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. 2003 Aug 8;551(Pt 2):635–647. doi: 10.1113/jphysiol.2003.044024

Human skeletal muscle sympathetic nerve activity, heart rate and limb haemodynamics with reduced blood oxygenation and exercise

Akiko Hanada 1, Mikael Sander 1, José González-Alonso 1
PMCID: PMC2343217  PMID: 12909683

Abstract

Acute systemic hypoxia causes significant increases in human skeletal muscle sympathetic nerve activity (MSNA), heart rate and ventilation. This phenomenon is thought to be primarily mediated by excitation of peripheral chemoreceptors sensing a fall in arterial free oxygen partial pressure (Pa,O2). We directly tested the role of Pa,O2 on MSNA (peroneal microneurography), heart rate, ventilation and leg haemodynamics (n = 7–8) at rest and during rhythmic handgrip exercise by using carbon monoxide (CO) to mimic the effect of systemic hypoxia on arterial oxyhaemoglobin (≈20 % lower O2Hba), while normalising or increasing Pa,O2 (range 40–620 mmHg). The four experimental conditions were: (1) normoxia (Pa,O2≈110 mmHg; carboxyhaemoglobin (COHb) ≈2 %); (2) hypoxia (Pa,O2≈40 mmHg; COHb ≈2 %); (3) CO + normoxia (Pa,O2≈110 mmHg; COHb ≈23 %); and (4) CO + hyperoxia (Pa,O2≈620 mmHg; COHb ≈24 %). Acute hypoxia augmented sympathetic burst frequency, integrated MSNA, heart rate and ventilation compared to normoxia over the entire protocol (7–13 bursts min−1, 100–118 %, 13–17 beats min−1, 2–4 l min−1, respectively, P < 0.05). The major new findings were: (1) CO + normoxia and CO + hyperoxia also elevated MSNA compared to normoxia (63–144 % increase in integrated MSNA; P < 0.05) but they did not increase heart rate (62–67 beats min−1) or ventilation (6.5–6.8 l min−1), and (2) despite the 4-fold elevation in MSNA with hypoxaemia and exercise, resting leg blood flow, vascular conductance and O2 uptake remained unchanged. In conclusion, the present results suggest that increases in MSNA with CO are not mediated by activation of the chemoreflex, whereas hypoxia-induced tachycardia and hyperventilation are mediated by activation of the chemoreflex in response to the decline in Pa,O2. Our findings also suggest that Pa,O2 is not an obligatory signal involved in the enhanced MSNA with reduced blood oxygenation.

Acute systemic hypoxia in resting and exercising humans markedly increases skeletal muscle sympathetic discharge, ventilation, heart rate and presumably cardiac sympathetic tone with no or minor elevations in mean arterial pressure (Saito et al. 1988; Rowell et al. 1989; Somers et al. 1989; Seals et al. 1991a; Morgan et al. 1995; Smith et al. 1996; Hansen et al. 2000). Despite this enhanced vasoconstrictor activity during exercise, cardiac output, contracting skeletal muscle blood flow and coronary sinus blood flow increase with systemic hypoxia, thereby contributing to the maintenance of cardiac and peripheral O2 delivery and O2 uptake (Rowell et al. 1986; Knight et al. 1993; Grubbström et al. 1993; Richardson et al. 1995; Koskolou et al. 1997a Koskolou et al. 1997b; Roach et al. 1999; González-Alonso et al. 2001, 2002). In resting humans, hypoxaemia also prevents sympathetic vasoconstriction (Rowell & Blackman 1986; Weisbrod et al. 2001; Dinenno et al. 2003). The augmented sympathetic outflow to skeletal muscle with moderate acute hypoxaemia is thought to be primarily mediated by excitation of chemoreceptors within the carotid and aortic bodies sensing the concomitant fall in arterial blood free O2 (Pa,O2) (Marshall et al. 1994; Lahiri & Acker, 1999).

To identify the role of Pa,O2 in cardiovascular control, we have recently developed a model in vivo in humans that allows the independent manipulation of the O2 dissolved in the blood (Pa,O2) by varying the inspiratory fraction of O2, while using carbon monoxide (CO) to reduce the amount of O2 bound to haemoglobin (González-Alonso et al. 2001). By comparing normoxia, hypoxia, CO + normoxia, CO + hyperoxia and hyperoxia, we have demonstrated that alterations in contracting skeletal muscle blood flow and vascular conductance are unrelated to pronounced alterations in Pa,O2 (40–590 mmHg), but closely linked to the oxygenation state of haemoglobin (González-Alonso et al. 2001, 2002). Our findings suggest that the main vascular O2 sensor locus is located in the erythrocyte itself, rather than in the PO2-sensitive regions of the endothelium or vascular smooth muscle. Whether muscle sympathetic nerve activity (MSNA) at rest and during exercise reflects changes in O2 bound to haemoglobin, alterations in arterial free O2 or changes in whole blood O2 content has never been explored. Moreover, it remains unknown whether a mild CO load, which mimics the effect of systemic hypoxia on arterial oxyhaemoglobin (≈20 % lower O2Hba), results in an increase in MSNA without compromising blood flow, O2 delivery and muscle O2 uptake in the inactive limbs.

In contrast to the stimulatory effects of acute systemic hypoxia (Rowell et al. 1989; Somers et al. 1989; Seals et al. 1991b), MSNA, heart rate and ventilation have been shown to be unaltered or reduced with hyperoxia (breathing 100 % O2) (Seals et al. 1991b; Hansen & Sander, 2003). We therefore hypothesised that if Pa,O2 was an essential signal mediating the increased sympathoexcitation outflow to skeletal muscle, the cardiac acceleration and the hyperventilation normally observed with systemic hypoxia (Rowell et al. 1989; Seals et al. 1991a) would, with a very large increase in Pa,O2 from ≈40 mmHg in systemic hypoxia to ≈620 mmHg in CO + hyperoxia, completely restore these responses to normoxic levels despite the persistent equal reduction in arterial oxyhaemoglobin. Systemic hypoxia is thought to potentiate exercise-induced sympathetic neural activation (Seals et al. 1991a). However, this concept is based on studies using brief periods of hypoxia exposure (3–4 min), which are not sufficient to stabilise blood oxygenation and increase MSNA above control (Seals et al. 1991a). This finding clearly contrasts with the 260 % increase in MSNA in resting humans after 20 min of 10 % O2 under hypocapnic conditions (Rowell et al. 1989). Therefore, we hypothesised that the stimulatory effects of systemic hypoxia and CO inhalation would be similar at rest and during handgrip exercise when sufficient time for equilibration of bodily O2 stores is given. Lastly, we hypothesised that resting limb blood flow and aerobic metabolism will be preserved despite an augmented sympathetic vasoconstrictor activity with hypoxia and CO inhalation. To test these hypotheses, we measured skeletal MSNA (peroneal microneurography), heart rate, mean arterial pressure, ventilation and leg haemodynamics during supine rest, handgrip exercise and recovery in healthy males exposed to conditions producing the same reduction in arterial oxyhaemoglobin (i.e. hypoxia, CO + normoxia, CO + hyperoxia) compared to normoxia, but vastly different Pa,O2 (40–620 mmHg).

METHODS

Subjects

Twenty subjects participated in three studies. All subjects were healthy caucasian males, 26 ± 1 years of age, body weight 74 ± 4 kg, and height 182 ± 3 cm. The subjects were fully informed of any risks and discomforts associated with the experiments before giving their informed written consent to participate. The studies conformed to the code of Ethics of the World Medical Association (Declaration of Helsinki) and were approved by the Ethics Committee for Copenhagen and Frederiksberg communities.

