Regular aerobic exercise augments conduit vessel function (5,13). Interestingly, the improvement of vascular function has been observed in nonworking limbs, such as the forearm in response to leg cycling or walking (5,10,13,21). It has been supposed that the exercise-induced enhancement of vascular function could associate with an increase in blood flow and the elevated shear stress (9). Aerobic exercise induces an increase in mean blood flow even in nonworking limb (6–8,36,40). In addition, recent studies revealed that exercise changes a marked oscillatory blood flow pattern in the nonworking limb: there is antegrade blood flow during systole, followed by substantial retrograde diastolic flow (2,8,24). Furthermore, it has been suggested that changes in oscillatory blood flow pattern have important implications for the adaptation of vascular function observed with exercise training (11).
Recent studies have reported reductions in blood pressure (BP) at rest and during exercise after exercise in hypoxia (1,22,34). In addition, vascular function improved after aerobic exercise under hypoxic condition (26). From these results, it has been supposed that the aerobic exercise training in hypoxia may be useful to reduce cardiovascular risk factors (1). Blood flow pattern is tightly linked to the relationship between systemic perfusion pressure (upstream) and the “critical closing pressure” in the peripheral resistance vessels (downstream) (12,37). Exercise under systemic hypoxia is associated with augmented systolic function and systemic perfusion pressure (38). Also, it is predicted that a rise in sympathetic vasoconstrictor nerve activity during hypoxic exercise (18,31,35) should increase the critical closing pressure and peripheral vascular resistance (12,28). Based on these results, we hypothesized that oscillatory antegrade and retrograde blood flows to the nonworking limb would increase during incremental cycle exercise in hypoxia. Alternation of oscillatory blood flow pattern during aerobic exercise under hypoxic condition may be important modulators of the improvement on vascular function. However, to our knowledge, no studies have assessed changes in blood flow pattern in the nonworking limb during hypoxic exercise.
The purpose of present study, therefore, was to elucidate changes in mean blood flow and oscillatory blood flow patterns during cycling exercise under hypoxic condition. To accomplish this, we determined the changes in mean, antegrade, and retrograde blood flows to the upper limb during incremental leg cycling under normoxic and hypoxic conditions.
All were healthy males with no history of cardiorespiratory disease. Some subjects participated in moderate-intensity exercise a couple of times a week, but none of them were engaged in exercise training at high intensity. The subjects were informed of the experimental procedures and possible risks involved in the present study, and their written informed consent was obtained. The human research committee of the Research Center of Health, Physical Fitness and Sports, Nagoya University approved all procedures.
The subjects were first familiarized with the equipment to be used at a preliminary visit to the laboratory. During practice sessions, subjects were instructed to laterally extend both arms and were shown how to hold their arms during leg cycling using an electromechanically braked ergometer in a semirecumbent position (Aerobike 75XL III; Combi, Tokyo, Japan) (32,33). All subjects were asked to abstain from caffeine-containing beverages and to avoid strenuous exercise for 12 h before the experiment. The study was performed at least 2 h after a light meal.
Subjects reported to the laboratory on three additional occasions at the same time of day on three separate days. The exercise trials were performed at least 1 wk apart. All experiments were performed in an air-conditioned room maintained at a constant temperature (22°C–24°C). For the first and second visits, incremental exercise was performed while subjects breathed a normoxic or hypoxic gas mixture (normoxic and hypoxic trials). After the 30-min rest, subjects wore a facemask (5719 Hans Rudolph, Kansas City, MO), and inspired gas mixture was provided by a generator (YHS-310; YKS, Nara, Japan). First, cardiorespiratory and vascular parameters were measured for 5 min in normoxia (inspired oxygen fraction (FIO2) = 0.21; rest 1). After this period, the inspiratory gas mixture was either maintained or switched to a hypoxic (FIO2 = 0.12) gas mixture. The order of gas mixture (normoxia or hypoxia) was randomly assigned, and the subjects were blinded to this procedure. The subjects were exposed to the respective gas mixtures for 10 min at rest before incremental exercise (rest 2). Leg cycling exercises began while subjects were breathing a normoxic or hypoxic gas mixture. Exercise began at an initial power output of 30 W, and the workload was increased by 30 W every 2 min until exhaustion. The pedaling rate was kept constant at 60 rpm with the aid of a metronome, and exhaustion was defined as the point when they could not maintain a pedaling rate at 60 rpm. To affirm the reproducibility of experimental data, a third trial was performed, and all methods were performed using the same protocol while subjects breathed a normoxic (FIO2 = 0.21) gas mixture.
