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. 2007 Jul 19;583(Pt 3):1155–1163. doi: 10.1113/jphysiol.2007.137216

Mild central chemoreflex activation does not alter arterial baroreflex function in healthy humans

Grant H Simmons 1, Julie M Manson 1, John R Halliwill 1
PMCID: PMC2277196  PMID: 17640930

Abstract

We have previously shown that activation of peripheral chemoreceptors with isocapnic hypoxia resets arterial baroreflex control of heart rate and sympathetic vasoconstrictor outflow to higher pressures, without changes in baroreflex gain. We tested the hypothesis that activation of central chemoreceptors with mild hyperoxic hypercapnia also causes resetting of the arterial baroreflex, but that this resetting would not occur with matched volume and frequency hyperpnoea. Baroreflex control of heart rate (n = 16) and muscle sympathetic nerve activity (microneurography; n = 11) was assessed in healthy men and women, age 20–33 years, using the modified Oxford technique during hyperoxic eucapnia, hyperoxic hyperpnoea and hyperoxic hypercapnia (end-tidal PCO2+ 5 mmHg above eucapnia). Baroreflex trials were separated by 30 min of rest. While neither hyperpnoea nor hypercapnia changed mean arterial pressure (92.0 ± 1.8 during eucapnia versus 91.0 ± 1.2 and 90.7 ± 1.4 mmHg during hyperpnoea and hypercapnia; P = 0.427) or muscle sympathetic nerve activity (2301 ± 687 during eucapnia versus 2959 ± 987 and 2272 ± 414 total integrated units min−1 during hyperpnoea and hypercapnia; P = 0.653), heart rate was increased from 59.3 ± 2.7 during eucapnia to 63.2 ± 3.0 and 62.4 ± 2.8 beats min−1 during hyperpnoea and hypercapnia (both P < 0.017). Baroreflex gain was not altered by hyperpnoea or hypercapnia. Thus, acute activation of central chemoreceptors with mild hyperoxic hypercapnia does not affect arterial pressure, sympathetic vasoconstrictor outflow, or baroreflex gain. Heart rate is elevated during hyperoxic hypercapnia, but this response is not different from the increase in heart rate produced by matched volume and frequency hyperpnoea. Therefore, mild activation of central chemoreceptors does not appear to alter arterial baroreflex function.

Patients with obstructive sleep apnoea experience repeated episodes of partial or total upper airway collapse during sleep. These periods of apnoea/hypopnoea result in concomitant hypoxia and hypercapnia (i.e. asphyxia) on a systemic level (Parish & Somers, 2004). During asphyxia, hypercapnia activates both the central chemoreceptors, located near the ventral surface of the medulla (Bruce & Cherniack, 1987), and the peripheral chemoreceptors, located in the carotid and aortic bodies. Hypoxia activates primarily the peripheral chemoreceptors (Fitzgerald & Lahiri, 1986). Peripheral and central chemoreceptor stimulation during obstructive apnoea is associated with sympathetic activation and surges in blood pressure during sleep, and this repeated sympathoexcitation may contribute to daytime elevations in sympathetic nerve activity and blood pressure observed in obstructive sleep apnoea patients (Somers et al. 1995). However, the link between chronic chemoreflex activation and the development of hypertension is poorly understood. Evidence suggests that patients with obstructive sleep apnoea have altered baroreflex control of sympathetic outflow compared with healthy controls matched for age, body mass index and blood pressure (Narkiewicz et al. 1998). Thus, it is important to understand how baroreflex function is altered acutely during chemoreflex stimulation in order to better understand the root of daytime hypertension in obstructive sleep apnoea.

