Abstract
Arterial CO2 serves as a mediator of cerebral blood flow (CBF), and its relative influence on the regulation of CBF is defined as cerebral CO2 reactivity. Our previous studies have demonstrated that there are differences in CBF responses to physiological stimuli (i.e. dynamic exercise and orthostatic stress) between arteries in humans. These findings suggest that dynamic CBF regulation and cerebral CO2 reactivity may be different in the anterior and posterior cerebral circulation. The aim of this study was to identify cerebral CO2 reactivity by measuring blood flow and examine potential differences in CO2 reactivity between the internal carotid artery (ICA), external carotid artery (ECA) and vertebral artery (VA). In 10 healthy young subjects, we evaluated the ICA, ECA, and VA blood flow responses by duplex ultrasonography (Vivid-e, GE Healthcare), and mean blood flow velocity in middle cerebral artery (MCA) and basilar artery (BA) by transcranial Doppler (Vivid-7, GE healthcare) during two levels of hypercapnia (3% and 6% CO2), normocapnia and hypocapnia to estimate CO2 reactivity. To characterize cerebrovascular reactivity to CO2, we used both exponential and linear regression analysis between CBF and estimated partial pressure of arterial CO2, calculated by end-tidal partial pressure of CO2. CO2 reactivity in VA was significantly lower than in ICA (coefficient of exponential regression 0.021 ± 0.008 vs. 0.030 ± 0.008; slope of linear regression 2.11 ± 0.84 vs. 3.18 ± 1.09% mmHg−1: VA vs. ICA, P < 0.01). Lower CO2 reactivity in the posterior cerebral circulation was persistent in distal intracranial arteries (exponent 0.023 ± 0.006 vs. 0.037 ± 0.009; linear 2.29 ± 0.56 vs. 3.31 ± 0.87% mmHg−1: BA vs. MCA). In contrast, CO2 reactivity in ECA was markedly lower than in the intra-cerebral circulation (exponent 0.006 ± 0.007; linear 0.63 ± 0.64% mmHg−1, P < 0.01). These findings indicate that vertebro-basilar circulation has lower CO2 reactivity than internal carotid circulation, and that CO2 reactivity of the external carotid circulation is markedly diminished compared to that of the cerebral circulation, which may explain different CBF responses to physiological stress.
Key points
Arterial CO2 serves as a mediator of cerebral blood flow, and its relative influence on the regulation of cerebral blood flow is defined as cerebral CO2 reactivity.
Because of methodological limitations, almost all previous studies have evaluated the response of blood flow velocity in the middle cerebral artery to changes in CO2 as a measure of CO2 reactivity across the whole brain.
We found that the vertebral artery has lower CO2 reactivity than the internal carotid artery. Moreover, CO2 reactivity in the external carotid artery was markedly lower than in the cerebral circulation.
These results demonstrate regional differences in CO2 regulation of blood flow between the internal carotid, external carotid, and vertebro-basilar circulation.
Introduction
Cerebral blood flow (CBF) and its distribution are highly sensitive to changes in the partial pressure of arterial CO2 () (Ainslie & Duffin, 2009; Ainslie & Ogoh, 2009; Ogoh & Ainslie, 2009). This physiological response, termed cerebral CO2 reactivity, is a vital homeostatic function that helps regulate and maintain central pH and, therefore, affects the respiratory central chemoreceptor stimulus (Ainslie & Duffin, 2009). CBF increases with hypercapnia (elevation in
) to ‘washout’ CO2 from the vasculature of brain tissues, thereby attenuating the rise in central
, whereas hypocapnia (reduction of
) causes cerebral vasoconstriction, which reduces CBF and attenuates the fall of
in the vasculature of brain tissues (Kety & Schmidt, 1948; Wasserman & Patterson, 1961; Ainslie & Duffin, 2009). Because of methodological limitations, almost all previous studies have evaluated the response of mean blood flow velocity (Vmean) in the middle cerebral artery (MCA) to changes in CO2 as a measure of CO2 reactivity across the whole brain (Aaslid et al. 1989; Ainslie & Duffin, 2009; Ainslie & Ogoh, 2009). These previous studies were based on the concept that regional brain or head circulations (e.g. posterior cerebral and external carotid circulation) have similar CO2 reactivity to the MCA, but this assumption has yet to be rigorously tested.
The common carotid artery (CCA) divides into an external carotid artery (ECA), which supplies blood to the face and cranium wall, and an internal carotid artery (ICA), which supplies the large part of cerebral cortex via intracranial arteries (e.g. MCA, anterior, and posterior cerebral artery). On the other hand, the vertebral artery (VA) and the basilar artery (BA), the vertebro-basilar system, supply blood to the occipital cortex, cerebellum, spinal cord and medulla oblongata. It is unknown if regulation of blood flow to these different regions of the brain and head is differentially regulated, yet our recent studies have demonstrated that there appear to be differences in CBF responses to physiological stimuli between arteries (Sato & Sadamoto, 2010; Sato et al. 2011). Of particular note, in contrast to ICA blood flow, there was no relationship between end-tidal CO2 () and either ECA or VA blood flow during graded dynamic exercise (Sato et al. 2011). In addition, we observed that 60 deg head-up tilt caused a significant decrease in ICA blood flow with decreases in
while VA blood flow did not respond to orthostatic stress (Sato et al. unpublished observation). These findings suggest that dynamic CBF regulation, especially cerebral CO2 reactivity, is different in the anterior and posterior cerebral circulation, although previous studies have not detected differences (Ogawa et al. 1988; Hida et al. 1996; Park et al. 2003). Indeed, previous studies observed a lower CO2 reactivity in the posterior inferior cerebellar artery compared with the MCA (Reinhard et al. 2008), indicating that differences may be related to the vascular territories perfused by specific cerebral arteries. Unfortunately, these previous investigations evaluated cerebral CO2 reactivity using blood flow velocity by TCD instead of CBF, and a critical limitation of TCD is that any change in diameter of the insonated artery will change blood flow velocity even when blood flow is constant (Aaslid et al. 1989; Ainslie & Duffin, 2009; Ainslie & Ogoh, 2009). Moreover, changes in blood flow velocity under- or overestimate CBF responses in larger or smaller diameter vessels, respectively. Indeed, vessel diameter in VA is approximately two-thirds that of ICA and the relative contributions of ICA and VA blood flow to total CBF at rest are estimated to be ∼75% and ∼25%, respectively (Schöning et al. 1994; Sato & Sadamoto, 2010; Sato et al. 2011). It is thus reasonable to hypothesize that previously undetected differences in actual CBF reactivity to CO2 may exist that influence regional blood flow in the brain.