Respiratory and cardiovascular variables and myoelectrical activity
For breath-by-breath measurement, respiratory parameters at rest and during exercise were determined with the same online system that was used in our previous studies (19,20). The gas fractions were analyzed by a mass spectrometer (ARCO-1000; Arco System, Chiba, Japan). Inspired and expired gas volumes were measured by a Fleisch pneumotachometer (PN-230; Arco System). Breath-by-breath data were analyzed continuously using customized software on a computer to calculate oxygen uptake (V˙O2), carbon dioxide output (V˙CO2), expiratory minute ventilation (V˙E), and respiratory exchange ratio (RER). Respiratory variables were averaged during a 30-s sampling interval. The highest value obtained for V˙O2 during exercise was used as the peak oxygen uptake (V˙O2peak). An ECG was also measured using a three-lead arrangement throughout the experiment, and HR was calculated from every R-R interval obtained from the ECG. Arterial oxygen saturation (SpO2) was measured by a pulse oximeter (Biox 3740; Ohmeda, Madison, WI) placed on the tip of the right forefinger.
EMG was measured with active electrodes to verify the lack of muscular movement from the radial and ulnar muscles (40) (brachioradialis muscle and flexor carpi ulnaris muscle, respectively) on the right forearm. The skin surface was cleaned with alcohol and rubbed with sand particles. Surface bipolar electrodes (Ag–AgCl, 6-mm contact diameter, 10-mm interelectrode distance) were placed on the muscle. The EMG signals were connected to an amplifier (input impedance = 5.1 MΩ, gain = 1000×, common-mode rejection ratio >110 dB), with a bandwidth of 5 to 500 Hz (FA-DL-140 sensor and FA-DL-720 8-main amplifier unit, 4 assist, Tokyo, Japan).
The ECG, SpO2, and EMG signals were sampled at a frequency of 1000 Hz through an analog-to-digital converter (Power Lab 16/s; ADInstruments Co., Ltd., Bella Vista, New South Wales, Australia) and were stored in a computer (MT7000; Epson, Nagano, Japan). To determine arm muscle activity, the EMG RMS for brachioradialis and flexor carpi ulnaris muscles was calculated using a commercially available software (Chart ver. 5; ADInstruments). The cardiorespiratory parameters at rest were averaged during the last 1 min at rest 1 and rest 2. During exercise, the parameters were reported as time averages of the last 30 s at each workload. Arterial BP was taken in the left arm using an automated BP unit at 1-min intervals (Colin STBP-780; Colin Medical Instruments, San Antonio, TX) (39). Before measurement, pressure values were confirmed using a mercury sphygmomanometer, which was joined to the pressure line using a Y-connector (18,39). The sound signal was synchronized to the ECG-R wave, and a detection algorithm was used to determine both systolic and diastolic BP (SBP and DBP). The elevation of HR during exercise causes a change in the ratio between the systole and diastole period of the cardiac cycle (25,29). Thus, we calculated the MBP from DBP, HR, and pulse pressure (PP): MBP = DBP + [0.33 + (HR × 0.0012)] × PP (29).
