MCCORD, JENNIFER L.; PELLINGER, THOMAS K.; LYNN, BRENNA M.; HALLIWILL, JOHN R.
Postexercise hypotension occurs after a single bout of dynamic exercise (9,14,20). In most subjects, postexercise hypotension, observed in the supine position, results from a persistent increase in active muscle vascular conductance (postexercise hyperemia) that is not completely offset by ongoing elevations in cardiac output (22). Thus, during exercise recovery, a greater proportion of blood volume is moved to the periphery, decreasing central venous pressure. Evidence suggests that the hyperemia in active muscle leading to postexercise hypotension occurring within 30 min after exercise is mediated by histamine 1 (H1) receptors in the vasculature. Our laboratory found that with the ingestion of an H1-receptor antagonist, the postexercise vasodilation is markedly reduced, and the fall in mean arterial pressure is blunted 30 min after exercise (19). Thus, an H1-receptor antagonist can prevent a modest (∼4-8 mm Hg) decrease in arterial pressure during recovery from exercise in the supine position.
Orthostatic intolerance resulting in syncope ("fainting") after a bout of exercise is thought to stem from an exaggerated form of postexercise hypotension (16). In the standing position after exercise, the fall in arterial pressure (i.e., magnitude of postexercise hypotension) may reach a level where presyncopal signs or symptoms occur. Even without the stress of exercise, orthostatic stress challenges the regulation of arterial pressure. Venous pooling occurs on moving to an upright posture due to compliant veins and an inactive muscle pump. Thus, assuming an upright posture for a prolonged period creates a decrease in central venous pressure and stroke volume. A fall in cardiac output ensues, and despite a baroreflex-mediated increase in heart rate, ultimately, arterial pressure will fall (16,25). Taking the two stressors together, elevations in skeletal muscle blood flow combined with an inactive muscle pump and falling cardiac output can create detrimental reductions in arterial pressure. A hot environment can exacerbate the mismatch of cardiac output and arterial inflow (9), when there is a redistribution of blood volume to the compliant cutaneous vascular bed to aid in thermoregulation (17). Because an increased peripheral vascular conductance has been found to be a culprit underlying orthostatic intolerance (2) and given that H1-receptors contribute to postexercise hypotension by mediating this increased peripheral conductance, could H1-receptors also contribute to postexercise orthostatic intolerance during recovery from exercise in a hot environment? The aim of this study was to test the ability of an H1-receptor antagonist to reduce the severity of postexercise orthostatic intolerance in a hot environment. We hypothesized that the orthostatic hypotension during immediate recovery from exercise in a hot environment would be reduced by the administration of an H1-receptor antagonist. We further hypothesized that brachial and cutaneous vascular conductances would be attenuated during recovery from exercise in a hot environment by an H1-receptor antagonist.
This study was approved by the Institutional Review Board of the University of Oregon, and each subject gave written informed consent before participation.
Fifteen healthy, nonsmoking, normotensive subjects (8 men and 7 women) between the ages of 18 and 31 yr participated in the study. Subjects were of average height (mean = 173 cm, range = 158-186 cm) and weight (mean = 65.7 kg, range = 52.2-83.0 kg). All subjects completed no less than 4 h of endurance exercise·wk−1 (Baecke Sport Index: mean = 11.1 arbitrary units, range = 8.9-14.7 arbitrary units; index of physical activity: mean = 100 MET·h·wk−1, range = 70-141 MET·h·wk−1 (1,15)). V˙O2max values were within the normal range for this population (mean = 55.1, range = 45.0-78.7 mL·kg−1·min−1). Subjects were taking no medication other than oral contraceptives. Women subjects had a negative pregnancy test on the screening visit.