In animals, a major central interaction between chemoreflexes and baroreflexes was demonstrated by Heistad et al. (1974, 1975) on the basis that ventilatory and haemodynamic responses to chemoreceptor stimulation were different at varying levels of baroreceptor activity. Later work confirmed the presence of interactions between peripheral chemoreflexes and baroreflexes in humans (Somers et al. 1991; Halliwill et al. 2003). Peripheral chemoreflex activation with mild isocapnic hypoxia resets the arterial baroreflex to higher heart rates, arterial pressures, and levels of sympathetic nerve activity, without changes in reflex sensitivity (Halliwill & Minson, 2002; Halliwill et al. 2003). However, the effects of central chemoreflex activation on baroreflex function remain poorly characterized. Dean et al. (1990) have demonstrated that neurons located in the nucleus tractus solitarii are stimulated by hypercapnia in vitro, providing a neuroanatomical/physiological framework for interactions between central chemoreflexes and cardiovascular function. In vivo, Bristow et al. (1971) and Henry et al. (1998) have demonstrated a downward resetting of baroreflex control of R-R interval (to higher heart rates) during activation of central chemoreceptors. More recently, Cooper et al. (2005) studied carotid baroreflex control of forearm vascular resistance during central chemoreflex activation. In that study, chemoreceptor stimulation was associated with increases in mean arterial pressure and forearm vascular resistance, raising the possibility that baroreflex control of the vasculature was altered in some way. Thus, in vitro evidence, as well as in vivo evidence from human studies, suggests that central CO2 chemoreception may affect arterial baroreflex function. Importantly, previous human studies of central chemoreflex–baroreflex interactions have either failed to control for possible influences of increased ventilation on autonomic outflow (Cooper et al. 2005), or have only assessed baroreflex control of heart rate (Bristow et al. 1971; Henry et al. 1998). Furthermore, none of these studies have assessed baroreflex control of sympathetic outflow using direct nerve recordings.

One aspect common to the studies cited above is the use of relatively severe hypercapnia (end-tidal PCO2≥ 10 mmHg above eucapnia) to probe interactions between central chemoreflexes and baroreflexes. In contrast, several studies suggest a mild CO2 stimulus (+5 mmHg) can alter cardiovascular regulation (Morgan et al. 1995; Shoemaker et al. 2001). For example, Shoemaker et al. (2001) demonstrated that mild hypercapnia (end-tidal PCO2 5 mmHg above eucapnia) abolishes the increase in muscle sympathetic nerve activity during orthostasis. These data could be explained by a number of possibilities, including a peripheral vascular effect during hypercapnia (Shoemaker et al. 2002), baroreflex inhibition by hyperpnoea (Van De Borne et al. 2000), or a hypercapnia-mediated reduction in arterial baroreflex gain. Concerning the latter, arterial baroreflex function has not been tested during central chemoreceptor stimulation with mild hypercapnia.

With the above information as a background, the current investigation was undertaken to assess the effect of mild central chemoreflex activation on baroreflex function while controlling for increases in ventilation. We used hyperoxia to isolate the central chemoreflex from peripheral chemoreflex responses (Lahiri & DeLaney, 1975). Baroreflex control of heart rate and sympathetic vasoconstrictor outflow was tested in healthy subjects exposed to mild hyperoxic hypercapnia and matched hyperoxic hyperpnoea. Specifically, we tested the hypothesis that hyperoxic hypercapnia, and not hyperoxic hyperpnoea, alters baroreflex function in healthy humans.

Methods

This study was approved by the institutional review board of the University of Oregon, and each subject gave written, informed consent prior to participation. Experiments were performed according to the Declaration of Helsinki.

Subjects

Sixteen healthy, non-smoking, normotensive subjects (seven males, nine females) between the ages of 20 and 33 years participated in this study (height 176 ± 9 cm (s.d.), weight 73.0 ± 12.9 kg, body mass index 23.6 ± 3.1 kg m−2). Subjects were taking no medications except for oral contraceptives, and none had been to altitude (>1500 m) within 5 months. Females were either studied during the early follicular phase (1–4 days after the onset of menstruation) of the menstrual cycle or during the placebo phase of oral contraceptive use to minimize the potential effects of female hormones on cardiovascular regulation (Minson et al. 2000a, b). All female subjects had a negative urine pregnancy test within 1 h of participation.

Familiarization visit

Subjects underwent a familiarization visit several days prior to the protocol day to become familiar with the instrumentation and for determination of their individual ventilatory response during a 5 min period of hyperoxic hypercapnia (end-tidal PCO2 raised 5 mmHg above eucapnia). Details regarding the induction of hyperoxic hypercapnia are provided below. Following these measurements, each subject was instructed and allowed to practice controlled breathing at a prescribed tidal volume and breathing frequency (hyperpnoea) that was matched to their individual ventilatory response during the preceding bout of hyperoxic hypercapnia.

