Exercise of sufficient duration and intensity can lead to postexercise hypotension (PEH). PEH, a well-documented phenomena, is characterized by reductions in sympathetic nerve activity (SNA) (6,9,14) coupled with alterations in vascular vasoconstrictor responsiveness (9). There are likely local metabolic factors contributing to the peripheral vasodilation during PEH, including an H2-receptor-mediated vasodilation (19). The overall result is a postexercise decrease in systemic vascular resistance that cannot be completely compensated for by increases in cardiac output (8,9,12). In addition, central neural alterations within the arterial baroreflex network are known to occur, such that it is temporarily reset to a lower operating point (5,9). This effectively reduces sympathetic outflow compared with preexercise levels. The central neural mechanisms contributing to PEH seem to involve the modulation barosensitive neurons within the medulla, involving the nucleus tractus solitarius (3) and the rostral ventrolateral medulla (rVLM) (11). There is also decreased neural activity within higher brain centers, including the insular cortex (IC) (24).
Regions of the IC, a cerebral cortical site of autonomic regulation, show reduced neural activity after exercise, but only when PEH is present (24). The IC, via neural connections through the lateral hypothalamic area (LHA) and rVLM (2), is capable of modulating SNA (2,22). Cechetto and Saper (2) have used cobalt injection at the LHA to block sympathetic responses evoked from stimulation of the posterior IC in rats. Because SNA is typically reduced during PEH, this suggests that reductions in IC activity after exercise may contribute to PEH. However, ppenheimer (29) have reported changes in neuronal activity within the IC in response to pharmacologically induced blood pressure (BP) changes in the rat. More specifically, they have noted that sympathoexcitatory neurons showed increased activity in response to sodium nitroprusside (SNP)-induced BP decreases, whereas sympathoinhibitory wed a decreased activity in response to the same stimulus. Thus, it is not clear whether postexercise changes in patterns of IC activity are actually exercise induced (e.g., prior exercise produces a decrease in neural activity) or whether they are simply responding to BP decreases during PEH, similar to the pharmacologically induced changes (29).
The purpose of this investigation was to establish whether the decreases in IC activity during PEH were caused by prior exercise or by decreases in BP. Patterns of regional IC activation in response to hypotension produced by exercise (i.e., PEH) were compared with an SNP-induced hypotension of similar magnitude. During PEH, it has been reported that heart rate (HR) is elevated and that SNA is decreased below baseline levels (6,9). On the other hand, SNP-induced BP decreases lead to increases in both HR and SNA (6). On the basis of these prior findings and the role of the IC in modulating SNA, it was hypothesized that regions of the IC would show decreased neural activity (below baseline levels) during PEH and would show increased neural activity during the SNP-induced hypotension. In addition, Floras et al. (6) have demonstrated that a cold pressor (CP) stimulus could be used during PEH to increase BP via increased SNA. Because a CP stimulus can produce activation of the IC (17), it was further hypothesized that a CP administered during PEH would increase IC activity and elevate BP. The regional cerebral blood flow (rCBF) distributions were assessed for several cerebral cortical regions of interest (ROI), using single-photon emission computed tomography (SPECT) as an index of changes in neuronal activity (21).
Ten subjects volunteered to participate in this experiment. All participants provided written informed consent before participating in this study, which was approved by the University of Texas Southwestern Medical Center institutional review board and radiation safety committee. The study group included five women and five men (aged 25 ± 6 yr). All study participants were healthy and normotensive (resting BP < 140/90 mm Hg), and none reported any history of neurological or cardiovascular disease. Further, none reported being involved in a regular exercise program, but all subjects performed some type of aerobic exercise (e.g., walking, stationary cycling) at least 1 or 2 d·wk−1. All had abstained from exercise and caffeine for at least 12 h before testing, and none were taking any prescription medications at the time of the investigation. Each participant completed three tests, performed in a random order on separate days. Additionally, four of the subjects (two men and two women) also completed a fourth test involving the CP stimulus. They were familiarized with all procedures and measurements before any data collection. Poststudy medical examination of individual magnetic resonance scans showed no significant abnormalities.
Instrumentation and procedures.