Subjects reported to the laboratory for a screening visit and graded maximal treadmill test at least 2 h postprandial and abstained from caffeine and alcohol for 12 h and exercise for 24 h before the screening visit. Subjects performed a graded maximal treadmill test composed of 2-min workload increments to determine maximal O2 uptake (V˙O2max). Specifically, after a 5-min warm-up at a comfortable speed (8.0 to 11.3 km·h−1), a constant speed was then used (between 9.6 and 19.3 km·h−1, depending on training and sex). The treadmill grade was then increased by 2% every 2 min until the subjects reached exhaustion (defined as the inability to continue exercise at the work rate of the current stage). Selection of the workload increment was subjective, with the goal of producing exhaustion within 8-12 min. Whole-body O2 uptake was measured via a mixing chamber (Parvomedics, Sandy, UT) integrated with a mass spectrometry system (Marquette MGA 1100; MA Tech Services, St. Louis, MO). All subjects reached subjective exhaustion (rating of perceived exertion on the Borg (3) scale of 19-20) within the 8- to 12-min period. After the subjects rested for 15-20 min, they returned to the treadmill for assessment of the workload corresponding to a steady-state oxygen consumption of 50% of V˙O2max. This workload was used on the two study days for the 45-min exercise bout. Subjects self-reported activity levels on two questionnaires (1,15).
Subjects reported for parallel experiments on two separate days. The order of experiments was randomized between a blockade day (administration of fexofenadine) and a control day, such that eight subjects underwent the blockade day first, and seven subjects underwent the control day first. For both study days, subjects reported for the study at least 2 h postprandial and abstained from caffeine for 12 h and from exercise and all medications for 24 h before the study. For all male subjects, the second study day was at least 5 d and not more than 10 d after the first studyday, providing more than adequate time for clearance of fexofenadine (half-life ∼12 h) (7). Women subjects were studied during consecutive early follicular phases of the menstrual cycle or placebo phases of the oral contraceptive use. Subjects ingested a temperature-sensing pill at least 5 h before each study visit; subjects reporting to the laboratory in the morning ingested the pill the night before.
A schematic of the experimental protocol is shown in Figure 1. On study days, subjects were given water with or without fexofenadine 60 min before the start of exercise. The subjects were brought into an environmental chamber with a controlled ambient temperature of 35°C and 30% humidity. The subjects were laid in the supine position on an electronic tilt table (Colin Medical Instruments Corporation, Valley City, ND) for instrumentation. A venous catheter was inserted into the left arm in the antecubital region to obtain blood samples. Two baseline measurement periods were completed at 35 and 50 min after entering the environmental chamber, where arterial pressure, heart rate, cardiac output, brachial artery blood flow, and cutaneous red blood cell flux were measured with subjects in the supine position. Then, subjects completed 45 min of treadmill running at 50% of V˙O2max. The average speed was 7.7 ± 0.2 km·h−1, and the average grade was 0.7 ± 1.3%. During exercise, arterial pressures and heart rates were obtained every 10 min. After exercise, the subjects were immediately laid into the supine position on an electronic tilt table for measurements of arterial pressure, heart rate, cardiac output, brachial artery blood flow, and cutaneous red blood cell flux. Five minutes after the completion of exercise, the subjects were passively tilted to a 60° head-up position supported by a foot board. Continuous measurements of arterial pressure, heart rate, cardiac output, brachial artery blood flow, and cutaneous red blood cell flux were taken in the head-up position until the subject was unable to continue with the tilt or 15 min had passed, whichever came first. The subjects were then returned to the supine position, and a cutaneous local heating protocol was conducted to standardize red blood cell flux measurements.
FIGURE 1-Schematic o...Image Tools
Subjects were considered unable to tolerate the tilt when systolic blood pressure fell (≥15 mm Hg) or a sudden drop in heart rate occurred (≥15 beats·min−1). In addition, subjects were asked to rate (0-3) symptoms of presyncope, including nausea, visual changes, head and neck discomfort, and overall feeling. The tilt test was terminated once subjects rated their symptoms a 2 or a 3.
Blood were drawn before exercise, during the last minute of exercise, 8 min into the head-up tilt, and after the cutaneous local heating protocol to determine histamine concentrations of whole blood and plasma and to track changes in plasma volume from changes in hematocrit and hemoglobin.
