic understanding of sympathetic activation following acute IH in humans.

Effects of Acute Intermittent Hypoxia on Maximal Respiratory Ability after Spinal Cord Injury

Effects of Acute Intermittent Hypoxia on Maximal Respiratory Ability after Spinal Cord Injury

Sympathetic Discharge Patterns and Neurovascular Transduction Following Acute Intermittent Hypoxia

BackgroundMuscle sympathetic nerve activity (MSNA) is augmented in patients with sleep apnea. This increase in activity is due to increases in firing probability and mean firing rates of individual vasoconstrictor neurons, in addition to multiple within‐burst firing; however, contributing mechanisms and the impact of such firing patterns on peripheral vascular tone are less clear. We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing and recruitment strategies and the relationship between changes in MSNA and neurovascular transduction following acute IH. We hypothesized exposure to acute IH would increase MSNA via an increase in action potential (AP) discharge rates and within‐burst firing. We further hypothesized any change in discharge patterns following acute IH would be positively related to a change in neurovascular transduction.MethodsBlood pressure (brachial arterial catheter) and MSNA (microneurography of the peroneal nerve) were assessed in 17 healthy adults (11M/6F; 31 ± 1 yrs) during quiet normoxic rest prior to and following 30‐min of experimental IH [30‐s hypoxic (0.05 FiO2) exposures alternating with 90‐s room air breathing]. AP patterns were studied from the filtered raw MSNA signal using wavelet‐based methodology. The slope of the relationship between diastolic blood pressure (DBP) and the preceding MSNA burst area at a fixed cardiac cycle lag was used to quantify neurovascular transduction.ResultsIH resulted in 15 events where oxygen saturation was reduced (SpO2: 99 ± 1% vs 92 ± 1%, P&lt;0.01). Compared to baseline, multi‐unit MSNA burst incidence (33 ± 4 to 43 ± 5 bursts/100 heart beats), AP incidence (272 ± 50 to 501 ± 112 AP/100 heart beats) and AP content per integrated burst (7 ± 1 to 10 ± 1 AP/burst; 4 ± 1 to 5 ± 1 clusters/burst) were increased following IH (all P&lt;0.05). Neurovascular transduction was not altered following IH (P=0.34); however, there was a positive relationship between the change (Δ) in neurovascular transduction (mmHg/%/s) and changes in AP discharge rate (AP/100 heart beats; R=0.52, P=0.03) and within‐burst firing (AP/burst; R=0.38, P=0.14) following IH.ConclusionsAcute IH increases sympathetic neuronal discharge by increasing within‐burst firing of low‐threshold axons. A positive relationship exists between increases in the neural discharge rates and neurovascular transduction following acute IH, such that those individuals with the greatest increase in AP firing exhibited the greatest increase in transduction of sympathetic activity into blood pressure. These data may have important implications for mechanistic understanding of sympathetic activation in sleep apnea and its down‐stream effects, including the development of hypertension and cardiovascular disease.Support or Funding InformationFunding: NIH HL130339, Mayo Clinic Center for Biomedical Discovery, Mizzou HES PURE, APS UGSRF.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sympathoexcitation following intermittent hypoxia in rat is mediated by circulating angiotensin II acting at the carotid body and subfornical organ

In anaesthetized rats, acute intermittent hypoxia increases sympathetic nerve activity, sympathetic peripheral chemoreflex sensitivity and central sympathetic-respiratory coupling. Renin-angiotensin system inhibition prevents the sympathetic effects of intermittent hypoxia, with intermittent injections of angiotensin II into the systemic circulation replicating these effects. Bilateral carotid body denervation reduces the sympathetic effects of acute intermittent hypoxia and eliminates the increases in chemoreflex sensitivity and sympathetic-respiratory coupling. Pharmacological inhibition of the subfornical organ also reduces the sympathetic effects of acute intermittent hypoxia, although it has no effect on the increases in chemoreflex sensitivity and central sympathetic-respiratory coupling. Combining both interventions eliminates the sympathetic effects of both intermittent hypoxia and angiotensin II. Circulating angiotensin II (AngII) is vital for arterial pressure elevation following intermittent hypoxia in rats, although its importance in the induction of sympathetic changes is unclear. We tested the contribution of the renin-angiotensin system to the effects of acute intermittent hypoxia (AIH) in anaesthetized and ventilated rats. There was a 33.7±2.9% increase in sympathetic nerve activity (SNA), while sympathetic chemoreflex sensitivity and central sympathetic-respiratory coupling increased by one-fold following AIH. The sympathetic effects of AIH were prevented by blocking angiotensin type 1 receptors with systemic losartan. Intermittent systemic injections of AngII (Int.AngII) elicited similar sympathetic responses to AIH. To identify the neural pathways responsible for the effects of AIH and Int.AngII, we performed bilateral carotid body denervation, which reduced the increase in SNA by 56% and 45%, respectively. Conversely, pharmacological inhibition of the subfornical organ (SFO), an established target of circulating AngII, reduced the increase in SNA following AIH and Int.AngII by 65% and 59%, respectively, although it did not prevent the sensitization of the sympathetic peripheral chemoreflex, nor the increase in central sympathetic-respiratory coupling. Combined carotid body denervation and inhibition of the SFO eliminated the enhancement of SNA following AIH and Int.AngII. Repeated systemic injections of phenylephrine caused an elevation in SNA similar to AIH, and this effect was prevented by a renin inhibitor, aliskiren. Our findings show that the sympathetic effects of AIH are the result of RAS-mediated activations of the carotid bodies and the SFO.