Protocol visit

On the study day, subjects were instrumented in the supine position for the measurement of heart rate via electrocardiography (Cardiocap/5; Datex-Ohmeda, Madison, WI, USA), ventilation via turbine pneumotach (VMM–400; Interface Associates, Laguna Niguel, CA, USA), arterial pressure via brachial artery auscultation (Cardiocap/5) and finger photoplethysmography (Finometer; Finapres Medical Systems BV, Arnhem, The Netherlands), end-tidal PO2 (Cardiocap/5), and end-tidal PCO2 via infrared capnography (Cardiocap/5). An intravenous catheter was placed in an antecubital vein for administration of vasoactive substances for the purpose of assessing baroreflex responses. In 11 of the subjects (five males, six females), we recorded muscle sympathetic nerve activity from the fibular (peroneal) nerve via microneurography. In the remaining five subjects, nerve recordings were either inadequate or were not stable during one or more of the study conditions.

After instrumentation, subjects were monitored during a 20 min rest period in which tidal PCO2 was measured via a nasal cannula. Mean end-tidal PCO2 over the last 5 min was defined as eucapnia for the remainder of the protocol. Subjects then underwent three measurement periods. Each measurement period lasted 8 min, and corresponded to one of the following conditions: hyperoxic eucapnia with uncontrolled breathing, hyperoxic hyperpnoea with controlled breathing, or hyperoxic hypercapnia with controlled breathing frequency only. Hyperoxia was maintained during each condition to minimize stimulation of peripheral chemoreceptors throughout this study (Hornbein et al. 1961; Biscoe et al. 1970; Lahiri & DeLaney, 1975). During the first 5 min of each measurement period, subjects rested under each condition for determination of the operating point of the baroreflex in terms of pressure and effector relationship. During the final 3 min, baroreflex trials using the modified Oxford technique were performed as previously described (Halliwill & Minson, 2002; Halliwill et al. 2003). Briefly, baroreflex responses were assessed by measuring heart rate and muscle sympathetic nerve activity during arterial pressure changes induced by nitroprusside and phenylephrine as developed by Ebert & Cowley (1992) and validated by Rudas et al. (1999). During each trial, 100 μg sodium nitroprusside was given intravenously as a bolus, followed 1 min later by 150 μg phenylephrine HCl. This protocol decreases arterial pressure ∼15 mmHg below baseline levels and then increases it ∼15 mmHg above baseline levels, over a short time course. Measurement periods were separated by 30 min of rest. Our prior work has shown that repeated baroreflex trials separated by at least 20 min of rest are reproducible (Rudas et al. 1999; Minson et al. 2000a, b; Halliwill & Minson, 2002; Halliwill et al. 2003). Heart rate, arterial pressure, end-tidal PO2 and PCO2, ventilation, and sympathetic activity were recorded continuously during each measurement period. Since we had previously determined each subject's ventilatory response to hypercapnia, we were able to randomize the order of conditions between hyperoxic eucapnia, hyperoxic hyperpnoea and hyperoxic hypercapnia.

Isolation of hyperoxic eucapnia, hyperoxic hyperpnoea and hyperoxic hypercapnia

In order to isolate conditions of hyperoxic eucapnia, hyperoxic hyperpnoea and hyperoxic hypercapnia, we used a self-regulating partial-rebreathe system developed by Banzett et al. (2000) to control alveolar fresh-air ventilation independent of changes in breathing frequency or tidal volume as we have done previously (Weisbrod et al. 2001; Dinenno et al. 2003; Halliwill et al. 2003; Simmons et al. 2007). Subjects breathed through a scuba mouthpiece with a nose-clip to prevent nasal breathing. This system allowed us to regulate end-tidal PCO2 levels despite large changes in minute ventilation (Simmons et al. 2007). Conditions of hypercapnia/eucapnia were produced by altering the amount of expired gas in the inspiratory mixture and hyperoxia was maintained by using 100% O2 as the fresh gas supply to the re-breathe circuit. Gas concentrations were monitored at the mouthpiece. Hyperpnoea was achieved by providing both an auditory and visual cue for breathing frequency and displaying real-time inspiratory tidal volume with predetermined target tidal volumes for each subject. During hyperoxic hypercapnia, only cues for breathing frequency were provided, and subjects' tidal volumes were not restricted.

Muscle sympathetic nerve activity

Muscle sympathetic nerve activity was recorded via microneurography (Sundlof & Wallin, 1977). Multiunit postganglionic muscle sympathetic nerve activity was recorded from the fibular (peroneal) nerve posterior to the fibular head with a tungsten microelectrode. The recorded signal was amplified 100 000-fold and band-pass filtered (700–2000 Hz), rectified and integrated (resistance-capacitance integrator circuit, time constant 0.1 s) with a custom-built amplifier system for analysis of muscle sympathetic nerve activity.