Experimental protocols

In all three investigations, the subjects were studied in the supine position. In the first study, eight of the subjects performed rhythmic handgrip (RHG) exercise under the following four conditions: (1) normoxia (inspiratory O2 fraction, FI,O2 21.4 ± 0.2 %; inspiratory O2 tension, PI,O2 163 ± 1 mmHg; blood carboxyhaemoglobin fraction, COHb 2.3 ± 0.1 %); (2) hypoxia (FI,O2 10.3 ± 0.1 %; PI,O2 78 ± 1 mmHg; COHb 2.2 ± 0.1 %); (3) CO breathing combined with normoxia (CO + normoxia; FI,O2 21.1 ± 0.1 %; PI,O2 160 ± 1 mmHg; COHb 20.3 ± 0.9 %); and (4) CO breathing combined with hyperoxia (CO + hyperoxia; FI,O2 95.9 ± 0.3 %; PI,O2 729 ± 3 mmHg; COHb 21.2 ± 0.9 %). Each of the four conditions was separated from the next by ≈20 min of supine rest. The normoxic and hypoxic trials were performed first and second, respectively, whereas the two CO trials were counterbalanced across subjects. The CO trials were performed last, due to the relatively long period required to return to baseline COHb levels. During each condition, MSNA, blood pressure, heart rate and respiratory rate were recorded during (1) 10 min of rest; and (2) 5 min of RHG (40 % of maximal voluntary contraction) followed by 2 min of post-exercise ischaemia and 3 min of recovery. In a second control study, five subjects were studied during four consecutive periods of normoxia to assess the effect of time and repeated exercise on MSNA and haemodynamics, while also breathing in the closed-circuit system. In a third study, seven of the subjects were studied under the same experimental conditions as in study 1 with the aim of assessing the ventilatory response as well as the resting leg haemodynamic response.

On arrival at the laboratory in studies 1 and 2, the subjects rested in the supine position while a catheter was inserted in an antecubital vein for blood sampling. In each condition, blood pressure was measured every 30 s by automated sphygmomanometry (Dinamap Pro 100, Critikon, Tampa, FL, USA). Mean arterial pressure (MAP) was calculated as [(2 × diastolic blood pressure) + systolic blood pressure]/3. Heart rate was determined from an electrocardiogram and respiratory rate from a strain-gauge pneumobelt tracing. These tracings and MSNA measured by peroneal microneurography were continuously recorded using a Powerlab system (ADInstruments, Sydney, Australia). In study 3, two catheters were placed under local anaesthesia into the femoral artery and vein of the resting right leg using the Seldinger technique. The femoral artery and vein catheters were positioned 1–2 cm proximal or distal from the inguinal ligament. A thermistor to measure venous blood temperature was inserted through the femoral venous catheter orientated in the anterograde direction for the determination of femoral venous blood flow. Femoral venous blood flow (an index of leg blood flow) was determined by the constant infusion thermodilution technique (Andersen & Saltin, 1985; González-Alonso et al. 2000). Arterial blood pressure was continuously monitored by a pressure transducer (Pressure Monitoring Kit, Baxter) at the level of the inguinal region. The ventilatory response was measured continuously in each condition using a pneumotach placed in the expiratory side of the closed-circuit system (OCM-2 metabolic cart, Applied Electrochemistry, USA).

Microneurography

Multiunit efferent postganglionic sympathetic nerve activity to the resting skeletal muscle bed was obtained with unipolar tungsten microelectrodes inserted selectively into muscle nerve fascicles of the peroneal nerve, posterior to the fibular head, by microneurography (Vallbo et al. 1979). The neural signals were amplified (99.5 × 103), filtered (bandwidth, 700–2000 Hz), rectified and integrated (time constant, 0.1 s) to obtain a mean voltage neurogram. A recording of MSNA was considered acceptable when these neurograms revealed spontaneous, pulse-synchronous bursts of neural activity, with a minimum signal-to-noise ratio of 3:1, that increased during phases II and III of the Valsalva manoeuvre, but not during arousal stimuli (loud noise). All recordings were allowed to stabilise for 10 min before measurements were initiated. Sympathetic traffic was measured as (1) sympathetic bursts min−1 and (2) bursts min−1× mean burst amplitude in that minute (total activity), normalised to individual baselines during normoxia. The overall neurogram recordings of 52 periods of rest with adjacent RHG were randomised by one researcher. Another researcher scoring all neurograms was blinded to subject identity and intervention.

Alteration of arterial oxygen content

To manipulate circulating oxygen before and during exercise, and during recovery in studies 1 and 3, the subjects breathed in a closed-circuit system described in detail previously (González-Alonso et al. 2001). In short, the composition of the inspiratory gas was manually adjusted using gas regulators connected to two tanks containing 10 % O2 in N2 and 100 % O2, while monitoring it on-line with a Medgraphics CPX/D metabolic chart (St Paul, MN, USA). CO (95 % purity) was administered through an extension line and a series of luer-lock stopcocks, using calibrated syringes. To guide the initial administration of CO, total haemoglobin content was estimated using the resting [Hb] and body weight, assuming an average circulating blood volume of 82 ml kg−1 (e.g. 70 kg person with 9.3 mmol l−1 Hb, total Hb = 53.4 mmol). The volume of CO administered was then calculated based on the following formula (Christiansen et al. 1993):

CO volume = 0.978(DnCO × 0.08206 × (273 +Ta))/(PB/760) × (1/FCO),

where 0.978 is the correction factor for CO remaining in the lung-bag system after equilibration with the blood; DnCO (mmol) is the fraction of total Hb occupied by CO (e.g. 53.4 mmol × 0.2 = 10.7 mmol); 0.08206 is the gas constant; Ta is the ambient temperature (°C); PB is the barometric pressure (mmHg); and FCO is the fraction of CO in the gas mixture (i.e. 0.95). To obtain a level of COHb of ≈20 %, a total of 250–545 ml of CO was administered in the closed-circuit system. In study 1, arterial oxygen saturation was measured by pulse oximetry (Satline, Datex, Helsinki, Finland). Haemoglobin concentration and carboxyhaemoglobin fraction were determined in forearm venous blood samples (OSM-3 Hemoximeter, Radiometer, Copenhagen, Denmark). In study 3, arterial and femoral haemoglobin concentration, carboxyhaemoglobin fraction and O2 saturation were determined spectrophotometrically (OSM-3 Hemoximeter). PO2, PCO2 and pH were determined with Astrup technique (ABL 5, Radiometer) and corrected for measured femoral venous blood temperature.

Handgrip exercise

In all studies, handgrip exercise was performed with a handgrip dynamometer connected to a force transducer (Stoelting). Prior to the experiment, each subject's maximal voluntary contraction was determined as the best of at least three short handgrip squeezes with verbal encouragement to improve. The handgrip protocol consisted of RHG exercise in which subjects matched force production to a visual target set at 40 % of the individual maximal voluntary contraction, to the rhythm of a metronome (40 beats min−1) with a 50 % duty cycle. Each period of RHG was followed by 2 min of post-exercise ischaemia (PEI) created by inflation of a cuff on the upper arm to suprasystolic pressures (280 mmHg) immediately before cessation of RHG. The purpose of this procedure is continued engagement of the muscle metaboreflex while disengaging central command and the muscle mechanoreflex.

Calculations

Blood O2 content (CTO2) was calculated as (1.39 ×[Hb]× O2Hb) + (0.003 ×PO2) using values obtained in study 3. O2Hb was calculated as [Hb]× (100 – COHb – MetHb/100), where MetHb is the fraction of methaemoglobin in the blood. Leg O2 uptake (leg Inline graphicO2) was calculated by multiplying the leg blood flow by the difference in O2 content between the femoral artery and vein (a-vO2diff). Leg O2 delivery was calculated by multiplying leg blood flow by arterial CTO2 (CTa,O2).

Statistical analysis

Data are presented as means ± s.e.m. Two-way repeated measures analysis of variance (ANOVA) was used to test significance among and within treatments. When relevant, post hoc analysis was performed by Tukey's honestly significant difference test. The significance level was set at P < 0.05.