Given this background, the aim of this study was to (1) identify cerebral CO2 reactivity by measuring blood flow as well as blood flow velocity, and (2) examine potential differences in CO2 reactivity between ICA, ECA and VA. We evaluated the ICA, ECA and VA blood flow responses using by duplex ultrasonography, and MCA Vmean and BA Vmean by TCD during two levels of hypercapnia (3% and 6% CO2 administrations), normocapnia and hypocapnia to estimate CO2 reactivity in extra- and intracranial arteries. We hypothesized that the cerebral CO2 reactivity would be different between ICA, ECA and VA or MCA and BA.
Methods
Subjects and ethical approval
Ten young subjects (5 men, 5 women) participated in this study (mean ± SD: 22 ± 2 years, 166 ± 6 cm, 58 ± 8 kg). Subjects were non-obese, normotensive and free from overt cardiovascular, pulmonary, metabolic, or neurological disease. Subjects were moderately active, non-smokers, who were not taking any medications. Written informed consent was obtained according to the Japan Women's College of Physical Education (2011–1), and this study was conducted in accordance with the principles of the Declaration of Helsinki.
Protocol
All subjects were familiarized with the equipment and procedures before any experimental sessions. Subjects were requested to abstain from caffeinated beverages for 12 h and strenuous physical activity and alcohol for at least 24 h before experimental sessions. On the experimental day, subjects arrived at the laboratory at least 2 h after a light meal. After instrumentation, the subjects were seated in a semi-recumbent position (∼30 deg) in a reclining chair and rested quietly for ∼30 min, while wearing a face mask and breathing room air. After the resting period, each subject performed four randomly assigned respiratory interventions (Fig. 1): (1) baseline normocapnia (room air) for 10 min; (2) mild hypercapnia for 10 min (3% CO2 in 21% O2 and N2 balance); (3) severe hypercapnia for 10 min (6% CO2 in 21% O2 and N2 balance); and (4) hyperventilation-induced hypocapnia for 5 min. In the hypocapnia intervention, subjects were instructed to increase their rate and depth of breathing to reduce to ∼20 mmHg for 5 min. Verbal feedback was provided to help subjects reach and maintain the target level of hyperventilation. Between interventions, subjects inspired room air for 20 min to ensure full recovery. According to previous studies (Ainslie et al. 2007; Cummings et al. 2007), cerebral CO2 reactivity is impaired in the early morning, so we avoided the early morning during experimentation (conducted between ∼10.00 and 18.00 h). In this study, the menstrual cycle was not considered for women subjects in all trials.
Figure 1. Experimental protocol and target time points of each cerebral blood flow measurement for four experimental conditions.
Cerebral blood flow and blood flow velocity measurements were performed by two operators by duplex ultrasonography (for ICA, ECA, VA and BA) and by transcranial Doppler (for MCA). Operator 1 measured ICA and ECA blood flow, and operator 2 measured VA blood flow and BA Vmean in the first and second trials. In order to measure BA Vmean, subjects shifted from a semi-recumbent to an upright seated position. ICA, internal carotid artery; ECA, external carotid artery; VA, vertebral artery; BA, basilar artery; MCA, middle cerebral artery; Vmean, mean blood flow velocity.
In this study, blood flow in three extracranial arteries (i.e. ICA, ECA and VA) and Vmean in two intracranial arteries (i.e. MCA and BA) were measured by colour-coded duplex ultrasonography (for ICA, ECA, VA and BA) and by TCD (for MCA) (Figs 1 and 2). It was impossible to simultaneously evaluate blood flow in these cerebral arteries due to the technical limitations of duplex ultrasonography (e.g. insufficient neck surface area and interference between Doppler beams from multiple probes). Therefore, in order to obtain all the desired cerebral blood flow measurements, subjects performed the experimental protocol twice (first and second trial). In the first trial, left MCA Vmean and cardiorespiratory variables were continuously recorded while two operators simultaneously measured left ICA and right VA blood flows. During the second trial, left ECA blood flow and BA Vmean were simultaneously measured. The same two experienced operators performed all CBF measurements (Sato & Sadamoto, 2010; Sato et al. 2011). All trials for a single subject were conducted on the same day in order to avoid day-to-day variation of cerebrovascular and haemodynamic responses. All conditions and trials were performed at a room temperature between ∼23–24°C with external stimuli minimized. Subjects were asked to keep their eyes open and the room was illuminated.
Figure 2. Subject position and ultrasound Doppler screens while ICA, ECA, VA blood flow, and BA and MCA Vmean are measured during hypercapnia (3% CO2 administration) in one subject.
ICA, internal carotid artery; ECA, external carotid artery; VA, vertebral artery; BA, basilar artery; MCA, middle cerebral artery; Vmean, mean blood flow velocity.
Cerebral blood flow measurement
Left ICA and ECA blood flow measurements were performed ∼1.0–1.5 cm distal to the carotid bifurcation by duplex ultrasonography using a 10.0-MHz linear transducer (Vivid-e; GE healthcare, Japan) (Fig. 2). Right VA blood flow was measured between the transverse process of the C3 vertebra and subclavian artery using the same ultrasound machine equipped with a 10.0 MHz linear transducer. In addition, BA Vmean was measured using a different ultrasound device (Vivid-7 pro; GE Healthcare, Japan) equipped with a 2.0 MHz sector transducer held on the back of the neck, aiming upward through the foramen magnum. Operator 1 measured ICA and ECA blood flow, and operator 2 measured VA blood flow and BA Vmean. In order to measure BA Vmean, subjects shifted from the semi-recumbent to an upright seated position for the last two (during normocapnia and hypercapnia) or one (during hypocapnia) minute(s) of each protocol because it was difficult to insonnate the BA in the semi-recumbent position.