H1-Receptor Blockade and Biochemical Analyses
H1-receptors were blocked with 540 mg of fexofenadine. This amount of oral fexofenadine has been shown to adequately block H1-receptors (time to peak concentration ∼1.15 h and half-life ∼12 h) (26). Fexofenadine does not seem to cross into the central nervous system or possess sedative actions (4). Furthermore, it does not have any direct cardiovascular effects in the absence of histamine receptor stimulation (i.e., when given under normal resting conditions, this drug does not elicit any changes in heart rate, blood pressure, or smooth muscle tone) (4,19,21). Blockade of H1-receptors prevents the formation of local vasodilator substances such as nitric oxide and prostaglandins in response to histamine administration (4,11). Blockade of H1-receptors does not alter histamine release and should not affect histamine concentrations.
Heart rate and arterial pressure.
Heart rate and arterial pressure were monitored throughout all experimental procedures. Heart rate was monitored using a 5-lead ECG (Q710; Quinton Instruments, Bothell, WA). Arterial pressure was measured in the arm by using an automated oscillometric device (Dinamap Pro100 vital signs monitor; Critikon, Inc, Tampa, FL) and on a beat-by-beat basis with a finger photoplethysmographic blood pressure monitor (Finometer; Finapres Medical Systems BV, Arnhem, the Netherlands).
Cardiac output was estimated using an open-circuit acetylene wash-in method as described previously (12,18). This method allows for the noninvasive estimation of cardiac output. We chose an open-circuit method because subjects are exposed to stable oxygen and carbon dioxide levels throughout the measurement in contrast to rebreathe techniques. Subjects breathed a gas mixture containing 0.6% acetylene-9.0% helium-20.9% oxygen-balance nitrogen for 8-10 breaths via a two-way nonrebreathing valve. During the wash-in phase, breath-by-breath acetylene and helium uptakes were measured by a respiratory mass spectrometer (Marquette MGA 1100; MA Tech Services), and tidal volume was measured via a pneumotach (Model 3700; Hans Rudolph, Kansas City, MO) linearized by the technique of Yeh et al. (32) and calibrated using a test gas before each study. The pneumotach and valve system had a combined dead space of 24 mL. Cardiac output calculations have been described previously (12). Stroke volume was determined from cardiac output/heart rate. Systemic vascular conductance was calculated as cardiac output/mean arterial pressure and expressed as milliliters per minute per millimeters of mercury (mL·min−1·mm Hg−1).
Arm blood flow.
Brachial artery diameter and blood velocity were measured using an ultrasound probe (10-MHz linear-array vascular probe, Vingmed System 5; GE, Horton, Norway). The entire width of the artery was insonated with an angle of 60°. Velocity measurements were taken simultaneously with diameter measurements by averaging the mean velocity curve for each cardiac cycle via R-wave-gated analysis. Diameters were analyzed by using custom-designed edge-detection and wall-tracking software (31). Arm blood flow was calculated as artery cross-sectional area multiplied by brachial mean blood velocity. Brachial vascular conductance was calculated as flow for both arms/mean arterial pressure and expressed as milliliters per minute per millimeters of mercury (mL·min−1·mm Hg−1).
Forearm cutaneous blood flow.
Red blood cell flux was used as an index of skin blood flow via laser-Doppler flowmetry (DRT4; Moor Instruments, Ltd., Devon, England). Laser-Doppler probes were placed on the forearm. Skin blood flows were expressed as cutaneous vascular conductance, calculated as laser-Doppler flux/mean arterial pressure, and normalized to the maximal values achieved during a cutaneous local heating protocol to 43°C at the end of the study (13). The two sites were averaged giving one value for each time point.
Internal body temperature was assessed by an ingestible pill telemetry system (HQ, Inc., Palmetto, FL) (5,28).
Percentage changes in plasma and blood volume from preexercise were calculated from changes in hemoglobin and hematocrit by the method of Dill and Costill (6).
Samples were collected in prechilled tubes and immediately separated (plasma) and stored (plasma and whole blood) at −80°C until analysis. The concentration of histamine was then assessed by measuring plasma and whole-blood concentrations with a commercially available enzyme immunoassay kit. Concentration was expressed in nanograms per milliliter (IBL-America, Minneapolis, MN). The reported lower limit for the detection of histamine is 0.1 ng·mL−1. Across the range of values in this study, inter- and intraassay coefficients of variation are 8% and 12%.