RESULTS

Study 1. MSNA and heart rate with reduced blood oxygenation and exercise

Reductions in blood oxygenation with systemic hypoxia and CO inhalation

During the entire protocol of study 1, [Hb] was similar among conditions (e.g. at rest 143 ± 3, 146 ± 3, 145 ± 4 and 145 ± 4 g l−1 in normoxia, hypoxia, CO + normoxia and CO + hyperoxia, respectively). However, the arterial O2 saturation (based on pulse oximetry) was lower with hypoxia compared to the other conditions (at rest, 98.9 ± 0.2, 70.4 ± 2.4, 98.0 ± 0.2 and 98.9 ± 0.1 % in normoxia, hypoxia, CO + normoxia and CO + hyperoxia, respectively). During exercise and recovery, arterial O2 saturation in hypoxia was 67–68 % whereas it was maintained at ≈99 % in the other conditions. As expected, COHb increased from 2 % in the normoxia and hypoxia trials to 20–21 % in the CO trials, leading to markedly different levels of arterial and femoral venous oxyhaemoglobin.

Resting leg MSNA increases during hypoxia and CO inhalation

Example recordings of MSNA at rest during the four experimental conditions are shown in Fig. 1A–D. The summary data presented in Fig. 2A and B identify significant increases in the number of bursts per minute and total activity during both hypoxia and CO + normoxia (11–13 bursts min−1 and 118–121 % increase above normoxic baseline, respectively; P < 0.05). In CO + hyperoxia, integrated MSNA increased 63 % above normoxic baseline values (P < 0.05), due to the increase in burst amplitude as sympathetic burst frequency was not significantly elevated. There were no significant differences between the increases in integrated MSNA seen during hypoxia, CO + normoxia and CO + hyperoxia. In the four conditions at rest and during exercise, MAP (mean range at rest 82–85 mmHg), diastolic blood pressure (59– 63 mmHg), systolic blood pressure (125–130 mmHg) and respiratory rate (13–15 breaths min−1) were unchanged.

Figure 1. Representative recordings of leg muscle sympathetic nerve activity.

Figure 1

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Recordings were made at rest and during exercise under normoxia (FI,O2 21 %; A), hypoxia (FI,O2≈10 %; B), CO inhalation combined with normoxia (FI,O2 21 %; C), and CO inhalation combined with hyperoxia (FI,O2 98–100 %; D).

Figure 2. Time course of MSNA and haemodynamic responses.

Figure 2

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Results were obtained at rest, and during dynamic handgrip exercise, post-exercise ischaemia and recovery when exposed to normoxia (FI,O2 21 %), hypoxia (FI,O2≈10 %), CO + normoxia (FI,O2 21 %), and CO + hyperoxia (FI,O2 98–100 %) in the experimental (n = 8) and control groups (n = 5). A, leg MSNA in the experimental group; B, integrated leg MSNA in the experimental group; C, heart rate in the experimental group; D, mean arterial blood pressure in the experimental group; E, MSNA in the control group; F, integrated MSNA in the control group; G, heart rate in the control group; H, mean arterial pressure in the control group. Values during hypoxia (*), CO + normoxia (†), and CO + hyperoxia (§) are significantly higher than normoxia (P < 0.05).

Resting heart rate increases during systemic hypoxia but not during CO exposure

Heart rate increased during hypoxic breathing compared to normoxia (75 ± 3 vs. 60 ± 3 beats min−1, respectively; P < 0.05). In contrast, heart rate did not increase during the CO trials. Figure 3 depicts, on one hand, the uncoupling between the changes in Pa,O2 and the alterations in MSNA (Fig. 3B) and, on the other hand, the close relationship between the alterations in Pa,O2 and the changes in heart rate (Fig. 3E). To further illustrate this differential response, we have added in Fig. 3B and E the MSNA and heart rate responses from a previously published study (Seals et al. 1991a), which have been replicated in follow-up studies from our laboratory (González-Alonso et al. 2002; Hansen & Sander, 2003).

Figure 3. Relationships between circulating O2, MSNA and heart rate.

Figure 3

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Influence of arterial O2Hb content, PO2 and whole blood O2 content on integrated leg MSNA and heart rate at rest when exposed to normoxia (FI,O2 21 %), hypoxia (FI,O2≈10 %), CO + normoxia (FI,O2 21 %), and CO + hyperoxia (FI,O2 98–100 %). Note that B and E also depict data from a published study during hyperoxia (Seals et al. 1991b).

Hypoxia and CO inhalation do not potentiate MSNA during exercise

The time course of MSNA during 5 min of RHG exercise followed by 2 min of post-exercise ischaemia is depicted in Fig. 2A and B, which demonstrates similar significant increases in both sympathetic burst frequency and total activity in all conditions (mean range 5–10 bursts min−1 and 53–77 % increase above corresponding baseline values). Therefore, integrated MSNA remained significantly higher over the 5 min of handgrip exercise with hypoxia and both CO conditions (116 ± 24, 144 ± 42 and 80 ± 19 % above normoxia in hypoxia, CO + normoxia and CO + hyperoxia, respectively, all P < 0.05). During post-exercise ischaemia, integrated MSNA in systemic hypoxia and CO conditions remained 80–100 (± 21)% higher than normoxic values (P < 0.05; Fig. 2A). In recovery, sympathetic burst frequency and integrated MSNA with systemic hypoxia and CO + normoxia declined to the corresponding baseline levels after 3 min of the cuff release. Nevertheless, sympathetic burst frequency and integrated MSNA with acute hypoxia and CO + normoxia were still significantly higher than in normoxia (16 ± 3 and 9 ± 2 bursts min−1 and 125 ± 28 and 85 ± 19 %, respectively; P < 0.05). During exercise, post-exercise ischaemia and recovery, heart rate remained elevated in systemic hypoxia, but was similar to that in normoxia during the CO trials (Fig. 2C).

Study 2. Control study

In the control group exposed only to normoxia, O2 saturation and COHb, and thus the amount of O2 bound to haemoglobin and free O2 in the arterial blood, were unchanged during the four trials. Moreover, MSNA, MAP, heart rate and respiratory rate were unchanged over time (Fig. 2E and F).

Study 3. Blood oxygenation, leg haemodynamics and ventilation with reduced blood oxygenation and exercise

Systemic hypoxia and CO inhalation evoke equal reductions in O2 bound to haemoglobin in arterial and femoral venous blood, but vastly different Pa,O2

At rest, during exercise and after 10 min of recovery, [Hb] was similar in all conditions (Table 1). However, the arterial O2 saturation was lower with hypoxia compared to the other conditions (70–80 % vs. 99–100 %, respectively). As expected, COHb increased from 2 % in the normoxia and hypoxia trials to 23–24 % in the CO trials, leading to markedly different levels of arterial and femoral venous O2 bound to haemoglobin. Arterial O2 content was 196 ml l−1 in normoxia and was equally reduced to 155–157 ml l−1 in hypoxia, CO + normoxia and CO + hyperoxia (≈20 % reduction; Table 1). By design, arterial free O2 varied from ≈40 mmHg during hypoxia, to ≈110 mmHg during normoxia and CO + normoxia, to ≈620 mmHg during CO + hyperoxia (Table 1). In addition, arterial and femoral venous PCO2 and pH were significantly different in hypoxia compared to the other conditions. Compared to the vast changes in Pa,O2 between hypoxia and CO + hyperoxia (40–620 mmHg; 15-fold range), Pa,CO2 declined ≈12 % and pH increased only ≈1 % with systemic hypoxia compared with the CO interventions and normoxia. In the CO trials, arterial and venous PCO2 and pH remained at normoxic levels (Table 1).

Table 1.