Effect of acute intermittent hypoxia on baroreflex sensitivity to decreasing and increasing blood pressures

ObjectivePatients with sleep apnea exhibit impairments in reflex responses to decreasing, but not increasing, arterial blood pressures (BP). Attenuated BP control may contribute to the increased risk of developing hypertension observed in patients with sleep apnea; however the mechanisms involved are not completely understood. Therefore, we aimed to examine the differential effect of acute intermittent hypoxia (IH) on baroreflex sensitivity during decreasing compared to increasing BP. We hypothesized acute IH would attenuate baroreflex sensitivity to decreasing, but not increasing, BP.MethodsHeart rate (HR, electrocardiography), BP (brachial arterial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of the peroneal nerve) were assessed in 14 healthy adults (8M/6F; 32±1 yrs, 26±1 kg/m2). Baroreflex sensitivity was evaluated during decreasing and increasing BP using the modified Oxford technique before and after 30‐min of IH [25‐s hypoxic (0.10 FiO2) exposures alternating with 120‐s room air breathing]. Data were analyzed from the depressor (nitroprusside) and pressor (phenylephrine) phases of the modified Oxford for measures of cardiovagal and sympathetic baroreflex sensitivity, as well as the T50 (diastolic BP with a 50% likelihood of an MSNA burst).ResultsIH resulted in 15 events where oxygen saturation was reduced (SpO2: 98±1% vs 92±2%, p&lt;0.01). Resting normoxic ventilation, carotid chemosensitivity to hypoxia, and MSNA were increased following IH (all p&lt;0.05). HR, systolic BP, diastolic BP, and the T50 were not altered following 30‐min of IH (p‐value range 0.08 to 0.90). Diastolic BP was greater than T50 at baseline (Decreasing BP: p=0.046); however, after IH, diastolic BP was no longer significantly different than the T50 (p=0.52). Cardiovagal baroreflex sensitivity to decreasing and increasing BP differed at baseline (14.0±1.7 vs 22.0±3.3 ms/mmHg, p=0.02) and following IH (11.3±1.1 vs 19.1±2.0 ms/mmHg, p&lt;0.01). Cardiovagal baroreflex sensitivity to decreasing BP tended to be lower following IH (p=0.09). Sympathetic baroreflex sensitivity to decreasing and increasing BP did not differ at baseline (−2.1±0.3 vs −2.5±0.3 %/mmHg; p=0.28) or following IH (−2.6±0.6 vs −3.0±0.4 %/mmHg, p=0.55) and was unaffected by IH (p‐value range 0.20–0.40).ConclusionsAcute IH has a differential effect on baroreflex sensitivity. Specifically, cardiovagal baroreflex sensitivity to decreasing, but not increasing, BP tends to be lower following IH. In contrast, sympathetic baroreflex sensitivity is unaffected by IH. Prior to IH, diastolic BP is greater than the T50, thus promoting lower MSNA. Despite no change in baroreflex sensitivity after IH, diastolic BP is no longer significantly different than the T50 – consistent with higher MSNA following IH.Support or Funding InformationNIH HL130339, Mayo Clinic Center for Biomedical DiscoveryThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of acute intermittent hypoxia on hand use after spinal cord trauma: A preliminary study.