CBF was assessed during steady-state conditions for analysis of cerebral CO2 reactivity. Specific target time points for each CBF measurement are shown in Fig. 1. Data represent average CBF across the time points indicated. For ICA, ECA and VA blood flow measurements, we first used the brightness mode to measure the mean vessel diameter in a longitudinal section. The Doppler velocity spectrum was subsequently identified by pulsed wave mode. In detail, the systolic and diastolic diameters were measured, and then the mean diameter (cm) was calculated as follows: mean diameter =[(systolic diameter × 1/3)]+[(diastolic diameter × 2/3)]. The time-averaged mean flow velocity obtained in pulsed wave mode was defined as the mean blood flow velocity (cm s−1) and was measured by tracing the average flow rate for each time phase. Measurements of blood flow velocity were averaged across ∼15 cardiac cycles to account for oscillatory effects caused by respiration. When recording blood flow velocity measurements, care was taken to ensure that the probe position was stable, that the insonation angle did not vary (<60 deg in most cases), and that the sample volume was positioned in the centre of the vessel and adjusted to cover the width of the vessel diameter. The mean blood flow velocity was calculated on the basis of velocity waveforms traced automatically by using the off-line analysis of the ultrasonography data.
Finally, blood flow was calculated by multiplying the cross-sectional area [π× (mean diameter/2)2] with mean blood flow velocity; Blood flow = mean blood flow velocity × area × 60 (ml min−1) (Sato et al. 2011). In the pilot study, we carried out a test–retest measurement to confirm the reproducibility of ICA, ECA and VA blood flow at normocapnia, hypercapnia (6% CO2) and hypocapnia (n= 5). The coefficients of variation (CV) in ICA, ECA and VA blood flow were 4.4 ± 1.8%, 4.1 ± 2.8% and 4.7 ± 1.9% during normocapnia, 5.4 ± 1.6%, 5.1 ± 2.5% and 4.7 ± 1.9% during hypercapnia, and 5.7 ± 2.6%, 5.2 ± 1.5 and 5.2 ± 1.9% during hypocapnia, respectively.
In order to measure BA Vmean, we used brightness mode imaging to visualize the BA with the real-time Doppler velocity spectrum in pulsed wave mode (Fig. 2). The BA Vmean was obtained with the sample volume set at ∼2–3 mm and with the vector of the cursor positioned in the centre of the blood stream (depth ∼50–80 mm). The measurements of blood flow velocity were also made from the average of ∼15 cardiac cycles. Technical or anatomical difficulties and time constraints limited BA Vmean measurements to six subjects. In addition, left MCA Vmean was measured by TCD (WAKI; Atys Medical, France). A 2 MHz Doppler probe was adjusted over the temporal window of the left MCA until an optimal signal was identified (depth ∼45–60 mm). The probe was then fixed and held in place using a headband strap.
Cardiorespiratory measurement
Ventilatory responses were measured using an open-circuit apparatus. Subjects breathed through a face mask attached to a low-resistance two-way valve with a flowmeter, allowing subjects to inspire room air or a selected gas mixture from a 200 litre Douglas bag containing 3% CO2 or 6% CO2 in 21% O2 with N2 balance. The total instrumental dead space was 200 ml. Respiratory data were recorded by an automatic breath-by-breath respiratory gas analysing system, consisting of a differential pressure transducer, sampling tube, filter, suction pump and mass spectrometer (ARCO2000, Arco system, Japan). We derived minute ventilation () and
. Heart rate (HR) was continuously monitored using a three-lead electrocardiogram (Radercirc; Dainippon Sumitomo Pharmacology, Japan). Beat-by-beat mean arterial pressure (MAP) was acquired using finger photoplethysmography from the middle or index finger of the right hand (Finometer; Finapres Medical Systems BV, Netherlands). Furthermore, stroke volume and cardiac output were determined from the blood pressure waveform by the Model flow software program, which incorporates sex, age, height and weight (Beat Scope 1.1; Finapres Medical Systems BV, Netherlands).
Cerebral CO2 reactivity
The cerebrovascular and cardiorespiratory responses were continuously recorded throughout the trials. The average CBF and in target time points of each trial were used for data analysis and calculation of cerebral CO2 reactivity (Fig. 1). Previous studies suggested that
overestimates
during hypercapnia but not hypocapnia and cerebral CO2 reactivity to hypercapnia is underestimated when assessed by
compared with
(Peebles et al. 2007; Ainslie & Duffin, 2009). Therefore, we estimated
for calculating cerebral CO2 reactivity using the regression equation developed by Peebles et al. (2007): estimated
. As used in other studies, CBF was expressed as percentage change from baseline normocapnia to allow between-study comparisons and to reduce interindividual variability that is unrelated to the experimental manipulation (Ide et al. 2003; Ainslie et al. 2007; Cummings et al. 2007; Peebles et al. 2007). In this study, cerebrovascular CO2 reactivity was expressed as the percentage change in blood flow or Vmean per mmHg change in estimated
. To characterize cerebrovascular CO2 reactivity, we used both an exponential and a linear model. In the exponential model, we calculated relative change in blood flow as blood flow or Vmean (%) =K exp(R estimated
), and determined K and R, where K corresponds to the theoretically measured change in blood flow or Vmean at an estimated
of 0 mmHg, and R corresponds to the slope defining the degree of individual CO2 reactivity in each vessel. For analysing the individual CO2 reactivity, the slope of the exponential function R was used (Tominaga et al. 1976; Ide et al. 2003; Ogoh et al. 2008). In the linear model, we calculated relative change in blood flow as blood flow or Vmean (%) =A+B estimated
, where the CO2 reactivity is given by the slope B, reactivity unit, % mmHg−1 (Ainslie & Duffin, 2009). Further, CO2 reactivity (% mmHg−1) was calculated separately from normocapnia to hypocapnia and hypercapnia using a linear model (Peebles et al. 2007).
Statistics
Changes in haemodynamics variables at each level of estimated and differences in CO2 reactivity between each cerebral artery were compared by repeated measures one-way ANOVA with Bonferroni post hoc tests for multiple comparisons (SPSS19.0, SPSS, Japan). The difference in CO2 reactivity between hypocapnia and hypercapnia or men and women in each vessel were assessed by Student's paired or unpaired t test. A value of P < 0.05 was accepted as statistically significant and all data were presented as means ± SD.