The primary goal of this investigation was to compare patterns of rCBF during PEH and SNP-induced hypotension. Testing involved three different trials performed in a random order on different days. The trials included a nonexercise control, an exercise trial, and a nonexercise SNP trial. After familiarization procedures for each study were completed, a venipuncture was made and capped with an injectable site to facilitate the innocuous administration of a retained blood flow tracer. For the nonexercise control (baseline) condition, the participants remained upright for 30 min of walking and standing in the laboratory. After walking/standing, each subject was placed in a supine position with the right hand positioned at the level of the heart for BP assessment, using a Finapres (Ohmeda 2300, Madison, WI) as verified with standard upper-arm auscultation. Subjects were asked to remain quiet with their eyes closed so that they would be unaware of the time of the injection of the brain blood flow tracer, which was injected after 10 min of supine rest. HR and BP data were recorded every 2 min.
For the PEH condition, a moderate exercise intensity was used to elicit a postexercise hypotensive response. Participants jogged (and one walked with an 8% incline) on a motorized treadmill (Quinton, Model 8500) for 20 min at approximately 60-70% of their maximal HR reserve using the American College of Sports Medicine training HR index for the HR reserve method (7). All subjects rated the exercise at 14-15 Borg units by the 20th minute of exercise using the 6-20 scale (1). Exercise was preceded by a 5-min walking warm-up and was followed by a 5-min walking cool-down (total time, 30 min). After exercise cool-down, participants were again placed on the bed in a supine position. Cardiovascular measurements were recorded at 2-min intervals, and injection of the retained blood flow tracer was initiated at minute 10 after exercise.
For the nonexercise SNP condition, the participants remained upright for 30 min of walking and standing in the laboratory, similar to the control trial. Subjects were again placed in a supine position, with HR and BP recorded continuously (data reported at each 2-min interval). The SNP was administered approximately 15-20 s before the SPECT tracer was injected at minute 10. The SNP (50 mixed in 250 mL of normal saline at a concentration of 1 mL = 1 mc·kg−1, using each individual's body weight. To elicit the appropriate decrease in BP, a dose of 0.7 mL was injected in the i.v. and was flushed with 10 mL of normal saline. The average dose was 51.4 ± 9.6 µg. This dose produced an immediate fall in BP of 8-13 mm Hg in all but one subject. One subject had no BP drop in response to the first SNP dose; thus, a second dose was administered, yielding a decrease of 14 mm Hg. None of the subjects reported any adverse responses after the SNP dose.
An additional test was performed in four subjects. Exercise procedures were identical to those of the prior exercise trial. After exercise, subjects were placed in a supine position, and at postexercise minute 10, they were administered a CP test. The left hand was immersed to the wrist into an ice and water slurry (34-36°F) for 120 s. The SPECT tracer was injected at minute 10 to allow for a temporal comparison with the other conditions. HR and BP were monitored continuously using the Finapres (data reported at each 2-min interval).
To determine the rCBF distributions during each testing condition, 20 mCi of freshly reconstituted Tc-99m ECD (Neurolite, DuPont Pharma, Billerica, MA) was injected intravenously. This retained brain blood flow tracer is a photon emitter with a physical half-life of 6 h. Increases or decreases in rCBF to a particular region of the brain are related to increases or decreases in neuronal activity and subsequently lead to changes in the amount of radioactivity recorded from that specific region compared with a baseline condition (21). The retained brain blood flow tracer uptake is rapid and is basically completed within 2 min of injection. Thus, the reported rCBF distributions represent a 2-min window of time. Although PEH can last for hours, the time frame for injection at 10-12 min postexercise was selected to correspond with reported times for peak changes in postexercise BP between 5 and 15 min (15,16). During this time, participants were asked to remain quiet with their eyes closed. A technician administered the blood flow tracer and flushed the catheter with normal saline. Participants were unaware of the exact time of injection and reported no noticeable side effects. With the tracer uptake completed and bound in brain tissue, subjects rested for an additional 20 min before rCBF was assessed. All subjects were taken to the SPECT camera room, and scanning was completed within 50 min of injection for all subjects. Brain-scanning procedures have been previously reported in detail (25).