The researchers who decided when to terminate the head-up tilt protocol and those collecting and/or analyzing the data were blinded regarding drug condition for each study day. The subjects were not blinded to the drug treatment. To simplify the results from the protocol, only data at 50 min preexercise supine, postexercise supine, and at 1, 6, and 12 min of the head-up tilt will be presented.
Because our preliminary statistical analysis did not indicate that sex had any affects on how subjects responded to the head-up tilt across the control and blockade day, all subsequent statistical analysis was performed with men and women combined as a single group. All variables were analyzed with a mixed model ANOVA (drug vs time) (SAS v9.1; SAS Institute, Inc., Cary, NC). To determine whether the drug condition had an affect on the duration of the head-up tilt, a fixed-effects partial likelihood survival analysis was completed (SAS v9.1, SAS Institute, Inc.). This statistical analysis is primarily reserved for larger subject populations (>30 subjects). Therefore, in addition to this test, a signed-rank test was also used to compare survival times. The signed-rank test is a nonparametric procedure that does not require data to be normally distributed. Differences were considered significant when P < 0.05. All values are reported as means ± SE.
Preexercise hemodynamics were measured in the supine position after 50 min of being in the hot environment (35°C). Under these conditions, supine heart rate was 64.5 ± 0.7 beats·min−1 on the control day and 63.5 ± 0.5 beats·min−1 on the H1-receptor antagonist day (blockade day). Supine mean arterial pressure was 76.4 ± 0.5 mm Hg on the control day and 74.9 ± 0.4 mm Hg on the blockade day. There were no differences in preexercise heart rate and mean arterial pressure values between study days (P > 0.39).
The goal was to have subjects exercise for 45 min at 50% V˙O2max. On both days, the average speed was 7.7 ± 0.2 km·h−1 with 0.7 ± 0.1% grade. On the control day, heart rate was 142.7 ± 1.1 beats·min−1 during exercise. This represented, on average, 63.7 ± 0.9% heart rate reserve (heart rate reserve is defined as maximal heart rate achieved during V˙O2max testing minus the preexercise supine heart rate). On the blockade day, heart rate was 142.5 ± 1.0 beats·min−1 during exercise. This represented, on average, 63.2 ± 0.9% heart rate reserve. There were no differences in the percentage of heart rate reserve (P = 0.78) or the mean arterial pressure response to exercise (control = 83.1 ± 0.4 mm Hg, blockade = 82.8 ± 0.4 mm Hg; P = 0.83) between the two study days.
Postexercise and head-up tilt hemodynamics.
Figure 2 shows mean arterial pressure, heart rate, and brachial vascular conductance in response to exercise and head-up tilt. Mean arterial pressure was increased immediately after exercise in the supine position on both study days (P < 0.05). As the head-up tilt progressed, mean arterial pressure was reduced compared with postexercise supine on both study days (P < 0.05). However, on the control day, mean arterial pressure was decreased at 1 min (Fig. 2) and 12 min (not shown) into the tilt compared with preexercise levels (both P < 0.05); this was not seen with blockade (P = 0.41). As expected, heart rate was increased immediately after exercise and increased further during the head-up tilt on both study days (P < 0.05). On both study days, brachial vascular conductance was increased in response to exercise (P < 0.05). As the head-up tilt progressed, brachial vascular conductance was reduced compared with postexercise supine on both study days (P < 0.05). Blockade did not affect heart rate or brachial vascular conductance at any time point (P > 0.11).
FIGURE 2-Mean arteri...Image Tools
Figure 3 shows stroke volume, cardiac output, and systemic vascular conductance in response to exercise and head-up tilt. Cardiac output and systemic vascular conductance were both decreased 6 min into the head-up tilt on both study days compared with pre- and postexercise supine values (P < 0.05). The blockade did not affect stroke volume, cardiac output, or systemic vascular conductance during head-up tilt (P > 0.25).