Brachial blood flow
The blood flow in the brachial artery was measured using a Doppler ultrasound system (LOGIQ 5 PRO; GE-Yokogawa Medical Systems, Tokyo, Japan) equipped with an 8.8-MHz linear transducer (GE-Yokogawa Medical Systems). Brachial arterial blood flow was measured in the distal third of the right arm. The anatomical sites at which ultrasound probes were placed were standardized. Arterial diameter and blood flow velocity were captured simultaneously. We first used brightness mode (B-mode) to measure the diameter of the brachial artery in the longitudinal section. The systolic and diastolic diameters were measured every 2 s (averaged 3 points each), and the values were averaged within every 10 s. The Doppler velocity spectrum was identified by pulsed-wave Doppler mode (PW-mode). The time-averaged “mean” blood flow velocity obtained during the automatic calculation mode (PW-mode) was defined as the mean blood flow velocity (cm·s−1). We obtained the time-averaged positive and negative “mean” blood flow velocities separately using automatic calculations to provide a global index of the velocity of antegrade (positive) and retrograde (negative) blood flows. Blood flow velocity measurements were performed with an insonation angle <60° and were corrected for the insonation angle (40). The sample volume gate was adjusted to cover the width of the vessel diameter. From the cross-sectional area of the brachial artery (cm2) and the time-averaged mean blood flow velocity (cm·s−1), the time-averaged blood flow was calculated: blood flow (mL·min−1) = [π × (diameter / 2)2 × mean blood flow velocity × 60] (28,37). Antegrade blood flow was calculated by time-averaged antegrade blood velocity and systolic diameter, and retrograde blood flow was derived from time-averaged retrograde blood velocity and diastolic diameter. Mean blood flow was calculated by subtracting retrograde blood flow from antegrade blood flow. Shear rate (s−1) was defined as: 4 × blood flow velocity / diameter (28,37). Antegrade and retrograde blood flow velocities and systolic and diastolic diameters were used to calculate antegrade and retrograde shear rates (37). Mean shear rate was calculated by subtracting retrograde shear rate from antegrade shear rate. Blood flow parameters at rest were averaged during the last 1 min of each session (rest 1 and rest 2), and variables during exercise were averaged during the last 30 s in each workload.
Reproducibility of the experimental data was assessed using coefficients of variation (CV) from repeated exercise trials in normoxia on separate visits to the laboratory.
All values are expressed mean ± SE. For all data, the assumption of normal distribution was verified using a Kolmogorov–Smirnov test, and the data were found to be normally distributed. To determine the behavior of observed variables during exercise in normoxia and hypoxia, a two-way ANOVA with repeated measures was performed. The trial (normoxia vs hypoxia) was one factor considered in the analysis, with workload as the second factor. Dunnett test was used to determine differences between baseline data and each workload. Comparison of parameters in normoxic and hypoxic trials was achieved using Bonferroni test. SPSS (version 11.5; SPSS, Inc., Tokyo, Japan) and StatView (version 5.0; SAS Institute, Tokyo, Japan) statistical packages were used for these analyses. Statistical significance was set at P < 0.05.
Physical characteristics of subjects
Eight males participated in this study. The mean ± SE for age, height, and body mass were 21.3 ± 0.5 yr, 173.8 ± 1.6 cm, and 70.7 ± 2.2 kg, respectively.
The CV for blood velocity and vessel diameter during incremental exercise were limited to data collected at 210 W, because one subject could not achieve 240 W of exercise during one testing session. Between-day CV were 3.1% for V˙O2peak, 17.8% and 1.5% at rest 1, and 7.0% and 2.0% at 210 W for blood velocity and diameter, respectively.
Baseline descriptive data
No differences in all variables at rest 1 were found between the normoxic and hypoxic trials. Statistical comparisons of variables between normoxic and hypoxic trials during submaximal exercise were limited to data collected at 150 W and at exhaustion, because one subject could not achieve 180 W of exercise during the hypoxic trial. The V˙O2peak and peak workload in the hypoxic trial were lower than those in the normoxic trial (normoxia vs hypoxia, V˙O2peak = 40.5 ± 1.5 vs 28.7 ± 1.2 mL·kg−1·min−1, and peak workload = 251.3 ± 11.3 vs 206.3 ± 8.9 W, P < 0.05). In addition, time to exhaustion was shorter in hypoxia than in normoxia (normoxia vs hypoxia, 16.6 ± 0.8 vs 13.2 ± 0.5 min, P < 0.05). The RMS for brachioradialis and flexor carpi ulnaris muscles showed 0.0 ± 0.0 mV throughout all experiments; thus, no myoelectrical activity was detected in the upper limb during leg cycle exercise.
