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1 Physiology of Exercise, De Montfort University, Lansdowne Road, Bedford, UK2 Department of Kinesiology, University of North Carolina, 9201 University City Boulevard, Charlotte, NC, USA3 Department of Sport Science, Tourism and Leisure, Canterbury Christ Church University College, North Holmes Road, Canterbury, UK
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(Received 15 January 2004;
accepted after revision 28 April 2004; first published online 29 June 2004)
Corresponding author R. Howden: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Building 101, Room E-214, Research Triangle Park, NC 27709, USA. Email: howden{at}niehs.nih.gov
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Introduction |
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Chemoreceptor control of peripheral blood flow has received little attention when investigating mechanisms associated with tolerance to orthostatic stress. Somers et al. (1991) reported that a possible interaction exists between baroreflexes and chemoreflexes in the control of sympathetic nerve activity, which has been shown to be a principal regulator of peripheral blood flow during orthostatic stress (Johnson et al. 1974).
There is confusion regarding the effect that stimulated chemoreceptors exert on the peripheral vasculature, as indicated by changes in either forearm blood flow (FBF), total peripheral resistance or muscle sympathetic nerve activity (MSNA) (Rowell, 1993). During hypercapnic acidosis, blood flow in the intact forearm has been shown to increase (Kontos et al. 1968a) or remain constant (Kontos et al. 1968b). Furthermore, total peripheral resistance during hypercapnic acidosis has been shown to increase (De Burgh Daly et al. 1965), decrease (Rothe et al. 1990a) or remain constant (Daugherty et al. 1967; Walker & Brizzee, 1990). However, only two of these investigations used human subjects (Kontos et al. 1968a, b), with the remainder being conducted in dogs (De Burgh Daly et al. 1965; Daugherty et al. 1967; Rothe et al. 1990a,b).
Furthermore, studies that induced hypercapnia reported increases (Somers et al. 1989) and decreases (Shoemaker et al. 2001) in MSNA in human subjects. There appears to be limited and equivocal data regarding the effect of hypercapnic acidosis on human peripheral vascular control during disturbances in blood distribution (orthostatic stress), and no published information regarding changes in calf circumference (CC) during hypercapnic conditions under this stress. Changes in FBF (Gilbert et al. 1966; Johnson et al. 1974) and calf circumference (Coles et al. 1957; Wolthius et al. 1975) provide important information regarding the control of peripheral blood flow during orthostatic stress. However, the role of chemoreflexes in the regulation of peripheral blood flow during supine rest or orthostatic stress requires further investigation.
The purpose of this study was to compare tolerance to LBNP while breathing room air and air containing 5% CO2. Our hypothesis was that breathing 5% CO2 would prolong presyncopal tolerance to orthostatic stress through its effects upon chemoreceptors. The additional measures of FBF, CC and cardiac responses might provide some insight into the possible mechanisms associated with any such change in presyncopal tolerance to orthostatic stress. The investigations were made during supine rest, followed by application of orthostatic stress (LBNP) until the onset of presyncopal signs and symptoms (Murray et al. 1968).
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Methods |
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Nine subjects (five males and four females; average ±S.D. age 21.9 ± 0.9 years, height 172.4 ± 9.7 cm, mass 70.3 ± 7.1 kg) volunteered to participate in this study following completion of a preparticipation medical questionnaire. Subjects gave written informed consent to participate in the study after receiving a verbal and written description of all experimental procedures, which were granted ethical approval by the De Montfort University Ethics Committee, and were performed according to the Declaration of Helsinki. All subjects reported to the laboratory at least 4 h postprandially and had avoided vigorous exercise for at least 24 h. During all tests laboratory temperature and humidity were maintained (23 ± 0.8°C, 32 ± 5%, respectively) and ambient barometric pressure was recorded from a mercury barometer for calculation of end-tidal PCO2 (see below).
Hypercapnia
Throughout both normocapnic and hypercapnic conditions minute ventilation (VE) and end-tidal CO2 (ETCO2; expressed as a percentage of total end-tidal expiratory gas) were measured using a Mass Spectrometer breath-by-breath gas analyser (Pulmolab EX 670, Morgan Medical Ltd, UK). ETCO2 values were then used to calculate end-tidal PCO2 (PETCO2; percentage gas concentration/100 x ambient barometric pressure).
