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1Department of Kinesiology, University of Waterloo, Waterloo; and 2School of Kinesiology, University of Western Ontario, London, Ontario, Canada
Submitted 21 July 2005 ; accepted in final form 17 October 2005
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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endothelium; shear stress; muscle chemoreflex; cold pressor test; mental stress
The various models of elevated SNA have different effects on mean arterial blood pressure (MAP) and reactive hyperemia. MAP increases but to different extents with the mental arithmetic test and the cold pressor test (24), whereas it is generally unaltered by lower body suction (3). In this study we utilized these three methods to elevate SNA as well as the activation of the muscle chemoreflex by sustained circulatory occlusion after muscle contraction (36). To account for differences in MAP response and in brachial artery diameter with these manipulations, we incorporated different durations of forearm occlusion before cuff release in an attempt to equalize the shear stress stimulus on the vascular endothelium. It was hypothesized that acute increases in SNA would cause equal impairment of FMD under similar shear stress conditions.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Eleven healthy, physically active men [age 23 (SD 2) yr] with no family history of premature cardiovascular disease were recruited for the experiment. Subjects were instructed to refrain from consuming caffeinated or high-fat foods or beverages for 24 h and to fast for 3 h before each experimental trial. Each subject gave written, informed consent for this study that was approved by the Office of Research Ethics at the University of Waterloo.
Physiological Measurements
All measurements were performed while the subjects were supine in a quiet, darkened room kept at a relatively constant temperature (21–23°C). Heart rate (Pilot 9200, Colin Medical Instruments, San Antonio, TX); MAP, estimated by finger photoplethysmography (Finapres 2300, Ohmeda, Englewood, CO); and brachial artery mean blood velocity (MBV), measured by pulsed-wave Doppler ultrasound (model 500V, Multigon Industries, Mt. Vernon, NY), were collected by using a data-acquisition system (PowerLab, ADInstruments, Colorado Springs, CO). The pulsed Doppler 4-MHz probe was secured above the brachial artery proximal to the cubital fossa with strips of tape. The signal was directed 45° relative to the skin, and the ultrasound gate was adjusted to encompass the total width of the artery (34). The brachial artery was continuously imaged with the use of high-resolution ultrasound with a 7.5-MHz probe in B-mode (model SSH-140A, Toshiba, Tochigi-Ken, Japan) and recorded to s-VHS tape for later analysis (1, 34). Brachial artery blood flow was arrested by rapid inflation (E-20 Rapid Cuff Inflator, D. E. Hokanson, Issaquah, WA) of a standard blood pressure cuff to 300 mmHg. The occlusion cuff was placed just distal to the right elbow. Reactive hyperemia was initiated by rapid deflation of the occlusion cuff after a time that varied with the experimental condition as described in Experimental Design.
Blood Collection and Analysis
Subjects rested supine with a catheter (20 gauge, BD Insyte, BD Medical Systems, Sandy, UT) inserted in the left antecubital vein. Blood samples (4 ml) were obtained at rest and 1 min after release of the occlusion cuff. Blood was divided into two tubes. One milliliter was transferred to tubes containing no anticoagulant and left to stand for 10 min on ice, rimmed, and centrifuged (Beckman GS-150, Irvine, CA) at 4°C for 10 min at 2,500 g. The serum supernatant was transferred to microtubes and frozen at –80°C. The remaining 3 ml of whole blood were transferred to tubes containing 75 µl of EGTA-glutathione anticoagulant and were centrifuged at 4°C for 10 min at 2,500 g. The plasma supernatant was transferred to microtubes and frozen at –80°C.
Epinephrine and norepinephrine were determined by HPLC with electrochemical detection (2465 Electro Chemical Detector, Waters, Milford, CT) after being extracted from plasma samples by acid-washed alumina and released into a 0.1 M perchloric acid solution and separated (2690 Separations Module, Waters). Serum cortisol was quantified by using a Coat-a-Count solid-phase 125I radioimmunoassay kit (Diagnostic Products, Los Angeles, CA) and gamma counter (Beckman Gamma 5500) according to the catalog No. TKCO2 procedure. Analysis was performed in duplicate.