Data analysis

Data were digitized at 250 Hz with signal processing software (WinDaq; Dataq Instruments, Akron, OH, USA) and analysed off-line. Each muscle sympathetic nerve activity recording was normalized by assigning the largest sympathetic burst under resting conditions an amplitude of 1000 (Halliwill, 2000). All other bursts for that recording were calibrated against that value. The zero nerve activity level was determined from the mean voltage during a period of neural silence between sympathetic bursts. A period in which bursts were absent for >5 s was found in each tracing and used for this purpose.

Baroreflex control of sympathetic outflow was determined from the relation between muscle sympathetic nerve activity and diastolic pressure during vasoactive drug boluses (Ebert & Cowley, 1992; Rudas et al. 1999). The slope of this relation was used as an index of reflex sensitivity. The operating point for the relation in terms of resting arterial pressure and nerve activity was determined as the average values over the 5 min period immediately preceding the nitroprusside bolus. Diastolic pressure was used because muscle sympathetic nerve activity correlates closely with diastolic pressure but not with systolic pressure (Sundlof & Wallin, 1977; Rudas et al. 1999). The methods used to analyse these data have been described extensively (Halliwill, 2000; Halliwill & Minson, 2002).

Baroreflex control of heart rate was determined from the relation between heart rate and systolic pressure during vasoactive drug boluses. The slope of this relation was used as an index of reflex sensitivity. The operating point for the relation in terms of resting arterial pressure and heart rate was determined as the average values over the 5 min period immediately preceding the nitroprusside bolus. Systolic pressure was used because heart rate correlates closely with systolic pressure but not with diastolic pressure (Sundlof & Wallin, 1977; Rudas et al. 1999). In order to perform a linear regression between heart rate and pressure, values for heart rate were first pooled over 2 mmHg pressure ranges as previously described (Ebert & Cowley, 1992; Rudas et al. 1999; Halliwill & Minson, 2002). The analogous regression between R-R interval and systolic pressure was also determined.

Statistics

Because there were no discernable differences between men and women, data from the two groups were combined for statistical analysis. The results were analysed with a one-way repeated measures ANOVA, and post hoc analysis was performed using the Bonferroni t test procedure. Differences were considered significant when P < 0.05. All values are presented as means ±s.e.m. unless otherwise indicated.

Results

Ventilatory and haemodynamic data

Table 1 shows ventilatory data during all three conditions. As planned, end-tidal PCO2 increased during hyperoxic hypercapnia only (P < 0.001), while end-tidal PO2 and respiratory rate were not different between conditions (both P > 0.189). Both tidal volume and minute ventilation increased to similar values during hyperoxic hyperpnoea and hyperoxic hypercapnia (all P < 0.001 versus eucapnia; both P > 0.782 between hyperpnoea and hypercapnia). Table 2 shows resting heart rate and arterial pressure during all three conditions. Both hyperoxic hyperpnoea and hyperoxic hypercapnia increased resting heart rate (both P < 0.017 versus eucapnia), and this increase was not different between the two conditions (P = 1.000). Resting systolic, diastolic and mean arterial pressures were not different between conditions (all P > 0.065).

Table 1.

Ventilation

Hyperoxic eucapnia Hyperoxic hyperpnoea Hyperoxic hypercapnia
End-tidal PO2 (mmHg) 690.5 ± 2.7 661.7 ± 22.8 665.3 ± 7.3
End-tidal PCO2 (mmHg) 39.7 ± 0.5 39.7 ± 0.6 45.1 ± 0.6*†
Ventilation (l min−1) 8.0 ± 0.8 15.1 ± 1.3* 16.1 ± 1.4*
Tidal volume (l) 0.6 ± 0.8 1.1 ± 0.9* 1.2 ± 0.1*
Respiratory rate (breaths min−1) 13.7 ± 1.1 14.3 ± 1.0 14.7 ± 1.2
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*

P < 0.05 versus hyperoxic eucapnia

†

P < 0.05 versus hyperoxic hyperpnoea. Values are means ±s.e.m.

Table 2.