Hypercapnic acidosis was induced when subjects inspired normoxic air containing 5% CO2 (BOC gases, UK) from Douglas Bags through a low-resistance valve. The low-resistance valve was connected to the volume turbine, capillary sampling tube and mouthpiece of the mass spectrometer (Pulmolab EX 670), which was calibrated prior to each test using known gases and a volume syringe (Hans Rudolph, USA). When under the control condition (i.e. breathing room air), subjects were instrumented with the same volume turbine, capillary sampling tube and mouthpiece, as above. Induction of hypercapnia was verified in a preliminary study (data not shown). To avoid any order effect, a cross-over study design was employed whereby four subjects were tested under control conditions first and five subjects were tested under hypercapnic conditions first.
FBF and CC
FBF was determined using forearm occlusion plethysmography (Whitney, 1953). Briefly, a mercury-in-silastic strain gauge was placed on the right forearm, distal to the lateral humeral condyle at the point of maximum forearm circumference. A small pneumatic cuff placed around the right wrist of the subject was inflated to a suprasystolic pressure to exclude circulation to the hand in the measurement of FBF. A second pneumatic cuff, placed around the upper right arm, was inflated abruptly to 50 mmHg, thus occluding venous drainage from the arm. Three signal slopes from the strain gauge, each during 8 s of venous occlusion, were recorded during every third minute during tests using an analog-to-digital converter (PowerLab, AD Instruments, Hastings, UK). FBF was calculated in units of ml dl min–1. CC was calculated from changes in the signal output from another mercury-in-silastic strain gauge placed around the right calf.
Cardiac output, stroke volume, heart rate and electromyography
Estimates of cardiac output (
) and stroke volume (SV) were made using measures of changes in thoracic impedance (Rheocardiomonitor, Rheo-Graphic PTE, Singapore) recorded from surface electrodes. SV was estimated using an altered Kubicek equation (Barin et al. 2000). A three-lead electrocardiograph was recorded from surface electrodes using an analog-to-digital converter (PowerLab, AD Instruments), from which heart rate (HR) was calculated instantaneously by expressing each R–R interval as beats per minute using specialized computer software (Chart v.4.04, AD Instruments). Electromyography was also recorded from three surface electrodes placed on the right vastus medialis muscle of the subjects during all tests. This signal was used as a visual indicator of any lower body movement, which subjects were instructed to avoid.
Orthostatic stress test
Upon arrival at the laboratory subjects were sealed into the LBNP chamber in a supine position and resting data were then recorded for a 15-min period while breathing either room air or 5% CO2. Following this 15-min period, internal LBNP chamber pressure was reduced by 20 mmHg for 3 min, after which a further reduction was made in chamber pressure of 10 mmHg every 3 min until the onset of presyncopal signs and symptoms. The criteria used for ending all LBNP tests were identical. The LBNP tolerance index (LTI; Lightfoot and Tsintgaris, 1995) was used to quantify LBNP tolerance.
Statistical analysis
Differences in VE, ETCO2, estimated arterial PCO2 (Pa,CO2), FBF, CC, Q, SV and HR were assessed using a two-way repeated measures ANOVA with these variables categorized by time (i.e. each time point at which data were recorded during both rest and orthostatic stress) and gas (i.e. breathing room air or 5% CO2). In variables that showed significant differences either by time, gas or time–gas interaction (P < 0.05), Fisher's protected LSD post hoc test was used to assess where the differences existed. Differences between LTI, peak HR and time to peak HR during orthostatic stress when breathing either room air or 5% CO2 (at the ‘commonly tolerated’ negative pressures) were compared using a paired Student's t test. Variables that are reported as single values for each test (e.g. peak HR, time to peak HR, SV and Q during orthostatic stress) were calculated from the LBNP data up to, but excluding, presyncopal values because these were often depressed.
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Tolerance to orthostatic stress
There was a significant increase in presyncopal tolerance to orthostatic stress when subjects were breathing 5% CO2 in air from compared with breathing room air (210.3 ± 20.9 vs. 191.9 ± 20.4, P < 0.05; see Table 2). All subjects tolerated LBNP until the onset of presyncopal signs and symptoms and no tests were terminated as a result of either discomfort experienced by the subject or of equipment failure. The recorded EMG signal did not indicate any lower body movement by subjects during orthostatic stress.
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There were no significant relative changes in HR, SV and Q during hypercapnia as compared with normocapnia or across time while in the supine position, prior to LBNP (P > 0.05; Fig. 1). Furthermore, there were no changes in FBF and CC when breathing either 5% CO2 or room air, or between these two conditions (P > 0.05; Fig. 2). However, VE, ETCO2 and Pa,CO2 were significantly elevated when breathing 5% CO2 as compared with breating room air during supine rest (Table 1, P < 0.001). While breathing 5% CO2 there was a significant increase in VE during supine rest from minute 6 compared with minute 3, which reached a plateau between the 12- and 15-min time points (P < 0.05, Table 1).