FIGURE 3-Stroke volu...Image Tools
Forearm cutaneous vascular conductance and core body temperature values are shown in Figure 4. Exercise elevated forearm cutaneous vascular conductance as noted by postexercise supine measurements. During head-up tilt, forearm cutaneous vascular conductance steadily fell below postexercise levels to baseline levels by the 12th min of the tilt (P < 0.05 vs postexercise, not shown). Blockade did not affect forearm cutaneous vascular conductance at any time point during the study (P > 0.37). Core body temperature was increased immediately after exercise on both study days (P < 0.05). Throughout head-up tilt, core body temperature was attenuated from postexercise supine values but remained above preexercise temperatures (P < 0.05). The elevation in core body temperature achieved by the end of exercise and maintained during head-up tilt was of higher magnitude on the control day compared with the blockade day (P < 0.05).
FIGURE 4-Core temper...Image Tools
Figure 5 shows the proportion of subjects completing each minute of head-up tilt on both study days. The median survival time (tilt time when the survival function is equal to 0.5) on the control day was 13 min 39 s, whereas the median survival time could not be calculated on the blockade day (i.e., >15 min). When comparing the difference in tilt time between each subject, the blockade lengthened the mean tilt time by 94 s (P = 0.098). Figure 6 shows individual tilt time and means for both study days. The blockade lengthened the duration of the head-up tilt in six of eight subjects that did not complete the tilt test on the control day.
Plasma and blood volume.
During exercise, both plasma volume (Δ = −14.0 ± 1.9% control and Δ = −10.6 ± 2.0% blockade; both P < 0.05) and blood volume (Δ = −8.8 ± 1.2% control and Δ = −5.9% ± 1.7% blockade; both P < 0.05) decreased from baseline. Exercise decreased blood volume to a greater extent at the end of exercise on the control day compared with blockade day (P = 0.05), but there were no differences in plasma volume changes between the two study days (P > 0.10). Reductions in plasma and blood volumes were maintained during head-up tilt after exercise (plasma volume: Δ = −11.0 ± 1.3% control and Δ = −10.5 ± 2.0% blockade; blood volume: Δ = −6.7 ± 1.0% control and Δ = −8.3% ± 1.4% blockade; all P < 0.05 vs preexercise), but the initial differences in blood volume changes between study days (observed at the end of exercise) were absent during head-up tilt. By the end of the protocol, both plasma volume (Δ = −2.2 ± 1.5% control and Δ = −2.0 ± 1.8% blockade; both P > 0.19) and blood volume (Δ = −1.4 ± 1.0% control and Δ = −1.6% ± 0.9% blockade; both P < 0.12) had returned to preexercise levels.
Whole-blood histamine concentrations did not differ between preexercise (6.7 ± 2.2 control and 6.8 ± 2.4 blockade), end of exercise (5.8 ± 1.6 control and 8.3 ± 2.9 blockade), tilt (8.7 ± 3.8 control and 8.1 ± 2.4 blockade), or at end of the study (5.7 ± 2.4 control and 6.5 ± 2.4 blockade) measurements (all time points P > 0.85 vs preexercise). There were no differences between study days (P = 0.92).
Likewise, plasma blood histamine concentrations did not differ between preexercise (0.60 ± 0.16 control and 0.51 ± 0.09 blockade), end of exercise (0.70 ± 0.21 control and 0.54 ± 0.14 blockade), tilt (0.81 ± 0.28 control and 0.80 ± 0.35 blockade), or at end of the study (0.62 ± 0.24 control and 0.55 ± 0.15 blockade) measurements (all time points P > 0.12 vs preexercise). There were no differences between study days (P = 0.98).
The focus of our investigation was to determine whether administration of an H1-receptor antagonist would alleviate postexercise syncope through blocking the histamine-receptor-dependent postexercise hyperemia response. Although antagonism of H1-receptors did not abolish the occurrence of postexercise presyncope under our experimental conditions, there was a reduced incidence of orthostatic hypotension with administration of the H1-receptor antagonist, and there was a trend for a lengthened time to the onset of presyncope with blockade.