Results
Changes during hypo- and hypercapnia
There were no significant differences in steady-state carodiorespiratory responses between the two trials in each condition (first and second trial), so these data were averaged. Steady-state responses of systemic and cerebral haemodynamics to hypocapnia, normocapnia and two levels of hypercapnia are presented Table 1. As expected, changed from normocapnia (baseline) to hypocapnia (−17.9 ± 3.7 mmHg) and severe hypercapnia (6% CO2; +15.0 ± 2.3 mmHg). Similarly, estimated
changed from normocapnia to hypocapnia (−15.8 ± 3.2 mmHg) and severe hypercapnia (6% CO2; +13.2 ± 2.0 mmHg).
was increased above normocapnia during severe hypercapnia (+15.6 ± 4.5 l min−1) and hyperventilation-induced hypocapnia (+35.6 ± 6.3 l min−1). HR was increased during hypocapnia (+22.5 ± 13.5 beats min−1) and severe hypercapnia (+8.5 ± 5.5 beats min−1). Compared to normocapnia, MAP increased during severe hypercapnia (+7.5 ± 5.4 mmHg). Cardiac output was increased above normocapnia during hypocapnia (+139 ± 21%) and severe hypercapnia (+120 ± 14%).
Table 1.
Steady-state cardiorespiratory and cerebrovascular changes from normocapnia to hypocapnia and two levels of hypercapnia
Hypercapnia | ||||
---|---|---|---|---|
Hypocapnia | Normocapnia (baseline) | 3% CO2 | 6% CO2 | |
Cardiorespiratory | ||||
![]() |
21.1 ± 3.1* | 38.9 ± 2.4 | 46.1 ± 3.1* | 53.9 ± 2.8* |
Estimated ![]() |
21.0 ± 2.8* | 36.8 ± 2.1 | 43.6 ± 2.7* | 50.0 ± 2.5* |
![]() |
45.0 ± 5.9* | 9.4 ± 1.2 | 16.2 ± 2.8* | 24.9 ± 4.7* |
HR (beats min−1) | 86 ± 15* | 63 ± 8 | 68 ± 11 | 72 ± 13* |
MAP (mmHg) | 89 ± 6 | 87 ± 9 | 90 ± 8 | 94 ± 9† |
Cardiac output (%) | 139 ± 21* | 100 | 110 ± 9† | 120 ± 14* |
Cerebrovascular | ||||
ICA blood flow (ml min−1) | 160±33* | 235±47 | 283±53* | 386±112* |
Dmean (cm) | 0.45±0.06 | 0.45±0.06 | 0.46±0.05 | 0.46±0.05 |
Vmean (cm s−1) | 17.7±4.4* | 24.7±4.8 | 28.9±5.7* | 38.1±9.4* |
VA blood flow (ml min−1) | 81±16* | 112±27 | 126±34† | 153±45* |
Dmean (cm) | 0.34±0.04 | 0.35±0.04 | 0.35±0.03 | 0.36±0.04 |
Vmean (cm s−1) | 15.8±4.7* | 20.4±5.6 | 22.0±5.3 | 25.9±6.6* |
ECA blood flow (ml min−1) | 102±37 | 113±42 | 113±43 | 127±55 |
Dmean (cm) | 0.37±0.07 | 0.36±0.07 | 0.37±0.07 | 0.37±0.07 |
Vmean (cm s−1) | 15.8±4.4† | 18.4±4.9 | 17.6±4.7 | 19.3±5.5 |
MCA Vmean (cm s−1) | 29.4±7.2* | 57.4±14.0 | 65.7±16.2* | 85.2±15.2* |
BA Vmean (cm s−1) | 22.8±6.7* | 32.0±7.3 | 37.1±5.5† | 46.3±7.7* |
Values are mean ± SD , end-tidal CO2; Estimated
, regression equation using end-tidal CO2 to estimated
;
, minute ventilation; HR, heart rate; MAP, mean arterial pressure; ICA, internal carotid artery; VA, vertebral artery; ECA, external carotid artery; Dmean, mean vessel diameter; Vmean, mean blood flow velocity. †Different from normocapnia (P < 0.05); *different from normocapnia (P < 0.01).
ICA blood flow decreased from normocapnia by −75 ± 30 ml min−1 (−31.4 ± 8.7%) during hypocapnia and increased +152 ± 79 ml min−1 (64.3 ± 29.4%) during severe hypercapnia. VA blood flow also decreased from normocapnia by –31 ± 23 ml min−1 (−26.4 ± 11.1%) and increased by +41 ± 23 ml min−1 (36.7 ± 18.4%) during hypocapnia and severe hypercapnia, respectively. However, there were no significant alterations in ICA or VA diameters to changes in CO2, indicating that ICA and VA blood flow were attributable to changes in blood flow velocities, not arterial diameters. Similarly, MCA Vmean decreased by −28 ± 10 cm s−1 (−47.9 ± 10.8%) and increased by +28 ± 9 cm s−1 (51.3 ± 19.0%), while BA Vmean decreased by −9 ± 4 cm s−1 (−29.1 ± 11.0%) and increased by +14 ± 4 cm s−1 (47.1 ± 17.9%) during hypocapnia and severe hypercapnia, respectively (n= 6). In contrast, ECA blood flow was unchanged during any intervention.
CBF response to change in CO2
Figure 3A illustrates the changes in CBF and Vmean relative to the change in in all subjects. We also calculated the estimated
from the
and Fig. 3B shows the relationship between the estimated
and mean CBF or Vmean, illustrated as an exponential model and a linear regression model.
Figure 3. Left. Each subject's blood flow and Vmean response to changes in estimated
. Right. The relationship between estimated CO2 and blood flow or Vmean, differentially analysed by exponential regression and linear regression.
The regression model in the right figure was tabulated using mean values from all subjects in Table 2. ICA, internal carotid artery; ECA, external carotid artery; VA, vertebral artery; BA, basilar artery; MCA, middle cerebral artery; Vmean, mean blood flow velocity; Estimated , regression equation using end-tidal CO2 to estimated
.
Table 2 shows the multiple correlation coefficient (R2), exponential model coefficient, and slope of the linear regression line (together forming an index for CO2 reactivity), determined by a creating a regression from both models for the relationship between the estimated and the CBF and Vmean values for all subjects. Table 2 also shows the means and standard deviations for all subjects, as well as the male–female differentiated means and standard deviations. The mean of the multiple correlation coefficient was higher for all CBF and Vmean in the exponential model than in the linear regression model. Women have a higher CO2 reactivity in VA than men (2.54 ± 0.93 vs. 1.67 ± 0.51% mmHg−1, P < 0.05).
Table 2.