Femoral blood variables at rest, during handgrip exercise and after 5 min of recovery when exposed to normoxia, hypoxia, CO inhalation combined with normoxia and CO inhalation combined with hyperoxia

Normoxia Hypoxia
Rest Exercise Recovery Rest Exercise Recovery
[Hb] (gl−1)
 Arterial 144 ± 4 143 ± 5 144 ± 4 143 ± 3 145 ± 4 145 ± 4
 Venous 145 ± 4 143 ± 4 142 ± 3 144 ± 3 144 ± 3 145 ± 4
COHb (%)
 Arterial 2.2 ± 0.1 2.2 ± 0.1 2.2 ± 0.1 2.0 ± 0.1 1.8 ± 0.1 1.8 ± 0.1
 Venous 2.0 ± 0.1 2.0 ± 0.1 2.0 ± 0.1 1.8 ± 0.1 1.7 ± 0.1 1.8 ± 0.1
O2 sat (%)
 Arterial 99.1 ± 0.2 99.2 ± 0.2 98.6 ± 0.5 79.7 ± 1.4* 70.3 ± 3.4* 70.3 ± 2.7*
 Venous 75.8 ± 3.8 80.2 ± 4.2 79.0 ± 3.4 58.8 ± 4.8* 55.3 ± 4.2* 55.5 ± 4.9*
O2<Hb (ml l−1)
 Arterial 193 ± 6 193 ± 6 193 ± 6 155 ± 4* 139 ± 7* 139 ± 7*
 Venous 150 ± 9 156 ± 8 152 ± 7 115 ± 10* 109 ± 8* 109 ± 10*
PO2 (mmHg)
 Arterial 113 ± 8 116 ± 8 116 ± 7 39 ± 1* 34 ± 2* 34 ± 2*
 Venous 39 ± 4 45 ± 4 42 ± 3 31 ± 2* 27 ± 2* 27 ± 2*
CTO2 (ml l−1)
 Arterial 196 ± 7 197 ± 6 197 ± 6 156 ± 4* 140 ± 7* 140 ± 7*
 Venous 150 ± 9 157 ± 8 153 ± 7 116 ± 10* 109 ± 8* 110 ± 10*
PCO2 (mmHg)
 Arterial 42 ± 1 41 ± 1 42 ± 1 37 ± 2* 37 ± 1* 37 ± 1*
 Venous 47 ± 1 46 ± 1 46 ± 1 41 ± 2* 41 ± 1* 41 ± 1*
pH
 Arterial 7.40 ± 0.01 7.41 ± 0.01 7.40 ± 0.01 7.45 ± 0.01* 7.46 ± 0.01* 7.45 ± 0.01*
 Venous 7.39 ± 0.01 7.39 ± 0.01 7.38 ± 0.01 7.43 ± 0.01* 7.43 ± 0.01* 7.43 ± 0.01*
CO + normoxia CO + hyperoxia
Rest Exercise Recovery Rest Exercise Recovery
[Hb] (g l−1)
 Arterial 143 ± 4 145 ± 4 143 ± 4 145 ± 4 145 ± 4 144 ± 4
 Venous 142 ± 4 143 ± 4 142 ± 4 144 ± 4 142 ± 4 142 ± 4
COHb (%)
 Arterial 22.6 ± 0.5*† 23.4 ± 0.6*† 22.9 ± 0.7*† 23.8 ± 0.5*† 23.1 ± 0.8*† 23.3 ± 0.9*†
 Venous 22.7 ± 0.5*† 23.6 ± 0.5*† 23.5 ± 0.5*† 24.2 ± 0.5*† 23.9 ± 0.7*† 24.0 ± 0.8*†
O2 saturation (%)
 Arterial 99.0 ± 0.2* 99.0 ± 0.2† 98.8 ± 0.2† 100.0 ± 0.0† 99.9 ± 0.0† 99.8 ± 0.1†
 Venous 74.2 ± 3.4† 78.9 ± 1.7† 78.2 ± 3.4† 80.0 ± 4. 1† 82.9 ± 4.4† 82.7 ± 4.0†
O2 Hb, (ml l−1)
 Arterial 152 ± 4* 153 ± 5* 151 ± 5* 153 ± 4* 155 ± 5* 153 ± 6*
 Venous 112 ± 4* 119 ± 2* 117 ± 6* 120 ± 3* 124 ± 5* 123 ± 3*
PO2 (mmHg)
 Arterial 103 ± 4† 118 ± 8† 117 ± 12† 609 ± 15*† 623 ± 19*† 590 ± 20*†
 Venous 31 ± 2* 33 ± 2* 34 ± 2* 41 ± 3 44 ± 3 45 ± 2
CTO2 (ml l−1)
 Arterial 155 ± 4* 157 ± 5* 155 ± 5* 172 ± 4* 173 ± 5*† 171 ± 6*†
 Venous 113 ± 4 119 ± 2 118 ± 6 121 ± 3 125 ± 5 124 ± 3
PCO2 (mmHg)
 Arterial 41 ± 1† 41 ± 1† 41 ± 1† 40 ± 1† 39 ± 1† 39 ± 1†
 Venous 45 ± 1† 45 ± 1† 45 ± 1† 47 ± 1† 45 ± 1† 45 ± 1†
pH
 Arterial 7.41 ± 0.01† 7.41 ± 0.01† 7.41 ± 0.01† 7.41 ± 0.02† 7.43 ± 0.01† 7.43 ± 0.01†
 Venous 7.39 ± 0.01† 7.39 ± 0.01† 7.39 ± 0.01† 7.38 ± 0.02† 7.39 ± 0.02† 7.39 ± 0.01†
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Values are means ± s.e.m. for 7 subjects.

*

Significantly different from normoxia, P < 0.05.

†

Significantly different from hypoxia, P < 0.05.

Ventilation and heart rate increase with systemic hypoxia but not with CO exposure

Ventilation and heart rate increased significantly with hypoxic breathing compared to normoxia during the entire protocol due to the rise in tidal volume (e.g. at rest 8.7 ± 0.6 vs. 6.5 ± 0.5 l min−1 and 90 ± 4 vs. 70 ± 4 beats min−1, respectively; P < 0.05; Fig. 4A and B). In contrast, neither ventilation nor heart rate increased during the CO trials.

Figure 4. Ventilatory response to reduced oxygenation and exercise.

Figure 4

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Results were obtained during normoxia (FI,O2 21 %), hypoxia (FI,O2≈10 %), CO + normoxia (FI,O2 21 %), and CO + hyperoxia (FI,O2 98–100 %). A, ventilation; B, tidal volume; C, respiratory rate. Values are means ± s.e.m. for 7 subjects. * Significantly higher than resting values, P < 0.05; † significantly higher than normoxia, P < 0.05.

Hypoxia and CO exposure do not alter leg circulation or aerobic metabolism

During the entire protocol, leg blood flow and leg vascular conductance remained unchanged in all conditions (see Fig. 5A and C; Fig. 6). Furthermore, leg O2 was kept essentially constant at rest, during exercise and during recovery (range among all conditions 25–34 ml min−1), accompanying small adjustments in leg a-vO2 difference and leg blood flow (30–61 ml l−1 and 0.6–0.8 l min−1, respectively; Fig. 5).

Figure 5. Haemodynamics and aerobic metabolism in resting limbs.

Figure 5

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Results were obtained during normoxia (FI,O2 21 %), hypoxia (FI,O2≈10 %), CO + normoxia (FI,O2 21 %), and CO + hyperoxia (FI,O2 98–100 %). A, leg blood flow; B, mean arterial pressure; C, leg vascular conductance; D, leg O2 delivery; E, leg a-vO2 difference; F, leg O2. Values are means ± s.e.m. for 5–7 subjects. * Significantly higher than resting values, P < 0.05.

Figure 6. Sympathetic activity and vascular conductance in resting and exercising limbs.