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There was a significant relative increase in HR from –30 mmHg of LBNP and reductions in SV from –20 mmHg of LBNP and Q from –30 mmHg of LBNP during hypercapnia and from –20 mmHg of LBNP during normocapnia when compared to the first period of data collection during supine rest (P < 0.05; Fig. 1), but this change was not different between the two conditions (P > 0.05; Fig. 1). Just prior to presyncope, peak HR was significantly higher during hypercapnia than during normocapnia (P < 0.05; Table 2). This higher peak HR was reflected by an increase in the time to peak HR, from the onset of orthostatic stress, during hypercapnia as compared with normocapnia (P < 0.05; Table 2) in addition to a further 22.3% reduction in SV during hypercapnia (Table 2).
There was a significant relative reduction in FBF during all stages of orthostatic stress as compared with the first period of data collection during supine rest, but these responses were not different between gases (P > 0.05; Fig. 2). However, CC increased significantly from the second stage of orthostatic stress (–30 mmHg of LBNP) during hypercapnia (P < 0.05; Fig. 2) and from –20 mmHg of LBNP during normocapnia (P < 0.05; Fig. 2). This increase was significantly greater at –50 mmHg of LBNP when subjects were breathing room air than when breathing 5% CO2 (P < 0.05; Fig. 2).
During orthostatic stress, PETCO2 and estimated Pa,CO2 did not show any further changes from values recorded during supine rest (P > 0.05; Table 1). However, VE increased above hypercapnic resting levels during orthostatic stress once the –30 mmHg level of LBNP had been reached (P < 0.001; Table 1). VE when breathing room air did not change at any stage of the experiment (P > 0.05; Table 1).
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It is difficult to explain the greater peak HR and time to peak HR observed in this study during hypercapnic orthostatic stress. We have shown previously (Howden et al. 2002) that increased tolerance to orthostatic stress is associated with increased time to peak HR. We suggested that this might be due to better maintenance of venous return. Indeed, at –50 mmHg of LBNP the increase in CC was significantly less during hypercapnia than during normocapnia. However, impedance estimates of SV may have been compromised by the increases in ventilation observed in this study. In addition, it is possible that there were differences in responses in the legs that were localized and which were not evident in the arms (where the flow changes were measured). Indeed, the reductions in CC were not matched by changes in FBF.
The respiratory pump is known to be an important factor in maintaining venous return during orthostatic stress (Rowell, 1993). In this study, during hypercapnia, VE was significantly elevated as compared with during normocapnia. Furthermore, VE continued to increase during orthostatic stress and may have played an increasingly important role in venous return as the orthostatic stress became more severe. However, it seems likely that this would have been accompanied by an attenuated reduction in SV and Q immediately prior to presyncope, which did not occur in this study. Indeed, the reduction in SV under hypercapnic conditions, during orthostatic stress, was 22.3% greater than the SV reduction during normocapnia. Furthermore, De Burgh Daly (1986) has suggested that deep and rapid breathing may induce excessive emptying of the vena cavae, reducing central venous pressure. With an accompanying translocation of blood into the lower limbs during orthostatic stress, also known to reduce central venous pressure (Johnson et al. 1974), the increase in VE observed in this study would probably be associated with an accelerated loss of central venous pressure and early presyncope. Because the effect of hypercapnia was to increase tolerance to orthostatic stress, other factors are likely to be responsible for a delay in the onset of presyncopal signs and symptoms, resulting in greater reductions in SV and increases in HR.
The effect of Pa,CO2 on CBF velocity and CBF (Serrador et al. 2000) is well known, and a 40–50% increase in CBF has been suggested when breathing 5% CO2 in air (Rowell, 1986). However, during orthostatic stress, CBF has been shown to decrease (Bondar et al. 1991; Grubb et al. 1991; Zhang et al. 1997; Serrador et al. 2000) and others have suggested that this reduction in CBF, below a point at which cerebral arterial pressure can no longer be maintained, initiates the onset of presyncope (Glaister & Miller, 1990; Grubb et al. 1991). This reduction in CBF during orthostatic stress has been associated with reductions in Pa,CO2 at presyncope, induced by hyperventilation (Morgan et al. 1997; Imms, 2000). Therefore, it is possible that under hypercapnic conditions with elevated Pa,CO2, the increased orthostatic tolerance was due to delayed reductions in CBF.
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References |
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) and normocapnia (•)
significant difference from normocapnia. Baseline values for CO2 and room air were: CC, 371.6 ± 9.5 vs. 370.3 ± 11.3 mm; FBF, 4.6 ± 1.6 vs. 4.6 ± 1.5 ml dl min–1, respectively.