Respiratory and cardiovascular variables
At rest 2, HR and RER were increased and SpO2 was decreased in hypoxia from rest 1 (P < 0.05; Table 1).
V˙E, V˙CO2, RER, HR, and SBP during submaximal exercise increased in both trials (P < 0.05), whereas DBP did not (Table 1). During exercise, a two-way ANOVA revealed a main effect of trial on respiratory and cardiovascular variables (P < 0.05), except MBP and DBP. At exhaustion, V˙O2, V˙CO2, and SpO2 were lower (P < 0.05), and RER was higher (P < 0.05) under hypoxia compared with normoxia.
Blood flow and vascular variables
Resting blood flow, shear rate, and vascular variables did not change markedly from rest 1 under hypoxic condition (rest 2; Table 2).
Retrograde blood velocity has main effects of trial and workload, and the change in retrograde blood velocity was greater in hypoxia as compared with normoxia (P < 0.05; Table 2). A two-way ANOVA revealed only one main effects of workload on systolic and diastolic diameters (P < 0.05), and those parameters decreased during exercise under both conditions (P < 0.05; Table 2).
There was only one main effect of workload on the mean blood flow, mean shear rate, and antegrade shear rate (P < 0.05). Mean blood flow and shear rate decreased during exercise at 30 to 120 W in the normoxic trial (P < 0.05), and those returned to preexercise levels at 150 to 210 W (Figs. 1A and 2A). Mean blood flow and shear rate during submaximal hypoxic exercise decreased below the resting value until exhaustion (P < 0.05). On the other hand, a two-way ANOVA revealed significant main effects of workload and trial on antegrade and retrograde blood flows and retrograde shear rate (P < 0.05). Antegrade and retrograde blood flows and retrograde shear rate were enhanced with increasing workload under both conditions (P < 0.05). Antegrade blood flow at 30, 60, and 120 W in hypoxia were higher than those in normoxia (P < 0.05; Fig. 1B). Antegrade shear rate during submaximal hypoxic exercise tended to be higher (P = 0.08) than during normoxic exercise (Fig. 2B), but it was not statistically significant. Retrograde blood flow and shear rate were also higher during submaximal hypoxic exercise at 30 to 150 W and at exhaustion compared with normoxic exercise (P < 0.05; Figs. 1C and 2C).
In this study, we obtained the following major findings: 1) mean blood flow to the nonworking limb during submaximal normoxic and hypoxic exercises decreased below the resting value, but the magnitude of the reduction in mean blood flow was not different between two exercises and 2) antegrade and retrograde blood flows in the inactive limb were greater during hypoxic exercise than during normoxic exercise. To the best of our knowledge, this is the first study to clarify mean, antegrade, and retrograde blood flows to the inactive limb during submaximal hypoxic exercise to exhaustion.
Mean blood flow in the resting upper limb during normoxic exercise exhibited a biphasic response pattern, i.e., an initial decline relative to the baseline flow, followed by a gradual increase. On the other hand, decreased mean blood flow during hypoxic exercise remained until exhaustion, but the extent of this decrease in blood flow did not differ from that during normoxic exercise (Fig. 1A). Changes in mean blood flow in the nonworking limb depend not only on exercise intensity but also on exercise duration (16,45). It was reported that exercise duration was related to changes in internal temperature and that skin blood flow was increased in proportion to the increase in internal temperature during leg cycling exercise (15,27). In the present study, time to exhaustion was longer in normoxia than in hypoxia (P < 0.05). Thus, it is speculated that the return (increase) of mean blood flow to preexercise levels during normoxic exercise may result from an increase in skin blood flow in the forearm (4,27,36). Also, mean blood flow in normoxia tended to decrease at exhaustion (Fig. 1A), and this result correspond with the data of previous studies (30,44), which may indicate a alternation of mean blood flow at exhaustion is due to change in skin blood flow.