Coefficient data for each subject, used to calculate the CO2 reactivity and multiple correlation coefficient in the exponential and linear regression models
ICA blood flow | VA blood flow | ECA blood flow | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Exponential | Linear | Exponential | Linear | Exponential | Linear | ||||||||
Subjects no. | Sex | R2 | Exponent | R2 | Slope | R2 | Exponent | R2 | Slope | R2 | Exponent | R2 | Slope |
1 | W | 0.91 | 0.046 | 0.78 | 5.64 | 0.99 | 0.041 | 0.98 | 3.99 | 0.86 | 0.016 | 0.82 | 1.60 |
2 | W | 0.94 | 0.030 | 0.86 | 3.54 | 0.88 | 0.024 | 0.81 | 2.91 | 0.03 | −0.003 | 0.02 | −0.18 |
3 | W | 0.98 | 0.027 | 0.97 | 2.40 | 0.90 | 0.016 | 0.84 | 1.64 | 0.83 | 0.007 | 0.81 | 0.69 |
4 | M | 0.95 | 0.036 | 0.89 | 4.37 | 0.99 | 0.023 | 0.98 | 2.43 | 0.17 | 0.006 | 0.20 | 0.87 |
5 | M | 0.94 | 0.023 | 0.91 | 2.29 | 0.99 | 0.017 | 1.00 | 1.59 | 0.52 | 0.005 | 0.52 | 0.55 |
6 | M | 0.93 | 0.022 | 0.87 | 2.23 | 0.89 | 0.015 | 0.89 | 1.33 | 0.26 | −0.002 | 0.24 | −0.22 |
7 | M | 0.97 | 0.036 | 0.99 | 3.08 | 0.88 | 0.018 | 0.83 | 1.88 | 0.87 | 0.020 | 0.86 | 1.67 |
8 | W | 1.00 | 0.022 | 0.97 | 2.30 | 0.95 | 0.021 | 0.89 | 2.04 | 0.54 | 0.003 | 0.53 | 0.35 |
9 | M | 0.96 | 0.027 | 0.90 | 2.88 | 0.96 | 0.011 | 0.96 | 1.12 | 0.17 | 0.003 | 0.19 | 0.30 |
10 | W | 0.90 | 0.027 | 0.79 | 3.04 | 0.97 | 0.025 | 0.99 | 2.13 | 0.87 | 0.007 | 0.86 | 0.72 |
All subjects mean | 0.95 | 0.030 | 0.89 | 3.18 | 0.94 | 0.021 | 0.92 | 2.11 | 0.51 | 0.006 | 0.50 | 0.63 | |
SD | 0.03 | 0.008 | 0.07 | 1.09 | 0.05 | 0.008 | 0.07 | 0.84 | 0.34 | 0.007 | 0.32 | 0.64 | |
Men mean | 0.95 | 0.029 | 0.91 | 2.97 | 0.94 | 0.017 | 0.93 | 1.67 | 0.40 | 0.006 | 0.40 | 0.63 | |
SD | 0.02 | 0.007 | 0.05 | 0.86 | 0.05 | 0.004 | 0.07 | 0.51 | 0.30 | 0.008 | 0.29 | 0.70 | |
Women mean | 0.95 | 0.031 | 0.88 | 3.38 | 0.94 | 0.025 | 0.90 | 2.54 | 0.63 | 0.006 | 0.61 | 0.63 | |
SD | 0.04 | 0.009 | 0.09 | 1.36 | 0.05 | 0.010 | 0.08 | 0.93 | 0.36 | 0.007 | 0.35 | 0.65 |
MCA Vmean | BA Vmean | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Exponential | Linear | Exponential | Linear | ||||||||||
Subjects no. | Sex | R2 | Exponent | R2 | Slope | R2 | Exponent | R2 | Slope | ||||
1 | W | 0.89 | 0.028 | 0.88 | 3.20 | 0.99 | 0.016 | 0.99 | 1.56 | ||||
2 | W | 0.99 | 0.053 | 0.90 | 4.88 | 0.98 | 0.021 | 0.98 | 2.05 | ||||
3 | W | 0.99 | 0.036 | 0.99 | 2.86 | — | — | — | — | ||||
4 | M | 0.88 | 0.045 | 0.81 | 4.48 | — | — | — | — | ||||
5 | M | 0.99 | 0.043 | 0.96 | 3.62 | — | — | — | — | ||||
6 | M | 0.97 | 0.032 | 0.97 | 2.78 | 0.95 | 0.024 | 0.91 | 2.66 | ||||
7 | M | 0.98 | 0.044 | 0.98 | 3.80 | — | — | — | — | ||||
8 | W | 0.94 | 0.028 | 0.98 | 2.29 | 0.99 | 0.033 | 0.98 | 3.18 | ||||
9 | M | 0.95 | 0.028 | 0.98 | 2.36 | 0.98 | 0.019 | 0.95 | 2.08 | ||||
10 | W | 0.99 | 0.031 | 0.97 | 2.79 | 0.95 | 0.023 | 0.88 | 2.22 | ||||
All subjects mean | 0.96 | 0.037 | 0.94 | 3.31 | 0.97 | 0.023 | 0.95 | 2.29 | |||||
SD | 0.04 | 0.009 | 0.06 | 0.87 | 0.02 | 0.006 | 0.05 | 0.56 | |||||
Men mean | 0.95 | 0.038 | 0.94 | 3.41 | 0.96 | 0.021 | 0.93 | 2.37 | |||||
SD | 0.05 | 0.008 | 0.07 | 0.84 | 0.02 | 0.004 | 0.03 | 0.41 | |||||
Women mean | 0.96 | 0.035 | 0.95 | 3.21 | 0.98 | 0.023 | 0.96 | 2.25 | |||||
SD | 0.04 | 0.011 | 0.05 | 0.99 | 0.02 | 0.007 | 0.05 | 0.68 |
Comparison of CO2 reactivity
Figure 4 shows the CO2 reactivity as calculated from both the exponential model and the linear regression models. Significant differences were found in both models for ICA, VA and ECA CO2 reactivity (P < 0.01). These CO2 reactivities were calculated from the relationship model between CBF and estimated through hypocapnia, normocapnia and hypercapnia. No statistical analysis was conducted to compare MCA and BA CO2 reactivity since BA Vmean was measured in only six subjects; however, the MCA was quantitatively higher than the BA.