Figure 6

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Results were obtained during normoxia (FI,O2 21 %), hypoxia (FI,O2 10–12 %), CO + normoxia (FI,O2 21 %), and CO + hyperoxia (FI,O2 90–100 %). A, integrated MSNA in the resting leg; B, vascular conductance in the resting leg (present study); C, rate of plasma arterial noradrenaline (norepinephrine, NE) during knee-extensor exercise (modified from González-Alonso et al. 2001); D, leg vascular conductance during knee-extensor exercise (modified from González-Alonso et al. 2001). * Significantly higher than normoxia, P < 0.05.

DISCUSSION

A major finding of this study was that, despite a normal or greatly elevated Pa,O2, CO in conjunction with either normoxia or hyperoxia increased MSNA at rest and during exercise in a similar manner to acute systemic hypoxia. However, these CO interventions did not result in the well characterised hypoxia-induced tachycardia, hyperventilation and hypocapnia. Together, these findings suggest that increases in MSNA with CO are not mediated by activation of the chemoreflex, whereas hypoxia-induced tachycardia and hyperventilation are mediated by activation of the chemoreflex in response to the decline in Pa,O2. Moreover, the present findings suggest that Pa,O2 is not an obligatory signal involved in the enhanced MSNA with reduced blood oxygenation.

Role of arterial oxygenation in sympathetic nerve discharge to skeletal muscle

Although there are numerous reports identifying the contribution of hyperventilation, barometric pressure and hypocapnia to MSNA (e.g. Somers et al. 1989; Trzebski et al. 1995), this is the first study aimed at identifying the role of Pa,O2, O2Hb and O2 content in MSNA when humans are exposed to acute reductions in blood oxygenation. This study is also the first to provide direct evidence for a CO-induced increase in MSNA. The only previous microneugraphic study used lower levels of CO exposure (COHb 8 %) and found no evidence for CO-induced increases in MSNA (Hausberg & Somers, 1997). An obvious difference that could explain the discrepancy between the studies is the much greater CO dose used in the present compared to the previous study (COHb 20–24 % vs. 8 %).

The effects of acute systemic hypoxia and CO loads on MSNA in this investigation were remarkably similar at rest and during handgrip exercise, which is in sharp contrast to a previous report using same level of hypoxic exposure (Seals et al. 1991a). The main difference between the studies seems to be related to the time allowed for equilibration during hypoxic breathing and thus the degree of arterial desaturation. This difference probably explains why hypoxia at rest had no significant effect in the study by Seals et al. (1991a), but caused a doubling of MSNA in the present investigation and in another study during 20 min of 10 % O2 exposure (Rowell et al. 1989). Hence, we suggest that the increased sympathetic response reported in the previous study (Seals et al. 1991a) is a consequence of the combination of effects of hypoxia not yet fully expressed and metaboreflex engagement. Our conclusion that there is no discernible effect of hypoxia or CO on the exercise pressor and metaboreflexes supports the findings of another study using static handgrip (Saito et al. 1991), and our recent knee-extensor exercise study, which provides indirect leg plasma noradrenaline (norepinephrine) data that suggest a similar sympathoexcitation to that observed in the present study (Fig. 6). Therefore, it seems reasonable to conclude that effects of hypoxic hypoxia and CO-hypoxia on MSNA are fully expressed at rest if sufficient time is allowed for equilibration of bodily O2 stores and COHb.

The regulation of MSNA at rest involves multiple reflexes originating in: (1) arterial and cardiopulmonary baroreceptors, (2) pulmonary mechanoreceptors, and (3) carotid body, aortic body and brainstem chemoreceptors. A central question in this investigation is whether alterations in any of these reflexes can explain the enhanced sympathoexcitation evoked by acute systemic hypoxia and CO inhalation. Firstly, the observation that mean blood pressure and diastolic blood pressure were similar among the four experimental conditions and the four control conditions when MSNA remained unchanged, strongly suggests that the afferent input from carotid and aortic baroreceptors (Marshall et al. 1994; Schmidt et al. 2001) did not change when superimposing systemic hypoxia, CO + normoxia and CO + hyperoxia onto normoxia. Similarly, the unaltered leg vascular conductance found in this study, and the previous indications that cardiac output and systemic vascular conductance are essentially unchanged with acute hypoxia and CO inhalation in resting humans (Asmussen & Chiodi 1941; Koskolou et al. 1997a; Roach et al. 1999), indirectly suggest that the contribution of cardiopulmonary baroreceptors to the hypoxia-induced MSNA activation at rest, if present, was slight. This contention is supported by the observation in three subjects in this study of an unchanged central venous pressure (≈5 mmHg) with systemic hypoxia (FI,O2 10 %) and normoxia during supine rest. Secondly, ventilation was only elevated with systemic hypoxia due to the greater tidal volume. It could therefore be assumed that afferent reflexes from pulmonary stretch receptors did not contribute to the enhanced MSNA with systemic hypoxia as these reflexes inhibit rather than augment MSNA (St Croix et al. 2000). Thirdly, given the drop in Pa,O2 and Pa,CO2 and enhanced ventilation with systemic hypoxia, it seems likely that peripheral chemoreceptors were involved in the hypoxia-induced increases in MSNA. Conversely, the lack of change in ventilation with CO provides compelling evidence that the chemoreflex was not activated by CO. This indicates that CO raised MSNA by some other mechanism that is independent of the chemoreflexes.

There is indeed compelling evidence in anaesthetised animals and in vitro preparations demonstrating that both carotid and aortic chemoreceptors are stimulated by steady-state falls in Pa,O2 at constant Pa,CO2 (Hatcher et al. 1978; Lahiri et al. 1981). In addition, there is evidence indicating that ex vivo peripheral and central chemoreceptors are only fully activated when Pa,O2 declines below 80–50 mmHg (Hatcher et al. 1978; Marshall 1994; Gonzalez et al. 1994). In the present in vivo conditions, however, vast elevations in Pa,O2 from ≈40 mmHg in hypoxia to ≈620 mmHg in CO + hyperoxia did not normalise MSNA in spite of the fact that Pa,O2 was below the activation threshold of peripheral and central chemoreceptors only during systemic hypoxia and that Pa,CO2 remained normal with CO. It should be borne in mind that the increase in MSNA during systemic hypoxia, which was equal to that occurring with CO + normoxia, might have been somewhat diminished by concomitant hypocapnia and the resulting decrease in peripheral chemoreceptor activation. Nevertheless, it is noteworthy that MSNA is unchanged or reduced with hyperoxia (100 % O2 breathing; Seals 1991b), which leads to identical high levels of Pa,O2 to those in the present CO + hyperoxia condition (≈620 mmHg), but a much higher arterial O2Hb (see Fig. 6A). Although a regulatory role of Pa,O2 and Pa,CO2 during exposure to systemic hypoxia cannot be completely excluded, our opposite results with CO + hyperoxia compared to those of Seals et al. (1991b) as well as the identical MSNA with hypoxia and CO + normoxia clearly argue against Pa,O2 being the key signal evoking the elevation in MSNA with reduced blood oxygenation.