Experimental Design
Subjects reported to the laboratory for familiarization with the test protocols, and at least 7 days later they then returned on four separate occasions, each separated by at least 2 days, for the data collection sessions. Tests were conducted at the same time of day to limit possible circadian effects. Each testing session consisted of a control trial, followed by 10 min of supine rest, and then one of four experimental condition trials was administered in random order. Data were collected continuously during 1 min of baseline, the full occlusion period, and 3 min after release of occlusion. The duration of forearm occlusion varied between trials to normalize the peak shear stimulus after occlusion cuff release. In each control trial, occlusion was maintained for 5 min, as it was during lower body suction and the cold pressor test. Preliminary testing revealed that the 3-min occlusion for the mental arithmetic test and the 2-min occlusion for the muscle chemoreflex test achieved similar peak shear on cuff release.
Acute Sympathetic Activation Protocols
Muscle chemoreflex activation. Before the trial, both calf muscles were placed under circulatory arrest just below the knees by inflating standard blood pressure cuffs to 250 mmHg. The muscle chemoreflex was activated by having the subjects perform rhythmic plantar flexion exercise until enough muscle activity had been completed to cause MAP to remain at least 20 mmHg above baseline during sustained muscle ischemia. The experimental protocol was completed during this postexercise ischemic period.
Lower body suction. Subjects were sealed into an airtight, lower body suction box at the level of the iliac crest by a neoprene kayak skirt. Suction was gradually applied with increments of –5 mmHg every 2 min, until a level of –30 mmHg of lower body suction was reached. The trial began 5 min later with suction maintained constant throughout the trial.
Cold pressor test. Before the trial, subjects were supine with knees bent over the edge of the table. Both feet were submerged in ice-water slurry (5°C). Forearm cuff inflation was initiated 2 min after submersion, and the feet remained in the slurry for the duration of the trial.
Mental arithmetic task. Based on the protocol described by Lind et al. (24), subjects were asked to subtract 13 or 17 from a three digit number called out by an investigator. The subjects were instructed that they would be required to announce the correct answer within 5 s or would be interrupted by a buzzer. In fact, the buzzer was initiated at random intervals and did not discriminate between correct or incorrect answers. The trial began after 1 min of questioning, and questioning continued until the FMD response was observed.
Data Analysis
Beat-to-beat brachial artery MBV was obtained as the average between consecutive R waves from the ECG. Brachial artery diameter was measured from the videotaped images at intervals of 30 s during the baseline and 60 s during occlusion periods, at 5 and 10 s after occlusion cuff release, and at 10-s intervals through the first 2 min after occlusion cuff release and every 30 s until the end of the trial. All measurements were taken during the diastolic phase of the cardiac cycle and were reported as the average of four measurements taken at each time point with the electronic calipers of the ultrasound unit. All data sets were coded without indication of subject or test condition, thus preventing any technician bias. Results from each test were compared against data from an independent observer, and any deviations >0.2 mm were resolved. To further minimize the effect of random error in the estimation of peak changes in diameter and to get a continuous estimate of diameter for calculation of forearm blood flow from the product of MBV and cross-sectional area, the entire time series data set of diameter values was fit by an exponential curve as previously described (1). This approach with least squares analysis prevents assignment of peak FMD to what could potentially be a point of measurement error. Shear rate was calculated as 8 x MBV/diameter. Baseline values were determined from averages over the last 30 s of baseline. Peak forearm blood flow and shear rate were determined from 10-s averages beginning 5 s after occlusion cuff release. Total flow and shear rate were reported as the time-weighted sum of values during the first minute after occlusion cuff release to give an index of potential stimulus before achieving peak FMD.
Statistical Analysis
Statistical analysis software (SAS Institute, Cary, IN) was used to examine the effect of each condition relative to its own control by repeated-measures ANOVA with one within-subject factor. A probability of P < 0.05 was accepted as statistically significant, and any differences were subsequently analyzed with the least squares difference post hoc test. Data are presented as means (SD). For the purpose of clarity, the four different control tests have been pooled into a single control value for visual presentation.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Significant elevations in systolic and diastolic arterial blood pressure were achieved during the muscle chemoreflex, cold pressor, and mental arithmetic protocols (Table 1). There was no change in blood pressure during the lower body suction protocol (Table 1). Heart rate was significantly elevated throughout the muscle chemoreflex and mental arithmetic protocols but was unaffected by the lower body suction and cold pressor test protocols (Table 1).