Several studies have identified a change in blood flow patterns during exercise under normoxic condition (7,8,41). The changes in antegrade and retrograde blood flows during normoxic exercise in this study were consistent with previous studies (7,8). In addition, in the present study, acute hypoxia had a significant effect on the magnitude of antegrade and retrograde blood flows during submaximal exercise. The extent of increase in antegrade and retrograde blood flows was greater during exercise in hypoxia than that in normoxia (Figs. 1B and C). The observed differences of blood flow pattern between normoxia and hypoxia may be related to the differences in pressure gradients between systemic perfusion pressure (upstream) and the critical closing pressure (downstream) (12,37). Exercise under hypoxic condition induced an increase in systemic perfusion pressure during systole; HR and SBP during hypoxic exercise were significantly higher than those during normoxic exercise (Table 1). In addition, hypoxia leads to an augmentation of left ventricular contractile force (3). Therefore, the greater antegrade blood flow during exercise in hypoxia than in normoxia may be due to the rise in the systemic perfusion pressure in hypoxia. However, DBP was not significantly different between two conditions, suggesting that there is no difference in systemic perfusion pressure during diastole. It was indicated that an increase in the sympathetic tone during exercise in hypoxia was greater compared with that in normoxia (18,31,35). The increased muscle sympathetic nerve activity enhanced the retrograde blood flow (28). In this study, the downstream resistance during exercise in hypoxia would be greater than that in normoxia, and this might induce higher retrograde blood flow in hypoxia. In addition, other candidate factors may also contribute to the change of antegrade and retrograde blood flows, such as stroke volume, HR, compliance (capacitance) of the vessel, varying reflex pathway involved, and redistribution of regional blood flow (28).
It is supposed that the exercise-induced enhancement of vascular function could associate with increases in blood flow and the elevated shear stress (9). In the present study, mean blood flow and shear rate during hypoxic exercise decreased below the resting value and remained until exhaustion (Figs. 1A and 2A). Thus, it is conceivable that hypoxic exercise does not induce the beneficial effect on vascular function. However, when we look at the changes in blood flow pattern, the magnitude of antegrade and retrograde blood flows and shear rates during exercise in hypoxia was greater than that in normoxia. It has been suggested that the magnitudes of antegrade blood flow and shear rate are associated with an improvement in endothelial function (11,42,43). Furthermore, substantial antegrade/retrograde oscillation may present more potent stimulus to endothelial cell than increases in antegrade flow alone (8). From these, it is likely that hypoxic exercise augments vascular function. On the other hand, increases in retrograde blood flow and shear rate, which is induced by cuff inflation, caused a dose-dependent attenuation of endothelial function (41). However, another study suggested that increases in antegrade shear might prevent any impairment in endothelial function associated with unopposed increases in retrograde flow and shear (42). Further investigation is needed to clarify whether higher antegrade and retrograde blood flows and shear rates during hypoxic exercise are related to vascular function.
There are potential limitations that should be mentioned. A lot of studies have used constant load exercise with the same duration, whereas we used incremental exercise protocol. Accordingly, time to exhaustion was different between normoxic and hypoxic exercises. The difference of exercise duration affects the change in skin blood flow (15,27) as mentioned previously, and thus, the differences in the skin blood flow would affect the changes in blood flow during submaximal exercise.
In the present study, the variables between normoxia and hypoxia were compared at the same absolute workload. Dynamic leg exercise under hypoxic condition precipitates reduced maximal exercise capacity, that is, reduced peak workload and V˙O2peak, which leads to a shift in the given absolute workload to a higher relative exercise intensity (17,23). Different relative work intensities are expected to influence the rate of increase in metabolism (14). Therefore, a comparison of blood flow pattern during exercise between normoxia and hypoxia at the same relative exercise intensity would be needed in future study.
In summary, we did not find a significant difference in mean blood flow in the brachial artery of the inactive limb during leg cycling exercise between normoxia and hypoxia. In contrast, hypoxic exercise caused a greater change in oscillatory blood flow pattern, and antegrade and retrograde blood flows were greater in hypoxia than in normoxia. These results indicate that hypoxia has a significant effect on blood flow patterns in the nonworking limb during cycling exercise.
This study was supported by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports, and Culture (grant No. 22700649).
The authors thank Dr. K Sato and Dr. A Ooue (Japan Women’s College of Physical Education) for informative discussions of blood flow data.
There is no conflict of interest with any organization regarding the result of this article.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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