Heart rate and arterial pressure

Hyperoxic eucapnia Hyperoxic hyperpnoea Hyperoxic hypercapnia
Heart rate (beats min−1) 59.3 ± 2.7 63.2 ± 3.0* 62.4 ± 2.8*
MAP (mmHg) 92.0 ± 1.8 91.0 ± 1.2 90.7 ± 1.4
Systolic pressure (mmHg) 125.8 ± 2.5 123.4 ± 2.0 122.7 ± 1.9
Diastolic pressure (mmHg) 75.1 ± 1.6 74.8 ± 1.0 74.6 ± 1.4
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MAP, mean arterial pressure.

*

P < 0.05 versus hyperoxic eucapnia. Values are means ±s.e.m.

Cardiovascular regulation

Figure 1 shows resting muscle sympathetic nerve activity recorded in a representative subject during hyperoxic eucapnia, hyperoxic hyperpnoea and hyperoxic hypercapnia. Note the similarity in burst magnitude and frequency during the three conditions. Group average resting nerve activity was not changed by hyperoxic hyperpnoea or hyperoxic hypercapnia (2301 ± 687 during eucapnia versus 2959 ± 987 and 2272 ± 414 total integrated units min−1 during hyperpnoea and hypercapnia; P = 0.653).

Figure 1.

Figure 1

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Resting muscle sympathetic nerve activity in a representative subject during hyperoxic eucapnia, hyperoxic hypercapnia and hyperoxic hyperpnoea Tracings: upper, hyperoxic eucapnia; middle, hyperoxic hypercapnia; lower, hyperoxic hyperpnoea. Note the similarity in total nerve activity across the three conditions. MSNA, muscle sympathetic nerve activity; HR, heart rate; MAP, mean arterial pressure.

Figure 2 shows the group average regressions between heart rate and systolic pressure and between sympathetic nerve activity and diastolic pressure during baroreflex trials. The operating point of the baroreflex in terms of pressure–effector relationship is represented by the bolded symbol for each condition. For both the heart rate and systolic pressure relation, and the sympathetic nerve activity and diastolic pressure relation, no differences in effector-axis intercept were observed during either hyperoxic hyperpnoea or hyperoxic hypercapnia (P = 0.720 and P = 0.775). Neither the slope of the heart rate and systolic pressure relation (P = 0.972) nor the slope of the sympathetic nerve activity and diastolic pressure relation (P = 0.228) were different between conditions (Fig. 3). Furthermore, slope analysis based on R-R interval shows no effect of hyperoxic hyperpnoea or hyperoxic hypercapnia (13.2 ± 1.4 during eucapnia versus 12.4 ± 1.0 and 12.0 ± 1.2 ms mmHg−1 during hyperpnoea and hypercapnia; P = 0.500).

Figure 2.

Figure 2

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Group average regressions between heart rate and systolic pressure, and between sympathetic nerve activity and diastolic pressure The operating points are indicated by symbol and error bars for each condition. The continuous line denotes the regression between pressure and effector response for hyperoxic eucapnia (heart rate = (182 ± 19) – (0.89 ± 0.13) × pressure, r2= 0.82 ± 0.05; nerve activity = (334 ± 48) – (4.4 ± 0.6) × pressure, r2= 0.72 ± 0.07). The dotted line denotes the regression between pressure and effector response for hyperoxic hyperpnoea (heart rate = (185 ± 13) – (0.89 ± 0.08) × pressure, r2= 0.84 ± 0.03; nerve activity = (270 ± 35) – (3.4 ± 0.5) × pressure, r2= 0.63 ± 0.08). The dashed line denotes the regression between pressure and effector response for hyperoxic hypercapnia (heart rate = (187 ± 18) – (0.88 ± 0.11) × pressure, r2= 0.83 ± 0.03; nerve activity = (339 ± 36) – (4.4 ± 0.5) × pressure, r2= 0.84 ± 0.02). Values are means ±s.e.m. (n = 16 for heart rate; n = 11 for MSNA).

Figure 3.

Figure 3

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Individual and group average slopes for the relationship between heart rate and systolic pressure and between sympathetic nerve activity and diastolic pressure during hyperoxic eucapnia, hyperoxic hyperpnoea and hyperoxic hypercapnia Upper panel, heart rate and systolic pressure; lower panel, sympathetic nerve activity and diastolic pressure. Individual slopes, ○; group average slopes, •.