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From the pretest baseline levels of plasma norepinephrine [161 (SD 54) pg/ml] and plasma epinephrine [20 (SD 9) pg/ml], the values observed 1 min after release of the forearm occlusion cuff were unchanged for control tests (Fig. 1). There was a significant increase in plasma norepinephrine in each of muscle chemoreflex, lower body suction, and cold pressor tests, but not for the mental arithmetic test (Fig. 1). Plasma epinephrine was increased only in the muscle chemoreflex test (Fig. 1). When compared with the pretest baseline values of serum cortisol [365 (SD 157) nmol/l], the values 1 min after cuff release were significantly increased in the muscle chemoreflex test and were slightly lower in all other conditions (Fig. 1).
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The objective of this study was to achieve relatively consistent shear stimulus to the vascular endothelium across the control and sympathetic activation conditions even with potential differences in brachial artery diameter and blood flow. Peak shear rate was not different between any sympathetic activation protocol and its control (Fig. 2). The total shear stimulus during the first minute of reactive hyperemia was not altered from control during muscle chemoreflex activation, lower body suction, or the cold pressor test, but it was lower in the mental arithmetic test [13,771 (SD 6,066) vs. 22,159 (SD 8,177) no units, P < 0.05].
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FMD
Peak dilation of the brachial artery occurred 
1 min after release of the forearm circulatory occlusion (Fig. 3). There was no difference in the FMD response measured during the control tests on each of the four test condition days [5.29 (SD 1.50)%, 5.64 (SD 2.00)%, 5.87 (SD 0.87)%, and 5.29 (SD 1.24)%]. FMD was significantly greater in muscle chemoreflex and significantly less in cold pressor tests (Figs. 3 and 4). When expressed as absolute brachial artery diameter values, baseline diameter was significantly reduced only during the muscle chemoreflex condition (Fig. 4); however, the diameter at peak response was not different between control and muscle chemoreflex.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Methodological Considerations
The models used to achieve increased SNA caused variable degrees of sympathetic activation with an increase in MAP during muscle chemoreflex activation, the cold pressor test, and with mental arithmetic, but there was no elevation with lower body suction. Elevated MAP in combination with potential changes in brachial artery diameter could dramatically alter the shear stimulus that is linked to the FMD response (20). Therefore, we adjusted the duration of forearm occlusion in these conditions to achieve similar peak shear stimuli. It was more difficult to achieve the same shear stimulus during the first minute after occlusion cuff release. However, the only condition in which FMD was impaired was the cold pressor test where the total shear stimulus in the first minute after 5-min circulatory occlusion was not different from control or from the muscle chemoreflex and lower body suction tests. The shear stimulus was reduced in the mental arithmetic tests, but there was no impairment of FMD. At present, there is debate concerning the specific stimulus to FMD, whether it is the peak shear or the sustained shear (1, 30), because some studies (4) have shown the rate of onset of shear to be important. In this study, we have direct measurements of blood flow velocity and diameter that allowed us to explore the relationship between shear stress and FMD, and we have indicators of sympathetic and psychological stress from direct measurements of norepinephrine, epinephrine, and cortisol.
In this study, we evaluated the FMD response by placing markers on videotaped images of vessel walls and taking the average of four measurements at each time point. The estimates of two trained observers were compared and resolved by consensus if differences were >0.2 mm. This approach is consistent with published recommendations (7). Although this is not as objective as new edge detection software, our approach was without bias because all records were coded to prevent identification of subjects and conditions. We further utilized a regression analysis of all data points (1), so that peak FMD was not biased by a single value that had the potential to be a measurement error.
Sympathetic Activation and Stress Response
After we took into account all the physiological and biochemical evidence collected in this investigation, it appeared that the muscle chemoreflex had the greatest sympathetic response and was also the only model that displayed a marked stress response. Significant elevations were observed in plasma norepinephrine in the muscle chemoreflex, cold pressor, and lower body suction tests. These data are consistent with observations from direct measurement of muscle SNA (MSNA) during muscle ischemia (39), cold pressor test (33), and lower body suction (23, 31). The effects of mental stress are equivocal, with some studies showing a small increase in MSNA (5), whereas with others there was a decrease (16).