To test the hypothesis that daily acute intermittent hypoxia (AIH) combined with hand opening practice improves hand dexterity, function, and maximum hand opening in persons with chronic, motor-incomplete, cervical spinal cord injury. Six participants completed the double-blind, crossover study. Participants received daily (5 consecutive days) AIH (15 episodes per day: 1.5 minutes of fraction of inspired oxygen [FIo2] = 0.09, 1-minute normoxic intervals) followed by 20 repetitions of hand opening practice and normoxia (sham, FIo2 = 0.21) + hand opening practice. Hand dexterity and function were quantified with Box and Block and Jebsen-Taylor hand function tests. We also recorded maximum hand opening using motion analyses and coactivity of extensor digitorum and flexor digitorum superficialis muscles using surface EMG. Daily AIH + hand opening practice improved hand dexterity, function, and maximum hand opening in all participants. AIH + hand opening practice improved Box and Block Test scores vs baseline in 5 participants (p = 0.057) and vs sham + hand opening practice in all 6 participants (p = 0.016). All participants reduced Jebsen-Taylor Hand Function Test (JTHF) time after daily AIH + hand opening practice (-7.2 ± 1.4 seconds) vs baseline; 4 of 6 reduced JTHF time vs sham + hand opening practice (p = 0.078). AIH + hand opening practice improved maximum hand aperture in 5 of 6 participants (8.1 ± 2.7 mm) vs baseline (p = 0.018) and sham + hand opening practice (p = 0.030). In 5 participants, daily AIH-induced changes in hand opening were accompanied by improved EMG coactivity (p = 0.029). This report suggests the need for further study of AIH as a plasticity "primer" for task-specific training in spinal cord injury rehabilitation. Important clinical questions remain concerning optimal AIH dosage, patient screening, safety, and effect persistence. NCT01272336.

Expression of adrenergic alpha 1 receptor subtypes in magnocellular, pre‐autonomic and medial parvocellular regions of the paraventricular nucleus of the hypothalamus (PVN): Effects of acute intermittent hypoxia

Catecholaminergic inputs to magnocellular, pre‐autonomic, and medial parvocellular neuroendocrine cells in the PVN may participate in activation of these neurons during chemoreflex stimulation. Current experiments evaluated the effects of acute intermittent hypoxia (AIH, 3 min 10% O2, separated by 5 min) on regional expression of alpha1 adrenergic receptor subtypes within the PVN. Spinally projecting PVN neurons were pre‐labeled in rats by prior IML injections of Fluorogold (2%,180 nl bilateral) to aid in visual identification of pre‐autonomic regions of the PVN. Conscious rats were exposed to AIH, while normoxic control rats (N) were exposed to changes in gas flow over the same times, but O2 concentration remained at 21%. One hour later, rats were deeply anesthetized, brains were removed, and the forebrains sectioned (10 μm) on a cryostat. Laser Capture Microscopy (LCM) was used to capture magnocellular, pre‐autonomic and medial parvocellular neurons in the PVN. RNA was isolated, cDNA synthesized and, using target specific primers, expression of mRNA for alpha 1 adrenergic receptor subtypes, 1a, 1b, and 1d and the reference gene GAPDH was evaluated by real time RT‐PCR. Capture of cell populations enriched for specific regions of the PVN was verified by high relative expression of mRNA for vasopressin in the magnocellular (1±0.55) compared to the medial (0.05±0.01) and pre‐autonomic regions (0.13±0.1), and high relative expression of glucocorticoid receptor mRNA in the medial (1±0.33) versus the magnocellular (0.16±0.03) and pre‐autonomic regions (0.09±0.02). Expression of the three alpha 1 receptor subtypes was not changed by AIH in pre‐autonomic and magnocellular regions of the PVN. In the medial parvocellular region, AIH decreased expression of alpha 1d receptors (N= 1±0.35; AIH = 0.28±0.06), while expression of alpha 1a and alpha 1b receptor subtypes remained unchanged. Using Fos‐IR as an index of neuronal activation, immunohistochemistry experiments found that, compared to continuous hypoxia (2 hr, 10% O2), activation of CRH‐IR neurons in the medial parvocellular region of the PVN was significant but modest in rats exposed to AIH (continuous hypoxia = 28±6%; AIH = 7±1%). It is possible that downregulation of adrenergic alpha 1d receptors in the medial parvocellular region during AIH limits excitation of these neurons.Support or Funding InformationFunded by Univ. MO Research Board to CMH and NIH HL 98602.