Endurance training attenuates the increase in peripheral chemoreflex sensitivity with intermittent hypoxia

Patients with heart failure and sleep apnea have greater chemoreflex sensitivity, presumably due to intermittent hypoxia (IH), and this is predictive of mortality. We hypothesized that endurance training would attenuate the effect of IH on peripheral chemoreflex sensitivity in healthy humans. Fifteen young healthy subjects (9 female, 26 ± 1 yr) participated. Between visits, 11 subjects underwent 8 wk of endurance training that included running four times/wk at 80% predicted maximum heart rate and interval training, and four control subjects did not change activity. Chemoreflex sensitivity (the slope of ventilation responses to serial oxygen desaturations), blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) were assessed before and after 30 min of IH. Endurance training decreased resting systolic blood pressure (119 ± 3 to 113 ± 3 mmHg; P = 0.027) and heart rate (67 ± 3 to 61 ± 2 beats/min; P = 0.004) but did not alter respiratory parameters at rest ( P > 0.2). Endurance training attenuated the IH-induced increase in chemoreflex sensitivity (pretraining: Δ 0.045 ± 0.026 vs. posttraining: Δ −0.028 ± 0.040 l·min−1·% O2 desaturation−1; P = 0.045). Furthermore, IH increased mean blood pressure and MSNA burst rate before training ( P < 0.05), but IH did not alter these measures after training ( P > 0.2). All measurements were similar in the control subjects at both visits ( P > 0.05). Endurance training attenuates chemoreflex sensitization to IH, which may partially explain the beneficial effects of exercise training in patients with cardiovascular disease.

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Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00253.2009 ◽

2010 ◽

Vol 299 (3) ◽

pp. H925-H931 ◽

Cited By ~ 73

Author(s):

G. S. Gilmartin ◽

M. Lynch ◽

R. Tamisier ◽

J. W. Weiss

Keyword(s):

Blood Pressure ◽

Sympathetic Nerve ◽

Intermittent Hypoxia ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Chronic Intermittent Hypoxia ◽

Sympathetic Activation ◽

Nerve Activity ◽

Blood Pressure Elevation ◽

Healthy Humans

Chronic intermittent hypoxia (CIH) is thought to be responsible for the cardiovascular disease associated with obstructive sleep apnea (OSA). Increased sympathetic activation, altered vascular function, and inflammation are all putative mechanisms. We recently reported (Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas RJ, Levy P, Weiss JW. J Appl Physiol 107: 17–24, 2009) a new model of CIH in healthy humans that is associated with both increases in blood pressure and augmented peripheral chemosensitivity. We tested the hypothesis that exposure to CIH would also result in augmented muscle sympathetic nerve activity (MSNA) and altered vascular reactivity contributing to blood pressure elevation. We therefore exposed healthy subjects between the ages of 20 and 34 yr ( n = 7) to 9 h of nocturnal intermittent hypoxia for 28 consecutive nights. Cardiovascular and hemodynamic variables were recorded at three time points; MSNA was collected before and after exposure. Diastolic blood pressure (71 ± 1.3 vs. 74 ± 1.7 mmHg, P < 0.01), MSNA [9.94 ± 2.0 to 14.63 ± 1.5 bursts/min ( P < 0.05); 16.89 ± 3.2 to 26.97 ± 3.3 bursts/100 heartbeats (hb) ( P = 0.01)], and forearm vascular resistance (FVR) (35.3 ± 5.8 vs. 55.3 ± 6.5 mmHg·ml−1·min·100 g tissue, P = 0.01) all increased significantly after 4 wk of exposure. Forearm blood flow response following ischemia of 15 min (reactive hyperemia) fell below baseline values after 4 wk, following an initial increase after 2 wk of exposure. From these results we conclude that the increased blood pressure following prolonged exposure to CIH in healthy humans is associated with sympathetic activation and augmented FVR.