Figure 4. Cerebral CO2 reactivity as calculated from both regression models.
*Differences between ICA, VA and ECA (P < 0.01). ICA, internal carotid artery; ECA, external carotid artery; VA, vertebral artery; BA, basilar artery; MCA, middle cerebral artery; Vmean, mean blood flow velocity.
Table 3 shows the CO2 reactivity of the CBF and Vmean from the linear regression model, differentiating between hypercapnia and hypocapnia. ICA, VA and BA CO2 reactivity was significantly higher during hypercapnia than during hypocapnia (ICA, P < 0.01; VA, P < 0.05; BA, P < 0.05), but ECA and MCA were not significantly different.
Table 3.
Calculated and compared CO2 reactivity during hypocapnia and hypercapnia as determined from the linear regression model
ICA | VA | ECA | MCA | BA | |
---|---|---|---|---|---|
Hypercapnic CO2 reactivivty (% mmHg−1) | 4.86 ± 2.56* | 2.79 ± 1.51† | 1.30 ± 1.60 | 3.90 ± 1.60 | 3.10 ± 1.04† |
Hypocapnic CO2 reactivivty (% mmHg−1) | 2.03 ± 0.58 | 1.71 ± 0.72 | 0.51 ± 1.01 | 3.15 ± 1.01 | 1.78 ± 0.62 |
Values are means ± S.D. Different from hyporcapnia; †P < 0.05, *P < 0.01.
Discussion
The major finding from the present study was that cerebral CO2 reactivity was significantly lower in the VA and its distal artery (BA) than in the ICA and its distal artery (MCA). These findings indicate that vertebro-basilar circulation has lower CO2 reactivity than internal carotid circulation. Our second major finding was that ECA blood flow was unresponsive to hypocapnia and hypercapnia, suggesting that CO2 reactivity of the external carotid circulation is markedly diminished compared to that of the cerebral circulation. These findings suggest that different CO2 reactivity may explain differences in CBF responses to physiological conditions (i.e. dynamic exercise and orthostatic stress) across areas in the brain and/or head.
CBF response to change in CO2
Although our study is based on four distinct levels of and the CBF responses (ICA, VA, MCA, and BA) over a range of estimated
from ∼20 to ∼50 mmHg, judging by R2, the exponential model was the better fit than the linear regression model to describe the CBF-estimated
relationship (Table 2). We acknowledge that numerous studies have quantified cerebral CO2 reactivity using a linear regression model because complex modelling methods may not be practical for clinical use (Ainslie & Duffin, 2009). Additionally, the exponential model needs many more data points to calculate an accurate reactivity than the linear model. However, the advantage of using exponential functions is that it allows more accurate data fitting when examining the reactivity to wide-range variations in
. Importantly, methodological differences in modelling methods have no practical impact on the difference in CO2 reactivity between the cerebral arteries in this study (Fig. 4).
It is possible that 6% CO2 administration maximally dilated the cerebral arterioles and that the exponential nature of the CBF curve was due, at least in part, to an increase in MAP during severe hypercapnia in this study (Table 1). Although in the normal range of autoregulation (range of 60–150 mmHg), the CBF response to CO2 may be independent of change in MAP (Lasen 1959). Recently Lucas et al. (2010) examined static autoregulation and showed that when CO2 tensions are held constant at resting values, CBF increases with systemic blood pressure. Thus, the concomitant MAP increase with severe hypercapnia may confound cerebral CO2 reactivity, because it could increase CBF (Ide et al. 2003; Lucas et al. 2010). However, the increase in MAP from normocapnia to severe hypercapnia (∼8%) was much lower than CBF (i.e. ICA ∼64%), suggesting that the effect of change in perfusion pressure on CO2 reactivity is minimal in the present study. Unfortunately, we did not specifically address the question of how changes in MAP might affect differences in CO2 reactivity in internal carotid and vertebro-basilar circulation or the difference in CBF-estimated sensitivity in hypocapnia and hypercapnia. Furthermore, previous reports have demonstrated that cardiac output has a direct impact on CBF at rest (Ogoh et al. 2005). In this study, however, CBF also showed a marked decrease in hypocapnia, in which cardiac output increased ∼40% (Table 1), and thus the influence of CO on CBF is likely to be lower than that of CO2 (Ainslie & Duffin, 2009). Importantly, the effect of perfusion pressure or cardiac output on CBF is unlikely to cause differences in CO2 reactivity observed between arteries.
Hypercapnic cerebral CO2 reactivity in global CBF was greater than the hypocapnic reactivity (Ide et al. 2003) (Table 3). The mechanisms underlying this greater reactivity to hypercapnia compared with hypocapnia may be related to a greater influence of vasodilator mediators on intracranial vascular tone compared with vasoconstrictive mediators (Toda & Okamura, 1998; Ainslie & Duffin, 2009). In humans, Peebles et al. (2008) recently reported that, during hypercapnia, there is a large release of nitric oxide (NO) from the brain, whereas this response was absent during hypocapnia.
CO2 reactivity in the internal carotid circulation versus vertebro-basilar circulation
The ICA provides blood to a large portion of the cerebral cortex via intracranial arteries (i.e. MCA), while the vertebro-basilar arteries supply blood to the occipital cortex, cerebellum, and brainstem. Our findings imply that dynamic CBF regulation is regionally specific in the brain. The difference in CO2 reactivity between vertebro-basilar territories (VA and BA) and the cerebral cortex (ICA and MCA) may be due to diverse characteristics of vasculature, e.g. regional microvascular density (Sato et al. 1984), basal vascular tone (Ackerman, 1973; Haubrich et al. 2004; Reinhard et al. 2008), autonomic innervation (Edvinsson et al. 1976; Hamel et al. 1988) and regional heterogeneity in ion channels or production of NO (Iadecola & Zhang, 1994; Gotoh et al. 2001). Regional sympathetic innervation of intracranial arterioles has been reported to be less extensive in the posterior cerebral cortex and cerebellum compared to arterioles in the anterior cerebral circulation (Edvinson et al. 1976). In the vertebro-basilar circulation, less autonomic-induced vascular tone might be related to a lower capacity for vasodilatation during hypercapnia (Reinhard et al. 2008). Moreover, other determinants of cerebrovascular tone have been proposed to explain regional differences, including NO synthase (Faraci & Brian, 1994) and K+ channel activity (Faraci & Sobey, 1998). Accordingly, anatomical and physiological factors probably contributed to differences in CO2 reactivity observed between the ICA and VA. However, the regional differences in CO2 regulation of blood flow between ICA and VA may not be attributed to different vessel size or blood flow volume because ICA and VA CO2 reactivity were identified by relative changes in blood flow in the present study.