Each individual's brain images were aligned in three dimensions by computer, using an automated volume coregistration algorithm widely used for positron emission tomography coregistration (27). Once the SPECT scans for a given subject were coregistered, normalization of total radioactive count variability was obtained by rescaling each volume so that total counts were equal for all volumes. The SPECT-MRI coregistration for each individual was performed using an interactive coregistration algorithm (18) implemented on a computer workstation. After the SPECT voxel size was made to match the MRI voxel size, the absolute and percentage count differences for each pixel were obtained between scans. These differences were then displayed, for each selected slice within the volume, as a color overlay superimposed on the MRI.
Specific brain regions and structures were located using the coregistered magnetic resonance scans as an anatomic reference. Using the computer, ROI were drawn around these areas as seen on the MRI slice. This procedure was repeated on contiguous transaxial slices until the entire brain region/structure had been assessed across all slices. The number of 1.5-mm slices assessed varied by specific region and subject but was consistent for all studies within subjects.
On the basis of findings from prior human studies involving the IC (4,13,20,23,24,26) and the spatial resolution of the SPECT methodology, the relatively large insular regions were divided into smaller divisions for analysis. The right and left insular regions were further subdivided into four equal quadrants according to each individual's anterior-posterior midline (rostral- caudal) through the insula and superior-inferior (dorsal-ventral) midline through the insula. The terminology selected best identifies the specific regions assessed using standard anatomic planes of reference for human study. Further, these regions are of adequate size such that the spatial resolution of the methodology would not be compromised.
The insular quadrants served as ROI for analysis and were termed anterior superior (rostral dorsal), anterior inferior (rostral ventral), posterior superior (caudal dorsal), and posterior inferior (caudal ventral) for the right and left sides, as used previously (24). Similarly, ROI were formed from the two halves of the thalamus divided into two equal superior (dorsal) and inferior (ventral) regions. Other regions/structures analyzed, with corresponding Brodmann's areas (BA) approximated when applicable, included the leg sensorimotor regions (BA 1-4), anterior cingulate cortex (BA 24 and 32), a white-matter region encompassing the anterior corpus callosum, and a gray-matter region (BA 44 and 45) involved in speech (not expected to be affected by the magnitude of BP changes).
The total number of radioactive SPECT counts within each ROI were then compared between conditions, for each subject, as absolute counts and as a percent change from the baseline condition. The SPECT data were corrected using white-matter rCBF from the baseline condition to negate the possibility that differences in global cerebral blood flow between conditions might account for any observed rCBF changes. During the processing and rCBF data assessment, data were coded such that the researchers performing these analyses were blinded to subject identity and order of experimental conditions.
A univariate analysis was used to assess normality. The data were normally distributed, and a repeated-measures ANOVA was used to compare differences in dependent variables across the baseline period and the two hypotensive periods (and CP test for N = 4) during the time frame when rCBF was assessed using the raw counts for each ROI. A Bonferroni correction was used to account for multiple comparisons. If significance was detected, a Tukey post hoc analysis was performed to determine specific differences for pairwise comparisons. The alpha level was set at P < 0.05 for all analyses.
Data (mean ± SD) for systolic BP (SBP), diastolic BP (DBP), and HR are reported across conditions (baseline, PEH, SNP, and PEH + CP), with data being compared during the periods when rCBF assessments were made (Table 1). There were significant decreases in both SBP (−8 ± 3 mm Hg) and DBP (−7 ± 2 mm Hg) from baseline during PEH and also during SNP (SBP = −6 ± 2 mm Hg, DBP = −11 ± 3 mm Hg). There was no difference in BP responses between the PEH and SNP conditions. The HR was elevated during PEH (+17 ± 6 mm Hg) and during SNP (+19 ± 5 mm Hg), with no difference between PEH and SNP (P < 0.05). During PEH + CP, SBP increased 16 ± 5 mm Hg, DBP increased 8 ± 3 mm Hg, and HR increased 21 ± 7 bpm.