Serum cortisol levels decreased slightly over the course of the test session, except in the muscle chemoreflex test. This suggests that the 10 min of quiet, supine rest used in this investigation might not have been sufficient to achieve a stable baseline value of circulating cortisol. However, useful information can still be gleaned from the observation that cortisol had a similar small decrease in each of the lower body suction, cold pressor, and mental arithmetic tests and that this response did not differ from the control experiments; that is, the muscle chemoreflex test was considerably more stressful than any of the other models examined.
Muscle chemoreflex.
To the best of our knowledge, this is the first study to examine the impact of activating the muscle chemoreflex on the FMD response. We observed a greater percent dilation as a consequence of an initial constriction of the brachial artery during the period of muscle ischemia followed by FMD to the same diameter as observed in the control tests; that is, it was only the initial constriction that made the percent change in FMD appear greater than that in the control. The muscle chemoreflex activates a general sympathetic response with increased total peripheral resistance and SNA (39) and, as we observed, elevated norepinephrine, epinephrine, and cortisol. It has been proposed that the magnitude of FMD is influenced by the initial vessel size (32), although this effect is likely due mainly to a greater hyperemic shear stress stimulus in small arteries (19). In this study, we attempted to control shear stress so that the peak and the total shears in the first minute of reactive hyperemia were not different between the chemoreflex and control tests. In the current study, it could only be speculated whether there was more nitric oxide (NO) and/or other vasodilator released in response to the shear stimulus to cause the greater percent dilation or whether the vascular smooth muscle was more responsive to the vasodilators. The elevated circulating catecholamines may have played a role in augmenting NO release from the endothelium. 
-Adrenergic receptors on the endothelium have been shown to facilitate the release of NO from the endothelium during hemorrhage (8), and 
2-receptor stimulation by salbutamol has been shown to mask hyperglycemia-induced endothelial dysfunction (21). It is unlikely that reaching the same peak dilation was a physiologically defined upper limit because many studies have shown greater dilation with nitroglycerin (18, 35) or with greater shear stimulus as after ischemic exercise (1).
Lower body suction. Reactive hyperemia and FMD were not significantly affected by lower body suction that was sufficient to cause a significant elevation in plasma norepinephrine. This finding contrasted with results from Hijmering et al. (18) that indicated a >50% reduction in FMD with no change in the forearm muscle blood flow as assessed by strain-gauge plethysmography during lower body suction. The reason for the discrepancy with the results of Hijmering et al. (18) is not obvious. There were some differences in methodology that might have influenced the results, including the duration of supine posture as well as the measurement of total forearm blood flow by strain gauge rather than flow through the brachial artery. In the study of Hijmering et al., subjects were supine for at least 90 min before the application of the final level of lower body suction, and this might have accounted for the >15% elevation in heart rate (18), whereas heart rate in the current study and other research (3, 31) showed little or no increase until lower body suction exceeded –20 mmHg. Even though heart rate increased very little with –20 to –30 mmHg lower body negative pressure, MSNA is increased by lower body suction (23, 31, 38). It is possible that prolonged supine posture might have interacted with the lower body suction to modify the cardiovascular response, resulting in elevated heart rate, as has been observed after very short durations of slight head-down bed rest (2, 25).
Cold pressor test.
The cold pressor test was the only condition that we examined where FMD was reduced. This finding is consistent with the results of Lind et al. (24) when they expressed their data relative to the blood flow stimulus. The cold pressor test elevates arterial blood pressure primarily by a sympathetic vasoconstrictor response, as evidenced by the 34% increase in MAP and the elevated plasma norepinephrine in the current study. Even though MAP remained high throughout the cold pressor test, subjective data indicated that for most subjects the painful nature of the stimulus subsided and gave way to numbness in the feet 2 min after immersion in the cold-water slurry. From the current data where we observed some of the anticipated signs of elevated SNA, it is not clear whether other unmeasured factors might have been responsible for the impairment of FMD. Spieker et al. (35) implicated endothelin as a cause of reduced FMD after mental stress, but it is not clear whether this could partially explain our findings with the cold pressor test and, if so, why it would happen only with this test condition.
