Hyperoxia lowers sympathetic activity at rest but not during exercise in humans.

Hyperoxia lowers sympathetic activity but not during exercise in humans

at rest

DOUGLAS R. SEALS, DAVID G. JOHNSON, AND RALPH F. FREGOSI Departments of Exercise and Sport Sciences, Internal Medicine, and Physiology, Arizona Health Sciences Center, The University of Arizona, Tucson, Arizona 85721

SEALS, DOUGLAS R., DAVID G. JOHNSON, AND RALPH F. FREGOSI. Hyperoxia lowers sympathetic activity at rest but not during exercise in humans. Am. J. Physiol. 260 (Regulatory Integrative Comp. Physiol. 29): R873-R878, 1991.-The primary aim of this study was to determine the influence of systemic hyperoxia on sympathetic nervous system behavior at rest and during submaximal exercise in humans. In seven healthy subjects (aged 19-31 yr) we measured postganglionic sympathetic nerve activity to skeletal muscle (MSNA) in the leg, antecubital venous norepinephrine concentrations, heart rate, and arterial blood pressure during normoxic rest (control) followed by 3- to 4-min periods of either hyperoxic (100% O2 breathing) rest, normoxic exercise (rhythmic handgrips at 50% of maximum force), or hyperoxic exercise. During exercise, isocapnia was maintained by adding CO, to the inspirate as necessary. At rest, hyperoxia lowered MSNA burst frequency (12-42%) and total activity (6-42%) in all subjects; the average reductions were 25 and 23%, respectively (P < 0.05 vs. control). Heart rate also decreased during hyperoxia (6 t 1 beats/min, P < 0.05), but arterial blood pressure was not affected. During hyperoxic compared with normoxic exercise, there were no differences in the magnitudes of the increases in MSNA burst frequency or total activity, plasma norepinephrine concentrations, or mean arterial blood pressure. In contrast, the increase in heart rate during hyperoxic exercise (13 t 2 beats/min) was less than the increase during normoxic exercise (20 t 2 beats/ min; P < 0.05). We conclude that, in healthy humans, systemic hyperoxia 1) lowers efferent sympathetic nerve activity to skeletal muscle under resting conditions without altering venous norepinephrine concentrations and 2) has no obvious modulatory effect on the nonactive muscle sympathetic nerve adjustments to rhythmic exercise. autonomic nervous blood pressure

system;

plasma

norepinephrine;

arterial

LINES OF EVIDENCE suggest that the level of oxygen in the systemic circulation influences sympathetic nervous system behavior in the human both at rest and during exercise. Sustained hypoxia increases efferent muscle sympathetic nerve activity (MSNA) in resting humans without any detectable increase in plasma norepinephrine concentrations (18). Systemic hypoxia markedly augments the plasma norepinephrine response to strenuous large muscle dynamic exercise (6), and we have recently reported a similar hypoxia-induced potentiation of the MSNA response to rhythmic handgrip exercise (21). Based on these experimental observations, one might postulate that hyperoxia would lower central sympaSEVERAL

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thetic outflow at rest and would attenuate the sympathoexcitatory response to acute exercise. Hesse et al. (10) reported that breathing 100% OZ blunted the plasma norepinephrine and epinephrine responses to leg cycling exercise but did not influence levels at rest. However, because venous plasma concentrations of norepinephrine can be a rather insensitive index of sympathetic nervous system activity (7, 8) and because changes in systemic oxygen levels can alter norepinephrine kinetics (18), direct measurements of sympathetic nerve activity may provide more definitive insight into this question. Unfortunately, no such data are currently available. Therefore, the primary aim of the present investigation was to determine the influence of systemic hyperoxia on sympathetic nervous system activity at rest and during submaximal exercise in healthy humans. To accomplish this, we recorded MSNA in the lower leg during periods of normoxic rest followed by hyperoxic (100% O2 breathing) rest, normoxic arm exercise, and hyperoxic arm exercise. Data from the normoxic exercise trial (i.e., control condition) have been presented previously (21). METHODS