In contrast to our findings, a study of regional CBF by positron emission tomography (PET) showed that vasomotor responses to hypercapnia were larger in vertebro-basilar territories than in most of the cerebral cortex supplied by the ICA, indicating higher vasodilatory reserve in the posterior cerebral circulation (Ito et al. 2000). One reason for this discrepancy may be the small range of hypercapnia (from ∼40 to 43 mmHg) used in their study. Furthermore, they studied older men (59.8 ± 5.5 years), in whom CO2 reactivity in the anterior cerebral circulation (i.e. MCA) is significantly lower than in younger subjects (Sorond et al. 2005). Others have shown that CO2 reactivity measured by TCD appears similar in the MCA and BA of healthy subjects (Ogawa et al. 1988; Hida et al. 1996; Park et al. 2003), whereas our results support differences in CO2 reactivity between the anterior and posterior cerebral circulation in humans (Sorond et al. 2005; Reinhard et al. 2008). Our measurements of cerebral CO2 reactivity in ICA blood flow and VA blood flow are difficult to directly compare to previous reports due to methodological differences in the evaluation of cerebral CO2 reactivity (e.g. method for CBF measurement, equations used to calculate reactivity, concentration of inhaled CO2, types of interventions used (hypocapnia, hypercapnia, or both), period of examination, posture and age of subjects).
CO2 reactivity in external carotid artery
Our second new finding is that ECA blood flow was unaffected by changes in CO2. While this is the first study to investigate CO2 reactivity in the ECA, indirect results from previous studies support our findings. CCA blood flow was unchanged after acetazolamide injection in patients who had ipsilateral ICA occlusion, indicating ECA blood flow was not influenced by this vasoactive drug (Eicke et al. 1999). In addition, 6% CO2 administration increased MCA Vmean in direct proportion to CCA blood flow (Ratanakorn et al. 2001), implying that little flow was diverted to the ECA due to vasodilatation.
The ECA supplies blood to the face, anterior neck and cranium wall. Our data indicate an attenuated vasomotor reaction in extracranial vascular beds perfused by the ECA (∼5-fold lower) compared to intracranial vascular beds perfused by the ICA (Fig. 4); however, the mechanism explaining reduced CO2 reactivity remains unclear. Interestingly, the response of the ECA to changes in CO2 may be similar to other peripheral arteries. It has long been appreciated that the vasodilatory effect of hypercapnia is much more profound in cerebral than in peripheral vasculature, particularly leg (Lennox & Gibbs, 1932; Ainslie et al. 2005) and brachial arteries (Miyazaki, 1973). These findings suggest that control of CO2 is particularly important in the cerebral circulation. The high resting metabolic requirements of the brain, compared with that of other vasculature, might be one reason why this circulatory arrangement is desirable (Ainslie et al. 2005). Specifically, high CO2 reactivity may be a way for the brain to match metabolism with flow (Ainslie et al. 2005). In contrast, ECA blood flow contributes to thermoregulation (Fan et al. 2008; Sato et al. 2011). The fact that the circulatory adjustments of ECA vasculature are seemingly opposite to those of the intracranial vasculature is of teleological relevance. If cutaneous arterioles in the face and scalp were to constrict equally in response to decreased , thermoregulation and cutaneous vasodilatation of the face and scalp would be impaired during vigorous exercise, especially in heat. On the other hand, heat is largely removed from the brain via the intracranial circulation (Nybo et al. 2002; Nielsen & Nybo, 2003). Thus, during exercise with hyperthermia, reduction in CBF due to hyperventilation-induced hypocapnia may impair heat removal from the brain and be expected to increase the rate of cerebral heat storage (Nybo et al. 2002). However, in this case, the contribution of ECA blood flow to heat removal from the brain and/or head should be increased because it was not affected by hyperventilation-induced hypocapnia (Fan et al. 2008; Sato et al. 2011).
In the present study, we did not find any significant differences in blood flow in the ECA for either hypocapnia or hypercapnia. However, a number of subjects experienced a change in ECA blood flow relative to CO2 (Table 2 and Fig. 3), suggesting there were individual differences. This effect may have been caused by the presence of anatomical differences between individuals.
Methodological considerations and limitations
A critical issue for the TCD technique is the inability to measure blood flow in the MCA and BA, and previous investigations measured blood flow velocity in intracranial arteries by TCD as an index of CBF although thorough assessment of cerebral CO2 reactivity requires volumetric measurements of CBF (Aaslid et al. 1989; Ainslie & Duffin, 2009; Ainslie & Ogoh, 2009). A change in CBF velocity represents a change in blood flow only if the diameter of the insonnated intracranial artery remains constant. The TCD response to hypercapnia may be influenced by a 10% vasodilatation of the MCA (Valdueza et al. 1999), which would lead to and underestimation of the true increase in blood flow if only changes in blood flow velocity were considered. In addition, Giller et al. (1993) found a change in BA diameter during moderate variation of MAP and . Our data may also be interpreted to support an increase in MCA diameter (i.e. vasodilatation) during hypercapnia since a ∼65% increase in ICA blood flow only translated to a ∼50% increase in MCA Vmean without a simultaneous increase in ECA blood flow.
However, there were no significant changes in ICA and VA diameters to changes in CO2. In support, in the study by Serrador et al. (2000) MCA diameter determined by magnetic resonance imaging (MRI) was unchanged during severe hypocapnia. These results are consistent with the concept that the bulk of cerebral CO2 reactivity occurs within small arterioles and capillaries, whereas large arteries are dedicated to blood distribution (Ainslie & Duffin, 2009). The resolution of ultrasonography used in the measurement of vessel diameter is an important issue. Our methods were sensitive enough to detect changes in ICA diameter of −0.2 mm during orthostatic stress (Sato et al. unpublished observations). Indeed, Eicke et al. (1999) showed an increase in CCA diameter of +0.4 mm with severe hypercapnia by means of ultrasonography. Therefore, we believe that the lack of change in vessel diameter observed in this study was not because of issues in image resolution. In reality, however, there are no strict borderlines between vessel types based on size, structure, or function, which change smoothly between arterial macro- and microcirculation (Ainslie & Duffin, 2009), thus complicating the diameter measurements.