Mental arithmetic task. In this study, FMD was not changed from control by the mental arithmetic task. Several different investigations (9, 14, 24, 35) have reported impaired FMD in response to an acute increase in SNA with mental stress, whereas one study (17) observed enhanced FMD with mental stress. A parallel between impaired FMD with acute mental stress and that with white-coat hypertension has been made (13), but not all investigations (29) find impaired FMD in white-coat hypertension in contrast to consistent findings with essential hypertension. In our study, where we used a mental arithmetic task very similar to that employed by Lind et al. (24), we observed a small increase in MAP. The other markers of elevated SNA and stress taken from norepinephrine, epinephrine, and cortisol were not elevated by the mental arithmetic task. Our results, coupled with the findings that MSNA is variably affected by mental stress (5, 16), lead us to question the validity of mental arithmetic as a model of sympathoexcitatory reflex activation. The slightly elevated heart rate observed in this condition might have been due to parasympathetic nervous system withdrawal.
An important factor that might influence FMD with acute mental stress is the magnitude of shear stress as determined by the peak and/or total reactive hyperemia. Lind et al. (24) noted that, although the magnitude of FMD with acute mental stress was not different from control, the ratio of FMD to blood flow was significantly reduced. Many of the studies (9, 13, 14, 17, 29, 35) cited here either did not measure blood flow during hyperemia or did not report the data. To achieve the same peak shear stress in our mental arithmetic test as in the control, we reduced the duration of the period of occlusion. However, shear stress declined more rapidly during the mental arithmetic task so that total shear stress over the first minute after occlusion cuff release was significantly reduced; that is, in contrast with Lind et al. (24), we might have concluded relatively enhanced FMD from the ratio of FMD to shear rate. This conclusion would be consistent with enhanced FMD reported by Harris et al. (17), but it is worth noting that they actually found reduced baseline diameter in the mental stress test with dilation to the same absolute end value, a finding similar to what we reported for muscle chemoreflex.
In summary and in conclusion, we have demonstrated that there is not a generalized impairment of endothelial FMD in a conduit artery caused by elevated SNA. The muscle chemoreflex test induced the greatest overall stress and sympathetic activation, and it was the only condition in which a baseline constriction of the conduit brachial artery was observed. However, FMD occurred to the same end diameter as in the control conditions so that the percent FMD response was greater than that in any other model. No impairment of FMD was observed in the lower body suction experiments where plasma norepinephrine was elevated nor in the mental arithmetic tests where blood pressure was elevated without an increase in norepinephrine. Impaired endothelial function was found only in the cold pressor test. In this test, blood pressure and plasma norepinephrine were elevated, but in contrast to the muscle chemoreflex test, there was no elevation in epinephrine or cortisol. Thus it does not seem that the sympathetic stress was as great in this condition, yet there was impaired FMD. The mechanism(s) responsible for the differences in FMD between the muscle chemoreflex and the cold pressor test remain to be identified. These data collectively indicate that FMD does not appear to be impaired by an acute increase in SNA. The data are consistent with the no impairment of FMD in one study of white-coat hypertension (29), but this finding is controversial (13, 22) and awaits further explanation of the link to the consistent finding of impaired endothelial function with essential hypertension (10, 26, 28). There are important implications from the current study. First, it is essential to monitor the shear stimulus as well as the FMD response. Second, the presence of any stressor may modify the FMD response, but the direction of change is dependent on complex interactions that appear to go beyond simple activation of the sympathetic nervous system. Thus we agree with one aspect of the conclusion of Tschakovsky and Pyke (37) in a recent point-counterpoint (15, 37) that FMD might be due to multiple cascade pathways with different mediators, but we do not concur with the statement that there is "unquestionable evidence that sympathetic activation influences the FMD response." We observed that FMD is not always reduced by every means of activating the sympathetic system.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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P < 0.05, significant difference from control; #P < 0.05, significant difference from percent FMD in control.