Subjects Seven healthy men aged 19-31 yr participated in this study after providing their written informed consent. The subjects were normotensive (i.e., had sphygmomanometry-determined brachial artery pressure levels 600 mmHg (29). End-tidal fractional concentrations of 0, and CO, were measured at the mouth with rapidly responding analyzers (Applied Electrochemistry) and monitored on a chart recorder. Chest wall excursions were monitored inductively with a pneumobelt placed at the midabdominal level. Exercise. Rhythmic forearm exercise was performed at 0.5 Hz with the right arm using a modified handgrip dynamometer (Stoelting, Chicago, IL). Rhythmic hangrip was chosen as the exercise mode because 1) it allows for stable microneurographic recordings from the leg yet can evoke marked increases in MSNA if performed at a strenuous level for a sufficient duration (25) and 2) it

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more closely simulates common physical activities than do sustained isometric contractions, which can result in painful ischemic conditions in the contracting muscles. Experimental Protocol Subjects were positioned supine in a quiet room with an ambient temperature of 22°C. The maximal handgrip contraction force for the right arm was determined as described previously (20). A 3-min period of quiet relaxation while breathing room air (normoxic rest) was followed by a 3- to 4-min intervention consisting of either hyperoxia (hyperoxic rest), exercise performed at 50% of maximum force while breathing room air (normoxic exercise), or the same level and duration of exercise performed while breathing 100% Oa (hyperoxic exercise). The 3- to 4-min exercise duration was used because it is known to evoke a clear increase in MSNA when performed during normoxia (i.e., our control condition) (25). The interventions were applied in random order among the seven subjects. All variables were recorded continuously during each control-intervention sequence on both a chart recorder (Gould ES 1000) and a video tape system (Vetter). A venous blood sample was obtained -1 min after each intervention because handgrip exercise-evoked peak venous plasma norepinephrine concentrations occur at this time (26). During exercise the target and handgrip forces were displayed on an oscilloscope as a visual aid for the subjects. All but the exercising limb remained relaxed and, based on the pneumobelt recordings, no abnormal respiratory maneuvers (e.g., Valsalva) were observed in any experiment. At least 15 min of quiet relaxation were allowed between the end of an intervention and the start of the subsequent resting control period to provide sufficient time to regain normal baseline levels for all variables. Data Analysis

Bursts of MSNA were determined by visual inspection of the mean voltage neurogram; all recordings were analyzed by the same investigator. MSNA is expressed as burst frequency (bursts/min) and as total minute activity (calculated as the product of bursts/min and average minute burst amplitude and presented in arbitrary units) as described previously (19, 20, 22). Data from each 3min resting control period were averaged; these values . I TABLE 1. Absolute levels of measured variables during normoxzc conwol perzoas and during final minute of three interventions 1

Heart rate, beats/min Mean arterial pressure, mmHg MSNA burst frequency, bursts/min MSNA total activity, units Plasma norepinephrine, pg/ml PETE,, mmHg PEQ~~, mmHg Values respective

57t3

51*3*-f

96t4

97t4

2153 264t42

209*39*-f

240t39 9323

43tl

14&2*-I275t85 627+7*-j42rtl

are means t SE; n = 7 subjects. MSNA, muscle sympathetic control value; “f P < 0.05 vs. normoxic exercise value.

nerve

.

7

59t2 97t3 19t3 220t39

431t59*

19t3 243t49

281t58

328t70

264rt56

94t3

94k3

95t3

42&l

42tl

42&l

activity;

79t4*

59t2

120-+3* 28t2"

lOOt5

PET, partial

pressure

of end-tidal

72*3*-I118t6* 31&2* 517t76" 325t62 640*9*-f 40+1* gas. * P < 0.05 vs.

Downloaded from www.physiology.org/journal/ajpregu by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on November 20, 2018. Copyright © 1991 the American Physiological Society. All rights reserved.

SYMPATHETIC

NERVE

ACTIVITY

DI. .RING

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and data from the final minute of the corresponding intervention period were used to calculate baseline-tointervention changes. An analysis of variance for repeated measures was used to determine differences in a variable between the control and intervention periods or among the three control periods and for the changes in a variable among the three interventions. Scheffe’s test was used for post hoc analysis. Values of P < 0.05 were considered to be statistically significant. Data are expressed as means t SE.