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Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans

Journal of Applied Physiology ◽

10.1152/japplphysiol.00036.2007 ◽

2007 ◽

Vol 103 (3) ◽

pp. 835-842 ◽

Cited By ~ 28

Author(s):

Urs A. Leuenberger ◽

Cynthia S. Hogeman ◽

Sadeq Quraishi ◽

Latoya Linton-Frazier ◽

Kristen S. Gray

Keyword(s):

Blood Pressure ◽

Sleep Apnea ◽

Sympathetic Activity ◽

Intermittent Hypoxia ◽

Muscle Sympathetic Nerve Activity ◽

Acute Hypoxia ◽

Short Term ◽

Healthy Humans ◽

Obstructive Sleep ◽

Normal Humans

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O2 saturation nadir 81.4 ± 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 ± 11 to 159 ± 21 units/min ( P = 0.001) and mean blood pressure from 92.1 ± 2.9 to 95.5 ± 2.9 mmHg ( P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O2 (FiO2) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 ± 4 vs. +49 ± 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (FiO2 0.5, for 5 min) were not changed significantly ( P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.

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Disruption of phase synchronization between blood pressure and muscle sympathetic nerve activity in postural vasovagal syncope

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00415.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. H1238-H1245 ◽

Cited By ~ 12

Author(s):

Christopher E. Schwartz ◽

Elisabeth Lambert ◽

Marvin S. Medow ◽

Julian M. Stewart

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Phase Synchronization ◽

Vasovagal Syncope ◽

Muscle Sympathetic Nerve Activity ◽

Nerve Activity ◽

Control Subjects ◽

Late Stages

Withdrawal of muscle sympathetic nerve activity (MSNA) may not be necessary for the precipitous fall of peripheral arterial resistance and arterial pressure (AP) during vasovagal syncope (VVS). We tested the hypothesis that the MSNA-AP baroreflex entrainment is disrupted before VVS regardless of MSNA withdrawal using the phase synchronization between blood pressure and MSNA during head-up tilt (HUT) to measure reflex coupling. We studied eight VVS subjects and eight healthy control subjects. Heart rate, AP, and MSNA were measured during supine baseline and at early, mid, late, and syncope stages of HUT. Phase synchronization indexes, measuring time-dependent differences between MSNA and AP phases, were computed. Directionality indexes, indicating the influence of AP on MSNA (neural arc) and MSNA on AP (peripheral arc), were computed. Heart rate was greater in VVS compared with control subjects during early, mid, and late stages of HUT and significantly declined at syncope ( P = 0.04). AP significantly decreased during mid, late, and syncope stages of tilt in VVS subjects only ( P = 0.001). MSNA was not significantly different between groups during HUT ( P = 0.700). However, the phase synchronization index significantly decreased during mid and late stages in VVS subjects but not in control subjects ( P < .001). In addition, the neural arc was significantly affected more than the peripheral arc before syncope. In conclusion, VVS is accompanied by a loss of the synchronous AP-MSNA relationship with or without a loss in MSNA at faint. This provides insight into the mechanisms behind the loss of vasoconstriction and drop in AP independent of MSNA at the time of vasovagal faint.

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Effects of selective slow-wave sleep deprivation on nocturnal blood pressure dipping and daytime blood pressure regulation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00368.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. R191-R197 ◽

Cited By ~ 55

Author(s):

Friedhelm Sayk ◽

Christina Teckentrup ◽

Christoph Becker ◽

Dennis Heutling ◽

Peter Wellhöner ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Slow Wave ◽

Slow Wave Sleep ◽

Muscle Sympathetic Nerve Activity ◽

Catecholamine Excretion ◽

Nocturnal Blood Pressure ◽

Healthy Humans ◽

Daytime Blood Pressure ◽

Nocturnal Blood Pressure Dipping

Nocturnal blood pressure (BP) decline or “dipping” is an active, central, nervously governed process, which is important for BP regulation during daytime. It is, however, not known whether the sleep process itself or, more specifically, slow-wave sleep (SWS) is important for normal dipping. Therefore, in the present study, healthy subjects (6 females, 5 males) were selectively deprived of SWS by EEG-guided acoustic arousals. BP and heart rate (HR) were monitored during experimental nights and the following day. Additionally, nocturnal catecholamine excretion was determined, and morning baroreflex function was assessed by microneurographic measurements of muscle sympathetic nerve activity (MSNA) and heart rate variability (HRV). Data were compared with a crossover condition of undisturbed sleep. SWS was successfully deprived leading to significantly attenuated mean arterial BP dipping during the first half ( P < 0.05), but not during the rapid-eye-movement-dominated second half of total sleep; however, dipping still evolved even in the absence of SWS. No differences were found for nighttime catecholamine excretion. Moreover, daytime resting and ambulatory BP and HR were not altered, and morning MSNA and HRV did not differ significantly, indicating that baroreflex-mediated sympathoneural BP regulation was not affected by the preceding SWS deprivation. We conclude that in healthy humans the magnitude of nocturnal BP dipping is significantly affected by sleep depth. Deprivation of SWS during one night does not modulate the morning threshold and sensitivity of the vascular and cardiac baroreflex and does not alter ambulatory BP during daytime.