An alternative explanation could be that factors related to the elevated COHb and/or the reduced arterial and venous O2Hb and O2 content were more heavily implicated in the elevation in MSNA. Evidence from in vitro preparations at normal Pa,O2 and Pa,CO2 shows a pronounced linear increase in aortic chemoreceptor discharge when COHb is increased beyond 10 %, whereas carotid chemoreceptors show very little increase in activity even when 60 % of Hb is combined with CO (Lahiri et al. 1981; Dampney et al. 1988). In the present human study, however, it is evident that CO did not evoke chemoreflex activation as ventilation was unchanged. Thus CO caused sympathoexcitation by a chemoreflex-independent mechanism. Alternatively, the strikingly similar MSNA response with and without CO (at rest: CO + normoxia vs. systemic hypoxia; peak exercise: CO + normoxia, CO + hyperoxia and systemic hypoxia) together with the somewhat lower resting MSNA in CO + hyperoxia compared to CO + normoxia, favour the idea that the effect of CO was predominantly the result of a simple reduction in O2Hb and O2 content. This notion is supported by the tight correlations between MSNA and blood O2 content at rest (r2 = 0.99 and 0.85 for arterial and venous blood, respectively) and MSNA and O2Hb during peak exercise (r2 = 0.83–0.85). Thus, even though the precise signal transduction pathway leading to the augmentation in MSNA with CO + normoxia, CO + hyperoxia and systemic hypoxia needs further elucidation, our data strongly suggest a primary role of circulating O2, particularly the amount of O2 bound to haemoglobin during exercising conditions.

Role of arterial oxygenation in resting skeletal muscle haemodynamics

Another important observation of this study was that the profound elevations in MSNA evoked by the superimposition of hypoxaemia onto exercise did not cause a reduction in blood flow, vascular conductance or oxygen uptake in the resting leg. It is generally accepted that the accumulation of metabolic by-products in the interstitium can activate group III and IV afferent nerve fibres (Mitchell et al. 1983) and initiate a signal transduction sequence that culminates in an augmented efferent sympathetic vasoconstrictor outflow to both resting and exercising skeletal muscle (Seals 1989; Sinoway et al. 1989; Hansen et al. 1994). The 2-fold increase in resting leg MSNA during 5 min of handgrip exercise in all experimental conditions appears largely related to metaboreflex activation. Consistent with previous findings in hypoxic humans at rest (Rowell & Blackmon 1986), we here observed that the 4-fold elevation in MSNA with combined hypoxaemia and handgrip exercise did not cause a reflex vasoconstriction in the resting limb. Paradoxically, such marked sympathoexcitation occurs in conjunction with a robust vasodilatation in the active limb, as indicated by previous knee-extensor (Rowell et al. 1986; Richardson et al. 1995; Koskolou et al. 1997a,b; Roach et al. 1999; González-Alonso et al. 2001, 2002; Richardson et al. 2002), forearm (Heistad & Wheeler, 1970; Leuenbenger et al. 1999) and cycle-ergometer exercise studies (Knight et al. 1993). This implies that potent vasodilatory factors must have effectively over-ridden the bloated sympathetic and adrenal vasoconstrictor stimuli in the resting and exercising limbs, a response that resembles the phenomenon traditionally termed functional sympatholysis, which is generally thought to occur only in contracting skeletal muscle (Remensnyder et al. 1962; Mitchell et al. 1983; Hansen et al. 1996, 2000). In an attempt to answer the question of how the skeletal muscle vasculature offsets the enhanced sympathetic vasoconstrictor activity with systemic hypoxia, recent reports suggest that hypoxia superimposes a vasodilatation without interfering with sympathetic vasoconstriction (Weisbrod et al. 2001; Dinenno et al. 2003). Although the precise signal transduction pathway remains elusive, it is clear that this regulatory mechanism helps maintain O2 uptake in the inactive skeletal muscle by preventing the fall in blood flow with a stable leg a-vO2 difference, whereas it does so in the contracting muscle by increasing blood flow with a lower a-vO2 difference.

Role of arterial oxygen tension in heart rate and ventilation

A third finding of this study was that CO combined with either normoxia or hyperoxia did not result in the well-known hypoxia-induced tachycardia and hyperventilation in the presence of a greatly elevated MSNA and circulating catecholamines. Our observation that systemic hypoxia evoked a 22–27 % increase in heart rate and 37 % elevation in ventilation is consistent with previous reports in humans (Hartley et al. 1973; Escourrou et al. 1984; Leuenberger et al. 2001; Schmidt et al. 2001) and animals (O'Donell et al. 1992; Marshall et al. 1994). The similarity in the heart rate elevation in the resting, exercise and recovery conditions (15–17 beats min−1) indicates that exercise, per se, did not potentiate the effects of hypoxia on heart rate. Moreover, heart rate was still elevated during post-exercise ischaemia, which prevented the outflow of locally produced metabolites back to the heart. This suggests that circulating factors released from recently active skeletal muscle were not critically important in mediating the hypoxic response. Instead, the increase in heart rate with systemic hypoxia appears to be closely linked to the small reduction in Pa,O2.

The molecular mechanisms underlying the augmented heart rate with hypoxia, but unchanged response in the CO trials, remain to be resolved. Intuitively, the signals maintaining heart rate with CO should be capable of nullifying the action of the elevated circulating catecholamines from the adrenal medulla and possibly the enhanced cardiac sympathetic activity (Dally et al. 1962; McLeod & Scott, 1964). Based on previously discussed in vitro data (Lahiri et al. 1981; Dampney et al. 1988), we could surmise that carotid chemoreceptors did not increase their activity with 20–24 % COHb levels whereas aortic chemoreceptors did (Lahiri et al. 1981). Conversely, moderate systemic hypoxia strongly increased both carotid and aortic chemoreflexes (Marshall 1994; Lahiri et al. 1999). Since aortic chemoreceptor stimulation is known to cause a reflex increase in both the sympathetic and parasympathetic supply to the heart at least in the dog (Dally et al. 1962; McLeod & Scott, 1964; Jewett, 1964; Davidson et al. 1976), it could be speculated that the unchanged heart rate during the present CO interventions was related to a balanced co-activation of sympathetic and parasympathetic activity to the heart in the CO trials vs. systemic hypoxia. However, this possibility is at odds with the observed unchanged ventilation in the CO trials reported here, which indicates that CO fails to elicit chemoreflex activation. A more likely possibility based on the observation in a parallel study that arterial and femoral venous plasma [ATP] in the CO + normoxia, normoxia and hyperoxia conditions were similar, whereas they were markedly elevated with hypoxia (González-Alonso et al. 2002), is that circulating ATP played a role in the hypoxia-induced tachycardia and in the maintenance of heart rate in the CO interventions. The additional finding from the same study that intra-arterial infusion of ATP evoked a dose-dependent increase in heart rate strongly supports this second possibility.

Lastly, the normal ventilatory response with the CO interventions reported here is in agreement with pioneering human studies showing an elevation in ventilation and cardiac output with systemic hypoxia but a normal cardiorespiratory response with CO-hypoxia (Asmussen & Chiodi, 1941; Chiodi et al. 1941). Because the hyperventilation with systemic hypoxia was accompanied by a large lowering in Pa,O2 and Pa,CO2 and a lesser increase in arterial pH, we are tempted to suggest that the unchanged ventilation with CO interventions was largely associated with the normalisation of Pa,O2, Pa,CO2 and pH.

To summarise, the present results showed that CO in conjunction with either normoxia or hyperoxia increased MSNA at rest and during exercise in a similar manner to acute systemic hypoxia, yet this did not evoke the well-characterised hypoxia-induced tachycardia, hyperventilation and hypocapnia. Secondly, the markedly augmented MSNA with combined hypoxaemia and exercise did not cause local skeletal muscle vasoconstriction or suppressed oxygen uptake in the resting or exercising limbs. This suggests the existence of compensatory mechanisms in resting and contracting skeletal muscle capable of over-riding the elevated vasoconstrictor stimuli. Finally, MSNA at rest and during exercise was more closely related to O2 bound to haemoglobin than to O2 dissolved in plasma, which fuels the hypothesis that the erythrocyte might act as an O2 sensor for MSNA activation. In stark contrast to MSNA, heart rate and ventilation appear closely related to the alterations in Pa,O2. Collectively, the present findings suggest that increases in MSNA with CO are not mediated by activation of the chemoreflex, whereas hypoxia-induced tachycardia and hyperventilation are mediated by activation of the chemoreflex in response to the decline in Pa,O2. Future experiments should address the question of whether the present results in male caucasians can be generalised to other populations.