p < 0.05 I

1 p < 0.05

I

I

r-L

I

*

* 1c

*I

4

p < 0.05

RESULT’S

General Experimental

Conditions

There were no differences for any variable among the normoxic control periods before the three interventions (Table 1). The partial pressure of end-tidal O2 averaged 627 t 7 mmHg during hyperoxic rest and 640 t 9 mmHg during hyperoxic exercise; corresponding values for endtidal CO, were 42 t 1 and 40 t 1 mmHg, respectively. The inspired minute ventilation was 9.2-9.7 l/min during the normoxic control periods and 10.8 l/min during hyperoxic rest, with breathing frequencies averaging 14 and 15 breaths/min, respectively. Exercise evoked small increases in ventilation during normoxia (-6.5 l/min) and hyperoxia (-8.5 l/min), due to small increases in breathing frequency (-6 breaths/min) and tidal volume (0.180.25 l/breath) in both conditions. Handgrip force was maintained near the 50% maximum force target level throughout the exercise interventions; there were no differences in the absolute force levels between the normoxie and hyperoxic trials (19.0 t 1.5 vs. 18.9 t 1.5 kg during the last minute of exercise, respectively). MSNA Rest. Figure 1 shows an original recording of the influence of hyperoxia on MSNA at rest. Hyperoxia lowered MSNA in all seven subjects (range E-42% for burst frequency and 6-42% for total activity); the average reduction was 25% for burst frequency and 23% for total activity (both P < 0.05; Table 1 and Fig. 2). Exercise. MSNA burst frequency and total activity increased to 163 t 17 and 206 t 18% of control, respecTotal Minute Room Air

Control

jLJak

““:T’

Plasma Norepinephrine (pg/ml)

168

EC

I

100 '

I

-r -

1

+l

I

T I

I

I

I

I

100%02 100%02 21%02 + + + EX EX Rest FIG. 2. Average (n = 7) changes in MSNA burst frequency, total minute MSNA, and venous plasma norepinephrine concentrations from normoxic rest (control) levels during hyperoxic rest, normoxic exercise (EX), and hyperoxic EX. Hyperoxia per se lowered MSNA by -25% on average but did not alter plasma norepinephrine concentrations. In contrast, MSNA and plasma norepinephrine responses to EX were not different in normoxia and hyperoxia. *P < 0.05 vs. control. See text for further details.

tively, by the end of normoxic exercise (both P < 0.05); the corresponding levels during the final minute of hyperoxic exercise were 196 t 37 and 236 t 27% of control (both P < 0.05 vs. control levels; Table 1 and Fig. 2). Neither the burst frequency nor the total activity responseswere different between hyperoxia and normoxia.

Initial 30 s of Hyperoxia

Venous Plasma Norepinephrine Concentrations

212

184

146

FIG. 1. Peroneal neurogram of muscle sympathetic nerve activity (MSNA) in 1 subject at rest. Note sympathoinhibitory effect of hyperoxia, which is already evident during initial portion of period (middle trace) and is sustained throughout (bottom truce). Arterial blood pressure was not affected by hyperoxia.

Rest. In contrast to MSNA, plasma norepinephrine concentrations were not influenced by hyperoxia at rest (108 t 15% of control, not significant, Table 1 and Figs. I and 2). Exercise. Plasma norepinephrine concentrations were 120 t 11 and 139 t 247o of control after normoxic and hyperoxic exercise, respectively (Table 1 and Fig. 2); these concentrations were not different from their respective control levels or each other.


R876

SYMPATHETIC

Heart Rate and Arterial

NERVE

ACTIVITY

Blood Pressure

DISCUSSION

There are two new findings from this study. First, in resting humans, systemic hyperoxia lowers sympathetic outflow to skeletal muscle without altering venous norepinephrine concentrations. Second, hyperoxia has no obvious influence on the magnitude of the exerciseinduced increase in sympathetic nerve activity to nonactive skeletal muscle.

p c 0.05

1

I

1

I *

I *

p < 0.05

30

3 1

I b

100%02 + Rest

p < 0.05 p c 0.05 I

21%02 + EX

HYPEROXIA

Influence of Hyperoxia on Sympathetic Outflow and Cardiovascular Function in Resting Humans

Rest. Hyperoxia at rest reduced heart rate by 6 t 1 beats/min (-10%; P < 0.05) but did not influence arterial blood pressure (Table 1 and Fig. 3). Exercise. Heart rate increased by 20 t 2 beats/min in response to normoxic exercise (P < 0.05); this was greater (P < 0.05) than the increase during hyperoxic exercise (13 t 2 beats/min; P < 0.05 vs. control). Mean arterial blood pressure increased 23 t 4 mmHg during normoxic exercise (P < 0.05 vs. control), but this response was not different from the increase during hyperoxic exercise (18 t 3 mmHg; P < 0.05 vs. control).