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Inorganic nitrate supplementation attenuates peripheral chemoreflex sensitivity but does not improve cardiovagal baroreflex sensitivity in older adults

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00389.2017 ◽

2018 ◽

Vol 314 (1) ◽

pp. H45-H51 ◽

Cited By ~ 13

Author(s):

Joshua M. Bock ◽

Kenichi Ueda ◽

Aaron C. Schneider ◽

William E. Hughes ◽

Jacqueline K. Limberg ◽

...

Keyword(s):

Blood Pressure ◽

Older Adults ◽

Heart Rate ◽

Baroreflex Sensitivity ◽

Arterial Blood ◽

Inorganic Nitrate ◽

Chemoreflex Sensitivity ◽

Nitrate Supplementation ◽

No Bioavailability ◽

Peripheral Chemoreflex

Aging is associated with increased peripheral chemoreceptor activity, reduced nitric oxide (NO) bioavailability, and attenuation of cardiovagal baroreflex sensitivity (BRS), collectively increasing the risk of cardiovascular disease. Evidence suggests that NO may attenuate peripheral chemoreflex sensitivity and increase BRS. Exogenous inorganic nitrate ([Formula: see text]) increases NO bioavailability via the [Formula: see text]-[Formula: see text]-NO pathway. Our hypothesis was that inorganic [Formula: see text] supplementation would attenuate peripheral chemoreflex sensitivity and enhance spontaneous cardiovagal BRS in older adults. We used a randomized, placebo-controlled crossover design in which 13 older (67 ± 3 yr old) adults ingested beetroot powder containing (BRA) or devoid of (BRP) [Formula: see text] and [Formula: see text] daily over 4 wk. Spontaneous cardiovagal BRS was assessed over 15 min of rest and was quantified using the sequence method. Chemoreflex sensitivity was assessed via ~5 min of hypoxia (10% fraction of inspired O2) and reported as the slope of the relationship between O2 saturation (%[Formula: see text]) and minute ventilation (in l/min) or heart rate (in beats/min). Ventilatory responsiveness to hypoxia was reduced after BRA (from −0.14 ± 0.04 to −0.05 ± 0.02 l·min−1·%[Formula: see text]−1, P = 0.01) versus BRP (from −0.10 ± 0.05 to −0.11 ± 0.05 l·min−1·%[Formula: see text]−1, P = 0.80), with no differences in heart rate responsiveness (BRA: from −0.47 ± 0.06 to −0.33 ± 0.04 beats·min−1·%[Formula: see text]−1, BRP: from −0.48 ± 0.07 to −0.42 ± 0.06 beats·min−1·%[Formula: see text]−1) between conditions (interaction effect, P = 0.41). Spontaneous cardiovagal BRS was unchanged after BRA and BRP (interaction effects, P = 0.69, 0.94, and 0.39 for all, up, and down sequences, respectively), despite a reduction in resting systolic and mean arterial blood pressure in the experimental (BRA) group ( P < 0.01 for both). These findings illustrate that inorganic [Formula: see text] supplementation attenuates peripheral chemoreflex sensitivity without concomitant change in spontaneous cardiovagal BRS in older adults. NEW & NOTEWORTHY Exogenous inorganic nitrate supplementation attenuates ventilatory, but not heart rate, responsiveness to abbreviated hypoxic exposure in older adults. Additionally, inorganic nitrate reduces systolic and mean arterial blood pressure without affecting spontaneous cardiovagal baroreflex sensitivity. These findings suggest that inorganic nitrate may attenuate sympathetically oriented pathologies associated with aging.