To show temporal responses across conditions, mean BP (MBP) data (mean ± SD) are presented in Figure 1. There were significant decreases (P < 0.05) in MBP from baseline for both PEH (−7 ± 2 mm Hg) and SNP (−9 ± 3 mm Hg), but there were no differences in BP responses between PEH and SNP. During PEH + CP, the MBP was elevated 11 ± 3 mm Hg above the baseline level.
For the two exercise conditions, subjects reported rating of perceived exertion values of 15 ± 2 units with an HR of 148 ± 12 bpm during the last minute of exercise. For the four subjects performing the additional CP test, exercise rating of perceived exertion (15 ± 2 units) and HR (152 ± 10 bpm) were similar to those from the initial exercise test.
In making comparisons of rCBF, statistical analyses were performed on raw counts (percent changes are also reported in Table 2) to allow for comparison with other related studies; changes in rCBF are shown for specific brain regions after exercise during PEH and during SNP-induced hypotension. The rCBF activity shown corresponds to the 10- to 12-min time period data reported for each condition in Table 1 and the rCBF data section of Figure 1. There were significant differences (P < 0.05) between the PEH and SNP-induced hypotension conditions for the following regions assessed: leg sensorimotor area, anterior cingulate cortex, right inferior thalamus, left inferior thalamus, right inferior anterior IC, right inferior posterior IC, and left inferior anterior IC. In each case, PEH elicited a decrease in rCBF, whereas SNP produced an increase (or no change) in these same regions; these differences can be seen in Figure 2. Additionally, Figure 3 shows data for subjects undergoing the PEH + CP condition. Compared with the PEH condition, the CP produced elevated activity in the right inferior thalamus (from −8 ± 2 to +2 ± 2%), left inferior thalamus (from −10 ± 2 to +3 ± 2%), right inferior anterior IC (from −9 ± 3 to +2 ± 2%), right inferior posterior IC (from −10 ± 3 to +5 ± 2%), and left inferior anterior IC (−8 ± 3 to +5 ± 2%).
Patterns of regional IC activity in response to the hypotension produced after exercise were compared with an SNP-induced hypotension of similar magnitude. The main finding was that there were specific regions of the IC with reduced rCBF (having decreased neural activity below baseline) after exercise, yet some of these same regions showed increases (or no change) in neural activity during the SNP-induced hypotension. Because the BP decreases were similar between the PEH and SNP conditions, it seems that moderate-intensity aerobic exercise is capable of temporarily decreasing or depressing neural activity within the IC (and other cortical regions). Consistent with prior work, a decrease in brain activity has been reported after exercise, but only when PEH was present (24). Likewise, the increased IC activation with SNP-induced hypotension is consistent with findings from Zhang and Oppenheimer (29) showing that sympathoexcitatory neurons, which exist in greater numbers within the IC, respond with increased neural activity during SNP-induced BP decreases in the rat. Additionally, in agreement with the findings of Floras et al. (6), the PEH was prevented (or reversed) when a CP stimulus was used. The CP stimulus, when administered during PEH, increased thalamic and IC activation in the same regions showing decreases after exercise. This further suggests that IC regions with depressed neural activity after exercise may be involved in postexercise BP modulation.
Whereas present data show that exercise may be involved in altering neural activity within regions of BP modulation, the finding of decreased cortical activity after exercise has been reported (24,28). Using transcranial magnetic stimulation, Zanette et al. (28) have observed depressed cortical activity after small-muscle exercise. Although they have not reported BP responses, they have shown that the specific task-related regions of brain activated during exercise demonstrated decreased excitability after exercise. In other words, the regions of the brain showing greater activation during a task were more likely to show depressed neural activity during recovery. Although specific mechanisms underlying exercise-related cortical depression remain undefined, current data support this concept.
There were postexercise decreases in leg sensorimotor areas and regions of the thalamus and the IC after moderate-intensity treadmill running, consistent with prior studies (24). Interestingly, Ichiyama et al. (10) have reported that contraction-sensitive neurons within the IC show a decreased discharge in response to contraction. The IC also can be activated during exercise, with the magnitude of activation being related to the intensity of exercise (25). Decreases in IC activity after exercise also seem to be related to the exercise intensity (24). It is likely that exercise and/or muscle contraction may have a differential effect on populations of contraction-sensitive and BP-sensitive neurons within the IC, and there may be interactions between these groups of neurons. However, it is not clear whether contraction-sensitive neurons play a role in the postexercise (i.e., resting) BP response.