Postexercise hypotension under thermoneutral conditions is characterized by a persistent rise in systemic vascular conductance that is not completely offset by increases in cardiac output when subjects are studied supine or seated (9). Forearm and calf vascular conductances increase in parallel with systemic vascular conductance; thus, the vasodilation that underlies postexercise hypotension is not restricted to the sites of previously active skeletal muscles (10). However, the degree of vasodilation is substantially greater in the previously active muscles relative to the inactive muscles. This postexercise hyperemia presents largely in skeletal muscle vascular beds with little or no contribution from skin, splanchnic, or renal circulations under thermoneutral conditions (24,27). Postexercise hyperemia is mediated by contributions from both H1- and H2-receptors in the vasculature, although the primary contribution of each receptor occurs at different times. Our laboratory found that with ingestion of an H1-receptor antagonist, postexercise hyperemia is markedly reduced and the associated fall in blood pressure is blunted 30 min after exercise, but the impact of H1-receptor antagonism becomes less at 60 and 90 min after exercise (19). In comparison, H2-receptor antagonism has a peak effect on postexercise hyperemia at 60 and 90 min after exercise, with a lesser impact at 30 min postexercise (21). The impact of H1- and H2-receptor antagonism is considerable in the previously active muscle, accounting for ∼80% of the response but has a smaller, more variable impact on nonexercised muscle (22). Because H1-receptors mediate the early portion of hyperemia after exercise, when the prevalence of syncope is highest (2), this study sought to determine whether H1-receptor antagonism could shift the hemodynamic profile sufficiently to prevent the occurrence of postexercise syncope.
Moving into the upright posture challenges the maintenance of arterial pressure; an inadequate perfusion pressure to the cerebral circulation can occur, thus leading to orthostatic syncope. On standing, gravity pulls 70% of total blood volume below the heart (26), increasing blood volume in the dependent limbs. The resulting reduction in central venous pressure will lessen cardiac output. Unless reflex circulatory adjustments are made to redistribute this blood volume to back toward the heart, arterial perfusion pressure will become compromised. Heart rate is increased rapidly on the decreased firing from baroreceptors; however, if central blood volume is the limiting factor, this response cannot maintain arterial pressure. Arguably, an increase in sympathetic activity to the vasculature is the necessary circulatory adjustment to prevent a further fall in pressure. Augmented sympathetic activity will decrease systemic vascular conductance through vasoconstriction. Vasoconstriction will reduce peripheral blood flow and displace blood out of compliant organs and dependent limbs, ameliorating the fall in cardiac preload. However, if the passive upright posture is maintained and/or if the vasoconstriction cannot prevent central venous pressure from falling further, arterial pressure will begin to fall. This response can be augmented in a hot environment and during postexercise hypotension when peripheral blood flow demands (i.e., skin and skeletal muscle vasodilation) further outstrip cardiac output (16,17,23,29). In fact, after exercise when the muscle pump is no longer active, the level of muscle blood flow needed during exercise is prevented from returning to the right ventricle, decreasing central venous pressure further than the reduction seen with passive upright posture alone. When blood flow in the periphery exceeds what the left ventricle can provide, arterial pressure drops below an adequate perfusion pressure for the maintenance of cerebral blood flow, and syncope will ensue.
We chose to test our subjects in a hot instead of a thermoneutral environment because exercise in a hot environment is associated with a greater incidence of postexercise syncope (8). In our attempt to develop a possible preventative measure against postexercise syncope, we wanted an environment that would predispose subjects to a greater incidence of postexercise syncope and therefore enhance our ability to discern any potential differences caused by the intervention, H1-receptor blockade. Although brachial and forearm cutaneous vascular conductances were not clearly altered during recovery from exercise or during head-up tilt by the H1-receptor antagonist, there was a reduced prevalence of orthostatic hypotension with the administration of the H1-receptor antagonist and a tendency toward longer tilt times before the onset of presyncope. We used a head-up tilt test that lasted up to 15 min to elicit presyncopal episodes. However, 6 of 15 subjects did not reach presyncopal signs or symptoms on either study day. Possibly, lengthening the time of head-up tilt or using graded lower-body negative pressure to reach syncope in all subjects would have shown a clearer, more obvious role for H1-receptors in postexercise syncope across all subjects.