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Endotoxemia causes central downregulation of sympathetic vasomotor tone in healthy humans

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90444.2008 ◽

2008 ◽

Vol 295 (3) ◽

pp. R891-R898 ◽

Cited By ~ 47

Author(s):

Friedhelm Sayk ◽

Alexander Vietheer ◽

Bernhard Schaaf ◽

Peter Wellhoener ◽

Gunther Weitz ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Blood Levels ◽

Burst Frequency ◽

Nerve Activity ◽

Healthy Humans ◽

Vascular Bed

Experimental endotoxemia as a model of the initial septic response affects the autonomic nervous system with profound cardiovascular sequelae. Whether the postsynaptic sympathoneural activity to the muscle vascular bed is altered in the early septic phase remains to be determined. The present study aimed to elucidate the early effects of LPS on muscle sympathetic nerve activity (MSNA) and cardiovascular regulation in healthy humans. Young, healthy volunteers randomly received either an LPS bolus (4 ng/kg body wt, n = 11) or placebo (saline; n = 7). Experimental baroreflex assessment (baseline measurements followed by infusion of vasoactive drugs nitroprusside/phenylephrine) was done prior to and 90 min following LPS or placebo challenge. MSNA, heart rate, blood pressure, and blood levels of catecholamines, TNF-α and IL-6 were measured sequentially. Endotoxin but not placebo-induced flu-like symptoms and elevated cytokine levels. In contrast to placebo, LPS significantly suppressed MSNA burst frequency 90 min after injection [mean ± SE: 12.1 ± 2.9 vs. 27.5 ± 3.3 burst/min (post- vs. pre-LPS); P < 0.005] but increased heart rate [78.4 ± 3.1 vs. 60.6 ± 2.0 beats/min (post- vs. pre-LPS); P < 0.001]. Baseline blood pressure was not altered, but baroreflex testing demonstrated a blunted MSNA response and uncoupling of heart rate modulation to blood pressure changes in the endotoxin group. We conclude that endotoxin challenge in healthy humans has rapid suppressive effects on postsynaptic sympathetic nerve activity to the muscle vascular bed and alters baroreflex function which may contribute to the untoward cardiovascular effects of sepsis.

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Prolonged blood pressure elevation following continuous infusion of angiotensin II—a baroreflex study in healthy humans

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00111.2015 ◽

2015 ◽

Vol 309 (11) ◽

pp. R1406-R1414 ◽

Cited By ~ 4

Author(s):

Friedhelm Sayk ◽

Isabel Wobbe ◽

Christoph Twesten ◽

Moritz Meusel ◽

Peter Wellhöner ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Plasma Levels ◽

Muscle Sympathetic Nerve Activity ◽

Ang Ii ◽

Blood Pressure Elevation ◽

Healthy Humans ◽

Input Signals ◽

Drug Challenge ◽

Infusion Period

ANG II interacts with the sympathetic nervous system at central nervous blood pressure-regulating structures, including the baroreflex. It is unknown whether prolonged BP elevation mediated by high ANG II plasma levels could induce a persistent shift of the central nervous baroreflex setpoint, lasting beyond the short ANG II plasmatic half time of a few seconds, thereby consolidating elevated BP and/or increased SNA in healthy humans. In a blinded crossover design, ANG II or placebo (saline) was infused for a 6-h period in 12 resting normotensive students (6 males, 6 females) raising BP to borderline hypertensive levels. Between 60 and 120 min after the infusion period, muscle sympathetic nerve activity (MSNA) was assessed microneurographically and correlated with oscillometric BP measurements and heart rate at supine rest (baseline) and during pharmacologic baroreceptor challenge. Infusion of ANG II increased BP to borderline-hypertensive levels, as intended, whereas heart rate remained unaltered. At baroreflex assessment (i.e., 60–120 min after end of infusion period), systolic BP was significantly higher compared with placebo (Δ8.4 ± 3.1 mmHg; P < 0.05), whereas diastolic values were nearly equal between conditions. Baseline MSNA was neither decreased nor increased, and baroreflex sensitivity to vasoactive drug challenge was not altered. Our results show that elevation of ANG II plasma levels over 6 h was able to increase systolic, but not diastolic, BP far beyond blood-mediated ANG II effects. MSNA or heart rate did not counter-regulate this BP elevation, indicating that ANG II had sustainably reset the central nervous BP threshold of sympathetic baroreflex function to accept elevated BP input signals without counter-regulatory response.

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