40

DURING

* I 100%02 + EX

FIG. 3. Average (n = 7) changes (A) in mean arterial blood pressure (MAP) and heart rate from normoxic rest (control) levels during hyperoxic rest, normoxic EX, and hyperoxic EX. Hyperoxia per se did not influence MAP but lowered heart rate by -10%. EX-induced increase in MAP was not affected by hyperoxia, but heart rate response was attenuated. bt/min, beats/min. *p < 0.05 vs. control. See text for further details.

In the present study, 3-4 min of hyperoxia significantly reduced MSNA (-25% decrease from normoxic control levels on average). This effect was quite consistent in that it was observed in every subject. In contrast, plasma norepinephrine concentrations were not altered by hyperoxia. The latter finding agrees with a previous report by Hesse et al. (lo), who found no effect of 100% O2 breathing on either venous plasma norepinephrine or epinephrine concentration in resting humans. Our observations may seem inconsistent in light of the fact that antecubital venous norepinephrine concentration is thought to be derived primarily from skeletal muscle norepinephrine spillover (11, 24) and that these plasma concentrations correlate with baseline levels of MSNA (27). However, previous findings indicate that, during experimental interventions, venous plasma norepinephrine concentrations are not sufficiently sensitive to reflect changes in MSNA of the magnitude observed here with hyperoxia (22). It is also possible that hyperoxiarelated changes in norepinephrine kinetics (e.g., synaptic release and/or reuptake) contributed to this dissociation, as is the case with hypoxia (18). As to the mechanism responsible for the sympathoinhibitory influence of hyperoxia at rest, there are several potential candidates. First, the effect may have been mediated via stimulation of the arterial baroreceptors. This is not likely, since hyperoxia did not alter arterial blood pressure (Fig. 3). A second possibility is that hyperoxia stimulated cardiopulmonary baroreceptors, possibly through an increase in cardiac filling pressure or contractility. The decrease in heart rate observed during hyperoxia would tend to increase central venous pressure, although this effect would be modulated by any local influence of hyperoxia on venous capacitance. The inhibition of arterial chemoreceptor afferent discharge is a third possibility, since carotid sinus nerve activity decreases from -2 Hz at an arterial 0, partial pressure (Pao,) of 100 mmHg to -0 Hz at a Pao, of 500 mmHg under isocapnic conditions in anesthetized cats (13). For this to be a viable mechanism, one would have to propose that this low-level afferent discharge during normoxia has a tonic excitatory influence on MSNA in the human, which is unknown. Furthermore, if the peripheral chemoreflex were involved, MSNA would be expected to decrease soon (within seconds) after the onset of hyperoxia. Although we cannot accurately determine changes in MSNA over such a brief time span, in the present study, MSNA was decreased from normoxic control levels over the initial 30-s period of hyperoxia in six of the seven subjects (range 18-36%); thus this mechanism could have contributed to the inhibition. However, the latency of the sympathoexcitatory response to hypoxia is several minutes (18), suggesting that the role of the arterial chemoreceptors in the regulation of MSNA in the resting human is complex. Finally, the inhibition of MSNA could be explained by a direct effect of hyperoxia on central sympathetic neurons, although our data cannot assessthe likelihood of this mechanism. This hyperoxia-induced reduction in MSNA may be