Due to the technical challenges of this study, blood flow was measured in the arm but not in the leg or other vascular beds. Measuring the larger and more active skeletal muscle vascular bed of the legs as in our prior studies (19,21,22,25) would likely have documented reduced postexercise hyperemia or possibly greater vasoconstrictor response to tilt in response to the H1-receptor antagonism. In addition, we have no measure of blood flow to other vascular beds such as the kidneys or splanchnic region, which can respond dramatically to preserve arterial pressure during combined heat and orthostatic stress (24). It is unclear whether these responses would be altered by prior exercise or by H1-receptor antagonism (25). However, H1-receptors have been shown to be involved in the active vasodilation response to heat stress in the cutaneous vasculature (30).
In the present study, forearm cutaneous vascular conductance after exercise, at a time when active vasodilation is present, seems to be unaffected by H1-receptor antagonism. Along these lines, Wong et al. (30) have suggested that oral H1-receptor antagonists such as fexofenadine do not affect active vasodilation of the skin vasculature, whereas intradermally administered antagonists do (31). In contrast, the dose of oral fexofenadine used in the present study is greater than that used by Wong et al. and has been shown to reduce the wheal and flare response to histamine skin-prick tests (21). As such, it remains unclear as to what extent fexofenadine will alter the cutaneous vascular response to whole-body heat stress. Further, we recognize that there may be differences in cutaneous vascular regulation between passive heating and exercise in the heat. Thus, the present results suggest that H1-receptors do not play a major role in the forearm skin vasodilation after exercise in the heat. It is likely that this pattern of response holds true for the majority of the nonacral portion of the cutaneous vasculature, but there may be regional differences in the degree of cutaneous vasodilation that is seen during recovery from exercise in the heat (27). In this context, it is interesting to note the apparent increase in cutaneous vascular conductance relative to body core temperature with blockade, which contrasts with what would be expected if H1-receptors contributed to active vasodilation of the skin. One possible explanation is that H1-receptor blockade is indirectly influencing the relationship between temperature and skin vasodilation in this protocol by diminishing the fall in central venous pressure during head-up tilt and that this alleviates the well-documented restraint of cutaneous vasodilation (and sweating) by cardiopulmonary reflexes and facilitates better heat transfer to the environment. Thus, an effect of H1-receptor blockade in the previously active muscle can reasonably explain the differences in body core temperature seen during upright tilt in our study. In essence, we are suggesting that, in the postexercise period, reducing postexercise hyperemia turns off a muscle steal phenomenon, allowing for better heat dissipation.
An alternative interpretation is that the H1-receptor blockade somehow reduces heat load relative to the control condition, and that this impacts orthostatic tolerance by reducing the degree of cutaneous vasodilation. Thus, we recognize that, currently, we cannot say whether the benefit of H1-receptor blockade stems from reductions in cutaneous blood flow, which may be secondary to changes in muscle blood flow, or stems directly from the reductions in skeletal muscle blood flow that we have documented in numerous studies.
In conclusion, the magnitude of the mean arterial pressure drop during head-up tilt shortly after exercise in the heat was blunted by the administration of an H1-receptor antagonist, and subjects tended to stand longer before the development of presyncopal signs and symptoms. These data suggest that H1-receptor activation might be a contributing factor to postexercise syncope. Furthermore, although the benefit of H1-receptor antagonism in healthy individuals after a moderate run in the heat may be limited, these data point the way toward the potential use of H1-receptor antagonism in some circumstances to improve orthostatic tolerance after exercise.
The authors sincerely appreciate the time and effort put forth by the subjects who volunteered for this study. The authors also thank Julie Manson, Breanna Dumke, and Martin Anderson for their technical assistance. This study was conducted by Jennifer L. McCord in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the University of Oregon. This research was supported by American Heart Association Grant-in-Aid 555632Z, Evonuk Fellowship, American College of Sports Medicine Carl V. Gisolfi Memorial Research Fund, and a Department of Defense University Research Instrumentation Program (DURIP) grant. The results of the present study do not constitute endorsement by American College of Sports Medicine.
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