Discussion

The goal of the present investigation was to test the effect of mild central chemoreflex activation on baroreflex function. Contrary to our hypothesis, we showed that mild central chemoreflex activation does not alter baroreflex function in healthy humans. The main evidence for this is that mean arterial pressure, muscle sympathetic nerve activity, cardiac and sympathetic baroreflex sensitivity, and cardiac and sympathetic baroreflex intercept with the effector-axis, were unaffected by hyperoxic hypercapnia. Heart rate was elevated during hyperoxic hypercapnia, but this response was not different from the increase in heart rate produced by matched volume and frequency hyperpnoea. Based on the data collected in this study, a ‘retrospective’ power calculation indicates that we would have to study >27 subjects to detect an effect of hypercapnia on baroreflex control. However, this calculation, by its very nature, is sample specific, and does not yield important information beyond what is given by the P value (Hoenig & Heisey, 2001). We caution against interpretation of ‘retrospective’ power.

Baroreflex control of heart rate

Two previous studies have assessed baroreflex control of heart rate (R-R interval) during central chemoreflex activation in humans (Bristow et al. 1971; Henry et al. 1998). Both studies used two different levels of chemoreflex activation, one of which was equivalent to the magnitude used in the current investigation. Bristow et al. (1971) found no consistent shift in cardiac baroreflex responses or sensitivity during mild hyperoxic hypercapnia. Henry et al. (1998) activated central chemoreflexes in the opposite direction (i.e. hyperoxic hypocapnia), but also failed to demonstrate shifts in reflex responses or sensitivity during mild activation. Thus, our data showing no effect of mild central chemoreflex activation on baroreflex control of heart rate agree with previous findings in this area. It should be noted that the studies of Bristow et al. (1971) and Henry et al. (1998) both demonstrated a downward resetting of baroreflex control of R-R interval (to higher heart rates) when more severe central chemoreflex activation was used. These findings raise two important points: (1) there may be a threshold for the effects of central chemoreflexes on baroreflex control of heart rate, and (2) these effects may not depend on the nature of the stimulus (i.e. hypercapnia versus hypocapnia).

Baroreflex control of sympathetic nerve activity

To our knowledge, this study is the first to demonstrate that mild central chemoreflex activation – sufficient to double resting ventilation – does not increase muscle sympathetic nerve activity in humans. In view of the observation that more severe hyperoxic hypercapnia is a potent activator of muscle sympathetic nerve activity (Somers et al. 1989a), these findings may indicate that a threshold exists for sympathetic stimulation by central chemoreceptors. However, our protocol did not address this issue directly. Previously, Shoemaker et al. (2002) have attempted to address this issue by measuring ventilatory and sympathetic responses to progressive central chemoreceptor stimulation induced by rebreathing. These investigators found that neither ventilation nor muscle sympathetic nerve activity increased until end-tidal PCO2 had risen by 15 mmHg. However, in their discussion, the authors raised concern about this apparent threshold, indicating that chemoreceptor mediated responses may require 2–3 min before full expression (see Narkiewicz et al. 1999a). Further confounding this issue are data indicating that increases in ventilation may restrain sympathetic responses during chemoreceptor stimulation (Somers et al. 1989a, b; Trzebski et al. 1995; Badra et al. 2001). The current investigation overcomes both of these issues, insofar as measurements were made in the ‘steady state’ (>4 min equilibration time), and the hyperoxic hypercapnia condition was compared with a condition of matched breathing frequency and volume. Therefore, the coupling of our negative findings, and previous reports of increased muscle sympathetic nerve activity during severe hyperoxic hypercapnia (Somers et al. 1989a), suggest that a threshold may exist for sympathetic stimulation by central chemoreceptors. Further investigation is warranted in this area. In contrast to sympathetic responses, our data show that central chemoreceptor control of ventilation is sensitive to even mild increases in end-tidal PCO2.