Acknowledgments

This study was supported by a grant from The Danish National Research Foundation (504–14). We thank Dr Jaya Rosenmeier, Dr José A. L. Calbet and Professor Bengt Saltin for their help with the catheterisations in the last study. We also thank Professor Bengt Saltin for his comments and support in this difficult endeavour. In addition, we thank Dr Niels H. Secher for helping us with experiments assessing central venous pressure. A.H. was on leave from the Department of Cardiovascular Medicine. Hokkaido University, Sapporo, Japan. M.S. was supported by a fellowship from the Kaj Hansen Foundation and by grants from the Danish Heart Foundation, the Novo Foundation and the Danish Medical Research Council.

REFERENCES

  1. Andersen P, Saltin B. Maximal perfusion of skeletal muscle in man. J Physiol. 1985;366:233–246. doi: 10.1113/jphysiol.1985.sp015794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Asmussen E, Chiodi H. The effect of hypoxemia on ventilation and circulation in man. Am J Physiol. 1941;132:426–436. [Google Scholar]
  3. Chiodi H, Dill DB, Consolazio F, Harvath SM. Respiratory and circulatory responses to acute carbon monoxide poising. Am J Physiol. 1941;134:683–693. [Google Scholar]
  4. Christensen P, Rasmussen JW, Henneberg SW. Accuracy of a new bedside method for estimation of circulating blood volume. Clin Care Med. 1993;21:1535–1540. doi: 10.1097/00003246-199310000-00023. [DOI] [PubMed] [Google Scholar]
  5. Dally M, Deb M, Scott MJ. An analysis of the pulmonary cardiovascular reflex effects of stimulation of the carotid body chemoreceptors in the dog. J Physiol. 1962;162:555–573. doi: 10.1113/jphysiol.1962.sp006950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dampney RAL, Blessing WW, Tan E. Origin of tonic GABAergic inputs to vasopressor neurons in the subretrofacial nucleous of the rabbit. J Auton Nerv Syst. 1988;24:227–239. doi: 10.1016/0165-1838(88)90123-3. [DOI] [PubMed] [Google Scholar]
  7. Davidson NS, Goldner S, McCloskey DI. Respiratory modulation of baroreceptor and chemoreceptor reflexes affecting heart rate and cardiac vagal efferent nerve activity. J Physiol. 1976;259:523–530. doi: 10.1113/jphysiol.1976.sp011480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dinenno FA, Joyner MJ, Halliwill JR. Failure of systemic hypoxia to blunt α-adrenergic vasocontriction in the human forearm. J Physiol. 2003;549:985–994. doi: 10.1113/jphysiol.2003.042507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Escourrou P, Johnson DG, Rowell LB. Hypoxemia increases plasma catecholamine concentrations in exercising humans. J Appl Physiol. 1984;57:1507–1511. doi: 10.1152/jappl.1984.57.5.1507. [DOI] [PubMed] [Google Scholar]
  10. Gonzalez C, Almaraz L, Obeso A, Rigual R. Carotid body chemoreceptors: from natural stimuli to sensory discharges. Physiol Rev. 1994;74:829–899. doi: 10.1152/physrev.1994.74.4.829. [DOI] [PubMed] [Google Scholar]
  11. González-Alonso J, Olson DB, Saltin B. Erythrocyte and the regulation of human skeletal muscle blood flow and oxygen delivery: role of circulating ATP. Circ Res. 2002;91:1046–1055. doi: 10.1161/01.res.0000044939.73286.e2. [DOI] [PubMed] [Google Scholar]
  12. González-Alonso J, Quistorff B, Krustrup P, Bangsbo J, Saltin B. Heat production in human skeletal muscle at onset of intense dynamic exercise. J Physiol. 2000;524:603–615. doi: 10.1111/j.1469-7793.2000.00603.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. González-Alonso J, Richardson RS, Saltin B. Exercising skeletal muscle blood flow in humans responds to reduction in arterial oxyhaemoglobin, but not to altered free oxygen. J Physiol. 2001;530:331–341. doi: 10.1111/j.1469-7793.2001.0331l.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Grubbström J, Berglund B, Kaiser L. Myocardial oxygen supply and lactate metabolism during marked arterial hypoxaemia. Acta Physiol Scand. 1993;149:303–310. doi: 10.1111/j.1748-1716.1993.tb09625.x. [DOI] [PubMed] [Google Scholar]
  15. Hansen J, Sander M. Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia. J Physiol. 2003;546:921–929. doi: 10.1113/jphysiol.2002.031765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hansen J, Sander M, Thomas G. Metabolic modulation of sympathetic vasoconstriction in exercising skeletal muscle. Acta Physiol Scand. 2000;168:489–503. doi: 10.1046/j.1365-201x.2000.00701.x. [DOI] [PubMed] [Google Scholar]
  17. Hansen J, Thomas GD, Harris SA, Parsons WJ, Victor R. Differential sympathetic neural control of muscle oxygenation in resting and exercising human skeletal muscle. J Clin Invest. 1996;98:584–596. doi: 10.1172/JCI118826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hansen J, Thomas GD, Jacobson TN, Victor RG. Muscle metaboreflex triggers parallel sympathetic activation in exercising and resting human skeletal muscle. Am J Physiol. 1994;266:2508–2514. doi: 10.1152/ajpheart.1994.266.6.H2508. [DOI] [PubMed] [Google Scholar]
  19. Hartley LH, Vogel JA, Cohen MI. Central, femoral, and brachial circulation during exercise in hypoxia. J Appl Physiol. 1973;34:87–90. doi: 10.1152/jappl.1973.34.1.87. [DOI] [PubMed] [Google Scholar]
  20. Hatcher JD, Chiu LK, Jennings DB. Anemia as a stimulus to aortic and carotid chemoreceptors in the cat. J Appl Physiol. 1978;44:696–702. doi: 10.1152/jappl.1978.44.5.696. [DOI] [PubMed] [Google Scholar]
  21. Hausberg M, Somers VK. Neural circulatory responses to carbon monoxide in healthy humans. Hypertension. 1997;29:1114–1118. doi: 10.1161/01.hyp.29.5.1114. [DOI] [PubMed] [Google Scholar]
  22. Heistad DD, Wheeler RC. Effect of acute hypoxia on vascular responsiveness in man. J Clin Invest. 1970;49:1252–1265. doi: 10.1172/JCI106338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jewett DL. Activity of single efferent fibres in the cervical vagues of the dog with special reference to possible cardio-inhibitory fibres. J Physiol. 1964;175:321–357. doi: 10.1113/jphysiol.1964.sp007520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Knight DR, Schffartizik W, Poole DC, Hogan MC, Bebout DE, Wagner P. Effects of hyperoxia on maximal leg O2 supply and utilization in man. J Appl Physiol. 1993;75:2586–2594. doi: 10.1152/jappl.1993.75.6.2586. [DOI] [PubMed] [Google Scholar]
  25. Koskolou MD, Calbet JAL, Rådegran G, Roach RC. Hypoxia and the cardiovascular response to dynamic knee-extensor exercise. Am J Physiol. 1997a;272:H2655–2663. doi: 10.1152/ajpheart.1997.272.6.H2655. [DOI] [PubMed] [Google Scholar]