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of interest with regard to the control of nonactive skeletal muscle blood flow. It has been demonstrated that hyperoxia results in a decrease in limb blood flow in resting humans (16). This effect has most often been ascribed to a direct influence of hyperoxia on vascular smooth muscle (1, 2); however, the possibility of sympathetically mediated vasoconstriction also has been proposed (3, 16). The present finding of a decrease in sympathetic outflow to skeletal muscle resistance vessels during hyperoxia provides the first direct evidence that this vasoconstriction is not of neural origin. We also observed a small reduction in heart rate during hyperoxia, which did not appear to be mediated by arterial baroreflexes, because arterial pressure did not change. The importance of this mild bradycardia is unknown, but its influence on cardiac output could act in concert with the reduction in sympathetic outflow to negate the local vasoconstrictor effects of hyperoxia and thus maintain arterial pressure near the normoxic control level. Influence of Hyperoxia on the Sympathetic-Circulatory Adjustments to Exercise In the present study the magnitude of the increase in MSNA was not different during normoxic and hyperoxic exercise. The fact that hyperoxia failed to attenuate the sympathetic response to exercise was unexpected for several reasons. First, we recently reported (21) an augmentation in the MSNA response to rhythmic handgrip exercise during hypoxia compared with normoxic conditions, leading us to postulate the reciprocal effect during hyperoxia. Second, Hesse et al. (10) has reported a marked attenuation in the plasma norepinephrine and epinephrine responses to large muscle dynamic exercise in subjects breathing 100% 02. Third, based on the separate responses to hyperoxia and exercise, one would predict that the increase in MSNA during hyperoxic exercise would be less than the increase during normoxic exercise due to the sympathoinhibitory effect of hyperoxia at rest. There are a number of possibilities that could explain why the predicted response did not occur. For example, during normoxic exercise, Hesse et al. (10) reported a sixfold increase in venous plasma norepinephrine concentration, which was reduced by 28-34% during hyperoxic exercise. In our study, we observed slightly more than a 100% increase in MSNA above control levels during normoxic exercise. Thus, if a sixfold increase in plasma norepinephrine concentration represents a greater degree of sympathetic neural activation than a 100% or more increase in MSNA, which is a good assumption (22), one could argue that Hesse et al. (10) may have generated a more optimal level of sympathetic activity from which to seean attenuation with hyperoxia. While this could explain our results, it is also possible that autonomic control mechanisms engaged during exercise override those responsible for the sympathoinhibitory effects of hyperoxia at rest. It is generally considered that the sympathetic nervous system is stimulated by two primary signals associated with voluntary exercise, central command and chemo- and mechanosensitive

DURING

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HYPEROXIA

afferent feedback from the contracting skeletal muscles (17). If the level of excitatory central nervous system input generated by these mechanisms was similar during normoxic and hyperoxic exercise, similar increases in sympathetic outflow should occur in the two conditions. This would be especially true with regard to muscle chemoreflex activation, because this signal appears to be the main stimulus for MSNA during small muscle exercise in humans (14, 25). Because this mechanism is governed to a large extent by O2 delivery to active muscle and its consequent metabolic effects (23) and because 0, delivery to the exercising limb is not different in systemic hyperoxia vs. normoxia (28), muscle chemoreflex drive may be the same under these conditions. Furthermore, force output (mechanoreceptor stimulus) was virtually identical during the two exercise conditions in the present study, and perceived effort (4) and the rate of muscle fatigue (12) during rhythmic small muscle exercise are not influenced by systemic hyperoxia. These last observations suggest that muscle mechanoreflex activation and central command were probably similar during normoxie and hyperoxic exercise. The influence of hyperoxia on the cardiovascular responses to handgrip exercise in the present study was consistent with the results of earlier studies in which humans performed dynamic exercise with a larger muscle mass (5, 10, 28). We found a lesser increase in heart rate during hyperoxic compared with normoxic exercise, which was similar in magnitude to the hyperoxia-evoked bradycardia observed under resting conditions (Fig. 3). Moreover, as reported previously (5, 10, 28), we found that, in spite of the attenuated tachycardia, hyperoxia did not significantly influence the regulation of arterial blood pressure during exercise. Presumably the direct constrictor effects of hyperoxia on active skeletal muscle (28) and other regional circulations (1, 2, 16) offset any effect of a lower heart rate and cardiac output so that the exercise pressor response is not markedly altered. The authors thank Lisa Bare, Martha Elkin, Mary Jo Reiling, and N. Omar Suwarno for technical assistance during data acquisition and analysis. This study was supported by National Institutes of Health Grants HL-39966, HL-41790, and AG-06537 and Arizona Heart Association Grant G20889. D. R. Seals was supported by National Institute of Aging Research Career Development Award AG-00423. Address for reprint requests: D. R. Seals, Dept. of Exercise and Sports Science, McKale Center, Room 228-B, University of Arizona, Tucson, AZ 85721. Received

22 October

1990; accepted

in final

form

2 January

1991.

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