In addition, cerebral CO2 reactivity measured in terms of ICA blood flow was not much different from reactivity calculated from MCA Vmean (ICA 3.18 ± 1.09% mmHg−1 vs. MCA 3.31 ± 0.87% mmHg−1) suggesting that measurement of MCA Vmean by TCD is an appropriate technique for experimental assessment of cerebral CO2 reactivity (Aaslid et al. 1989; Ainslie & Duffin, 2009).
A limitation of the present study is that we did not measure .
during steady-state CO2 administration has been shown to overestimate
systematically. Peebles et al. (2007) reported that
overestimated
during steady-state increase in CO2, consistent with several humans studies using CO2 rebreathing (Ainslie & Duffin, 2009); this overestimation results in a lower measure of cerebral CO2 reactivity. In the present study, to better reflect
(i.e. the stimulus for CBF alterations), we corrected our
data to
(estimated
) on the basis of established equations (Peebles et al. 2007). However, more importantly, the aim of the present study was to identify differences in cerebral CO2 reactivity between ICA, ECA and VA. It is unlikely that
was different between arteries in the brain during our protocol, so the relative differences we report between cerebral arteries were not affected by the estimation of
from
.
Due to technical limitations of ultrasonography, each condition was performed in two separate trials. However, haemodynamics responses between two trials were not significantly different during either hypocapnia or hypercapnia. Moreover, all tests were conducted on the same day for a single subject to avoid errors caused by day-to-day variations in CBF and cardiorespiratory variables. Furthermore, in order to measure BA Vmean, subjects shifted from the semi-recumbent to an upright seated position. It is known that posture affects CBF and CBF–CO2 reactivity (Mayberg et al. 1996). However, we suggest that conclusions drawn from the data would be unchanged even if we had measured BA Vmean in the semi-recumbent position because of a lower CO2 reactivity was observed in proximal VA blood flow as well.
Implications
Regional differences in cerebral CO2 reactivity could play an important role in some physiological situations (e.g. dynamic exercise, orthostatic stress, and heat stress). Indeed, we previously observed a correlation between and ICA blood flow during graded dynamic exercise, whereas there was no relationship between
and ECA or VA (Sato et al. 2011). Differences in cerebral CO2 reactivity in this study might be related to regional heterogeneity of extracranial blood flow during dynamic exercise. During exercise, the operating point of cerebral CO2 reactivity in MCA Vmean is enhanced (Rasmussen et al. 2006): however, it is unclear if similar changes occur in the vertebro-basilar circulation. Moreover, we observed that head-up tilt caused a significant decrease in ICA blood flow and
while VA blood flow did not respond to orthostatic stress (Sato et al. unpublished observation), perhaps indicating that preservation of blood flow in vertebro-basilar circulation may be advantageous for protecting regions of the brainstem with homeostatic function, i.e. respiratory and cardiovascular systems. Lower CO2 reactivity in the vertebro-basilar system may be important for maintaining central respiratory function because
in central chemoreceptors is regulated by
and blood flow to maintain breathing stability.
We found sex difference in cerebral CO2 reactivity in VA, even with a small number of subjects. Women subjects had higher cerebral CO2 reactivity in VA than in men (2.54 ± 0.93 vs. 1.67 ± 0.51% mmHg−1; Table 2). Previous studies demonstrate a highly significant sex-related difference in CO2-induced cerebral vasomotor reactivity (Kastrup et al. 1997), and suggest that women have a stronger vasodilatory response to changes in than men. The mechanisms and the biological significance of increased VA CO2 reactivity in women are unclear. Increased vasomotor reactivity in women may also reflect their increased susceptibility to migraine (Kastrup et al. 1997). However, in this study the phase of the menstrual cycle was not considered, so the effect of sex hormones, such as oestrogen, on CBF responses to hypo- and hypercapnia is unknown.
Although hypocapnia and hypercapnia are widely used for estimating cerebral perfusion reserve in patients with occlusive cerebrovascular disease, regional differences in vascular responses should be considered. Our study would support the notion that internal carotid circulation measurement is unlikely to reflect blood flow in the vertebro-basilar territories. Further investigations of regional differences in cerebrovascular hemodynamics may enhance our understanding of pathophysological conditions like orthostatic intolerance, migraine and stroke.
In summary, our study shows that cerebral CO2 reactivity in the vertebro-basilar circulation is lower than that in the internal carotid circulation, while CO2 reactivity in the external carotid circulation is much lower compared with two other cerebral arteries. These findings indicate a difference in cerebral CO2 reactivity between different circulatory areas in the brain and head, which may explain different CBF responses to physiological stress. Lower CO2 reactivity in the vertebro-basilar system may be beneficial for preserving blood flow to the medulla oblongata to maintain vital systemic functions, while higher CO2 reactivity in the internal carotid system may imply a larger tolerance for varied blood flow in the cerebral cortex.
Acknowledgments
We appreciate the time and effort spent by our volunteer subjects in the present study. We especially thank Hiroyuiki Yamamoto (GE Healthcare, Tokyo, Japan) for his expert technical assistance. This research was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports and Culture (grant no. 22300205 to T.S. and no. 21700704 to K.S.).
Glossary
- BA
basilar artery
- CBF
cerebral blood flow
- CCA
common carotid artery
- CV
coefficient of variation
- ECA
external carotid artery
- HR
heart rate
- ICA
internal carotid artery
- MAP
mean arterial pressure
- MCA
middle cerebral artery
- MRI
magnetic resonance imaging
- NO
nitric oxide
partial pressure of arterial carbon dioxide
end-tidal partial pressure of carbon dioxide
- TCD
transcranial Doppler
- VA
vertebral artery
- Vmean
mean blood flow velocity
Author contributions
K.S. contributed to the conception, design of the experiment, and drafted the article; T.S. contributed to conception, design of the experiment, and drafted the article; A.H. contributed to data collection, analysis and interpretation; A.O. contributed to data collection, analysis and interpretation; T.M. contributed to data collection, analysis and interpretation; A.W.S. contributed to drafting the article and revising it critically for intellectual content; S.O. contributed to the conception and design of the experiment, and drafted the article and revised it critically for intellectual content.
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