  26. Koskolou MD, Roach RC, Calbet JAL, Rådegran G, Saltin B. Cardiovascular responses to dynamic exercise with acute anemia in humans. Am J Physiol. 1997b;273:H1787–1793. doi: 10.1152/ajpheart.1997.273.4.H1787. [DOI] [PubMed] [Google Scholar]
  27. Lahiri S, Acker H. Oxygen sensing in the body. Respir Physiol. 1999;115:115–260. doi: 10.1016/s0034-5687(99)00014-6. [DOI] [PubMed] [Google Scholar]
  28. Lahiri S, Mulligan E, Nishino T, Mokashi A, Davies RO. Relative responses of aortic body and carotid body chemoreceptors to carboxyhemoglobinemia. J Appl Physiol. 1981;50:580–586. doi: 10.1152/jappl.1981.50.3.580. [DOI] [PubMed] [Google Scholar]
  29. Leuenbenger UA, Gray K, Herr MD. Adenosine contributes to hypoxia-induced forearm vasodilation in humans. J Appl Physiol. 1999;87:2218–2224. doi: 10.1152/jappl.1999.87.6.2218. [DOI] [PubMed] [Google Scholar]
  30. Leuenbenger UA, Hardy JC, Herr MD, Gray KS, Sinoway LI. Hypoxia augments apnea-induced peripheral vasoconstriction in humans. J Appl Physiol. 2001;90:1516–1522. doi: 10.1152/jappl.2001.90.4.1516. [DOI] [PubMed] [Google Scholar]
  31. McLeod RDM, Scott MJ. The heart rate responses to carotid body chemoreceptor stimulation in the cat. J Physiol. 1964;175:193–202. doi: 10.1113/jphysiol.1964.sp007511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Marshall JM. Peripheral chemoreceptors and cardiovascular regulation. Physiol Rev. 1994;74:543–594. doi: 10.1152/physrev.1994.74.3.543. [DOI] [PubMed] [Google Scholar]
  33. Mitchell JH, Kaufmann MP, Iwamoto GA. The exercise pressor reflex: its cardiovascular effects, afferent mechanisms, and central pathways. Annu Rev Physiol. 1983;45:229–242. doi: 10.1146/annurev.ph.45.030183.001305. [DOI] [PubMed] [Google Scholar]
  34. Morgan BJ, Crabtree DC, Palta M, Skatrud JB. Combined hypoxia and hypercapnia evokes long-lasting sympathetic activation in humans. J Appl Physiol. 1995;79:205–213. doi: 10.1152/jappl.1995.79.1.205. [DOI] [PubMed] [Google Scholar]
  35. O'Donell CP, Bower EA. Heart rate changes evoked by hypoxia in the anesthetized, artificially ventilated cat. Exp Physiol. 1992;77:271–283. doi: 10.1113/expphysiol.1992.sp003587. [DOI] [PubMed] [Google Scholar]
  36. Remensnyder JP, Mitchell JH, Sarnoff SJ. Functional sympatholysis during muscular activity. Circ Res. 1962;11:370–380. doi: 10.1161/01.res.11.3.370. [DOI] [PubMed] [Google Scholar]
  37. Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, Wagner PD. Myoglobin O2 desaturation during exercise: evidence of limited O2 transport. J Clin Invest. 1995;96:1916–1926. doi: 10.1172/JCI118237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Richardson RS, Noyszewski EA, Saltin B, González-Alonso J. Effect of mild carboxy-hemoglobin on exercising skeletal muscle: intravascular and intracellular evidence. Am J Physiol. 2002;283:R1131–1139. doi: 10.1152/ajpregu.00226.2002. [DOI] [PubMed] [Google Scholar]
  39. Roach RC, Koskolou MD, Calbet JAL, Saltin B. Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans. Am J Physiol. 1999;276:H438–445. doi: 10.1152/ajpheart.1999.276.2.H438. [DOI] [PubMed] [Google Scholar]
  40. Rowell LB, Blackmon JR. Lack of sympathetic vasoconstriction in hypoxemic humans at rest. Am J Physiol. 1986;251:H562–570. doi: 10.1152/ajpheart.1986.251.3.H562. [DOI] [PubMed] [Google Scholar]
  41. Rowell LB, Johnson DG, Chase PB, Comess KA, Seals DR. Hypoxemia raises muscle sympathetic activity but not norepinephrine in resting humans. J Appl Physiol. 1989;66:1736–1743. doi: 10.1152/jappl.1989.66.4.1736. [DOI] [PubMed] [Google Scholar]
  42. Rowell LB, Saltin B, Kiens B, Christiansen NJ. Is peak quadriceps blood flow in humans even higher during exercise in hypoxemia. Am J Physiol. 1986;251:H1038–1044. doi: 10.1152/ajpheart.1986.251.5.H1038. [DOI] [PubMed] [Google Scholar]
  43. Saito M, Abe H, Iwase S, Koga K, Mano T. Muscle sympathetic nerve responsiveness to static contraction is not altered under hypoxia. Jpn J Physiol. 1991;41:775–783. doi: 10.2170/jjphysiol.41.775. [DOI] [PubMed] [Google Scholar]
  44. Saito M, Mano S, Iwase K, Koga K, Abe H, Yamazaki Y. Responses in muscle sympathetic activity to acute hypoxia in humans. J Appl Physiol. 1988;65:1548–1552. doi: 10.1152/jappl.1988.65.4.1548. [DOI] [PubMed] [Google Scholar]
  45. Schmidt HD, Raychhaus M, Francis DP, Davies CL, Nuding S, Peschel T, Schmidt DS, Coats AJ, Opitz H, Werdan K. Assessment of chemoreflex sensitivity in free breathing young subjects by correction for respiratory influence. Int J Cardiol. 2001;78:157–165. doi: 10.1016/s0167-5273(01)00377-1. [DOI] [PubMed] [Google Scholar]
  46. Seals DR. Sympathetic neural discharge and vascular resistance during exercise in humans. J Appl Physiol. 1989;66:2472–2478. doi: 10.1152/jappl.1989.66.5.2472. [DOI] [PubMed] [Google Scholar]
  47. Seals DR, Johnson DG, Fregosi RF. Hypoxia potentiates exercise-induced sympathetic neural activation in humans. J Appl Physiol. 1991a;71:1032–1040. doi: 10.1152/jappl.1991.71.3.1032. [DOI] [PubMed] [Google Scholar]
  48. Seals DR, Johnson DG, Fregosi RF. Hyperoxia lowers sympathetic activity at rest but not during exercise in humans. Am J Physiol. 1991b;260:R873–878. doi: 10.1152/ajpregu.1991.260.5.R873. [DOI] [PubMed] [Google Scholar]
  49. Sinoway L, Prophet S, Gorman I, Mosher T, Shenberger J, Dolecki M, Briggs R, Zelis R. Muscle acidosis during static exercise is associated with calf vasoconstriction. J Appl Physiol. 1989;66:429–436. doi: 10.1152/jappl.1989.66.1.429. [DOI] [PubMed] [Google Scholar]
  50. Smith ML, Niedermaier ON, Hardy SM, Decker MJ, Strohl KP. Role of hypoxemia in sleep apnea-induced sympathoexcitation. J Auton Nerv Syst. 1996;56:184–190. doi: 10.1016/0165-1838(95)00062-3. [DOI] [PubMed] [Google Scholar]
  51. Somers VK, Mark AL, Zavala DC, Abboud FM. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans. J Appl Physiol. 1989;67:2095–2100. doi: 10.1152/jappl.1989.67.5.2095. [DOI] [PubMed] [Google Scholar]
  52. Trzebski A, Smith ML, Beightol LA, Fritsch-Yelle JM, Rea RF, Eckberg DL. Modulation of human sympathetic periodicity by mild, brief hypoxia and hypercapnia. J Physiol Pharmacol. 1995;46:17–35. [PubMed] [Google Scholar]
  53. Vallbo Å, Hagbarth K-E, Torebjork H, Wallin B. Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev. 1979;59:919–957. doi: 10.1152/physrev.1979.59.4.919. [DOI] [PubMed] [Google Scholar]
  54. Weisbrod CJ, Minson CT, Joyner MJ, Halliwill JR. Effects of regional phentolamine on hypoxic vasodilatation in healthy humans. J Physiol. 2001;537:613–621. doi: 10.1111/j.1469-7793.2001.00613.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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