The IC serves as a cerebral cortical site of autonomic integration (2,20,22) and represents a source of sympathetic outflow (2) with direct projections to the LHA, which, in turn, synapse with the RVLM. Because the RVLM is critical in modulating sympathetic outflow, this suggests that changes in neural activity within the IC are likely capable of altering sympathetic outflow in humans, as shown by Cechetto and Saper (2) in rats. Although decreases in RVLM neuronal activity have been shown to contribute to PEH in rats (11), the spatial resolution of the SPECT technique does not allow us to determine whether there were concomitant decreases in neural activity within the human RVLM. However, it is very likely that neural activity was lower in both the IC and RVLM, because SNA is reduced during PEH (6,9,14).
Because the IC plays a role in modulating SNA, at least in animals, one would expect a consistent pattern of response for key regions related to changes in SNA. An SNP-induced hypotension, which increases SNA (6), activated the right and left anterior inferior insular regions as well as the right and left inferior thalamic regions. Floras et al. (6) report that a CP test administered during the period of PEH served to increase SNA and restore BP. In the four subjects who performed the CP test during PEH, all showed a significant increase in BP and also increases in the right and left anterior inferior insular regions and the right and left inferior thalamic regions. These same regions showed increased activity in response to postexercise circulatory occlusion (24), which traps muscle metabolites and stimulates increases in SNA and BP. Lastly, there is decreased activity in the right and left anterior inferior insular regions and the right and left inferior thalamic regions during PEH. Taken together, the animal and human evidence support our contention that an exercise-induced decrease in neural activity within specific regions of the IC most likely contributes to the neural component of PEH, involving decreases in SNA.
The cerebral cortical regions identified in this study may not be inclusive of all brain regions involved in postexercise rCBF changes, because the regions were preselected on the basis of prior data showing their involvement in BP modulation. Additionally, the spatial limitations of the SPECT technique (~10 mm) do not allow us to confidently assess smaller regions that may also play an important role in cardiovascular regulation, such as specific nuclei of the thalamus or other subcortical structures. The rCBF distributions reported reflect changes from the baseline or control condition, but they do not define the specific type of neural activity (i.e., excitatory or inhibitory) associated with the rCBF changes. The rCBF changes were intentionally assessed during a time period when the PEH response was near its nadir (15,16) and should not be extrapolated beyond this time point. Changes in PCO2 that can affect global CBF were not directly measured. However, assessment of white-matter blood flow, which is reflective of global cerebral blood flow, was not significantly different from baseline conditions, nor did it differ across conditions during the rCBF testing phase. Also, the potential influence of postexercise peripheral vasodilation cannot be discounted. Although the study hypothesis was supported, this human study alone cannot provide a definitive cause-and-effect relationship for exercise and IC activity. However, when taken together with prior studies, these data do provide a strong case to support the association between exercise and the IC.
Data show that there are exercise-induced rCBF reductions within specific regions of the IC involved in BP modulation. These regions of the IC that have been found to have reduced rCBF during PEH also have neural connections to brainstem regions of cardiovascular integration (2,21). Although these findings cannot define specific mechanisms of interaction between cerebral cortical regions and the brainstem nuclei involved in PEH (3,10), they do provide evidence that higher brain regions with the capacity for modulation of SNA can be altered after moderate-intensity exercise. Further, the specific mechanisms responsible for this exercise-related cortical depression have not been defined. Current findings suggest that single bouts of moderate-intensity exercise can lead to a temporary depression of neural activity within some regions of the IC and that this decrease in neural activity may govern, at least in part, the neural component involved in the modulation of BP after exercise.
We thank the subjects for their cooperation, and we also would like to acknowledge the expert technical assistance of Shawn Shotzman, Amber Shepherd, and Rhea Anne Campbell, as well as the cooperation of Zale Lipshy University Hospital, Dallas, TX.
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