This study is also the first to show that mild central chemoreflex activation does not affect the operating point or gain of arterial baroreflex control of muscle sympathetic nerve activity. One previous study has investigated baroreflex control of the circulation during more severe stimulation of central chemoreflexes. Cooper et al. (2005) studied carotid baroreflex control of arterial pressure and forearm vascular resistance while end-tidal PCO2 was raised to ∼55 mmHg (∼13 mmHg above eucapnia) with hyperoxic hypercapnia. In that study, central chemoreflex stimulation increased both resting arterial pressure and forearm vascular resistance, and the set-point of the carotid sinus-vascular resistance relation (point of maximal gain) was shifted to higher carotid sinus pressures. However, there are a number of methodological considerations which make interpretation of the data collected by Cooper et al. (2005) difficult. First, baseline data were not collected against a hyperoxic background. Thus, levels of tonic peripheral chemoreflex activity were not controlled. Second, no attempt was made to account for increased ventilation during hyperoxic hypercapnia. Therefore, the degree to which hyperpnoea per se affected sympathetically mediated responses is unclear (see Somers et al. 1989b). Third, brachial artery blood flow measurements – from which vascular resistance was calculated – were made without occlusion of the hand circulation. Thus, blood flow to the nonacral skin, the muscle and the hand were measured simultaneously, all of which are regulated differently by local, humoral and neural mechanisms (Green & Kepchar, 1959; Roddie, 1983; Rowell, 1993). Fourth, direct nerve recordings were not obtained and thus any inference regarding arterial baroreflex control of the vasculature was made on the basis of changes in vascular resistance (see above), ignoring the potential influence of CO2 and/or acidosis on vascular transduction of sympathetic outflow (McGillivray-Anderson & Faber, 1990). In view of these considerations, we feel there are insufficient data from which to speculate about baroreflex control of sympathetic outflow during more severe central chemoreflex stimulation.

The failure of mild central chemoreceptor activation to alter baroreflex function may provide insight into previously described changes in cardiovascular regulation during mild hypercapnia. For example, Shoemaker et al. (2001) demonstrated that a mild CO2 stimulus equivalent to that used in the current investigation (end-tidal PCO2 5 mmHg above eucapnia) abolishes the increase in muscle sympathetic nerve activity during orthostasis. These data raised the possibility that mild hypercapnia alters baroreflex control of sympathetic nerve activity. Indeed, attenuated sympathetic outflow during a given orthostatic stress is consistent with a reduction in arterial baroreflex gain. However, that study did not attempt to isolate central chemoreflex responses from peripheral chemoreflex input. Therefore, it was not clear from the data collected which of these reflexes contributed to the change in cardiovascular regulation. Based on the current findings, it is unlikely that central chemoreflex stimulation mediates the effects of mild hypercapnia on cardiovascular regulation during orthostasis.

Clinical significance

Baroreflex control of muscle sympathetic nerve activity appears to be altered in patients with obstructive sleep apnoea when compared with healthy controls matched for age, body mass index and blood pressure (Narkiewicz et al. 1998). A hallmark of this syndrome is repeated episodes of partial or total upper airway occlusion during sleep, and resultant hypoxia and hypercapnia chronically stimulate both peripheral and central chemoreceptors. Over the last 20 years, considerable work has been dedicated toward understanding how changes in peripheral chemoreception affect blood pressure regulation in patients with obstructive sleep apnoea (Somers et al. 1991; Narkiewicz et al. 1999b). We have previously shown that acute peripheral chemoreflex stimulation resets the arterial baroreflex to higher heart rates, arterial pressures, and levels of muscle sympathetic nerve activity, without changes in reflex gain (Halliwill & Minson, 2002; Halliwill et al. 2003). This baroreflex resetting bore striking resemblance to the classical resetting observed during dynamic exercise, with upward and rightward shifts in the operating point of the reflex. The combination of upward and rightward shifts in the operating point suggests that both baroreflex-dependent and baroreflex-independent mechanisms were involved (Rowell, 1993). In contrast to peripheral chemoreception, little research has focused on the effects of central chemoreception on blood pressure regulation. The current results show no evidence of impaired baroreflex control of heart rate or sympathetic outflow in healthy individuals exposed to mild central chemoreceptor activation. Therefore, blood pressure regulation appears to be unaltered by mild central chemoreflex activation in the acute setting. It remains unclear whether chronic activation of central chemoreceptors can alter baroreflex function.

Conclusion

In conclusion, mild central chemoreflex activation with hyperoxic hypercapnia does not affect arterial baroreflex control of heart rate, arterial pressure or sympathetic vasoconstrictor outflow in healthy humans.

Acknowledgments

The authors would like to express their gratitude to all of the subjects who participated in this study. These studies were conducted by Grant H. Simmons in partial fulfilment for the degree of Doctor of Philosophy in the Department of Human Physiology at the University of Oregon. This research was supported by a grant from the National Heart, Lung and Blood Institute HL-65305.

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