H1 receptor-mediated vasodilatation contributes to postexercise hypotension
1 Department of Human Physiology, University of Oregon, Eugene, OR 97403-1240 USA
Abstract
In normally active individuals, postexercise hypotension after a single bout of aerobic exercise is due to an unexplained peripheral vasodilatation. Histamine has been shown to be released during exercise and could contribute to postexercise vasodilatation via H1 receptors in the peripheral vasculature. The purpose of this study was to determine the potential contribution of an H1 receptor-mediated vasodilatation to postexercise hypotension. We studied 14 healthy normotensive men and women (ages 21.9 ± 2.1 years) before and through to 90 min after a 60 min bout of cycling at 60% on randomized control and H1 receptor antagonist days (540 mg oral fexofenadine hydrochloride; Allegra). Arterial blood pressure (automated auscultation) and femoral blood flow (Doppler ultrasound) were measured in the supine position. Femoral vascular conductance was calculated as flow/pressure. Fexofenadine had no effect on pre-exercise femoral vascular conductance or mean arterial pressure (P > 0.5). At 30 min postexercise on the control day, femoral vascular conductance was increased ( +33.7 ± 7.8%; P < 0.05 versus pre-exercise) while mean arterial pressure was reduced ( –6.5 ± 1.6 mmHg; P < 0.05 versus pre-exercise). In contrast, at 30 min postexercise on the fexofenadine day, femoral vascular conductance was not elevated ( +10.7 ± 9.8%; P = 0.7 versus pre-exercise) and mean arterial pressure was not reduced ( –1.7 ± 1.2 mmHg; P = 0.2 versus pre-exercise). Thus, ingestion of an H1 receptor antagonist markedly reduces vasodilatation after exercise and blunts postexercise hypotension. These data suggest H1 receptor-mediated vasodilatation contributes to postexercise hypotension.
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Introduction
Postexercise hypotension occurs after a single bout of dynamic exercise (Kenney & Seals, 1993; Halliwill, 2001; MacDonald, 2002). Although mechanisms behind postexercise hypotension have not been fully elucidated, this phenomenon, in most subjects, is due to a persistent rise in peripheral vascular conductance that is not completely offset by increases in cardiac output (Halliwill et al. 1996a, 1996b; Halliwill, 2001), although endurance-trained men are an exception (Senitko et al. 2002).
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The mechanisms of the vasodilatation underlying postexercise hypotension are poorly understood; several studies suggest an unknown vasodilator is largely responsible for the persistent vasodilatation. First, despite clear evidence of reduced sympathetic outflow to skeletal muscle vascular beds in humans (Floras et al. 1989; Halliwill et al. 1996a) and rats (Kulics et al. 1999), blockade of -adrenergic receptors was unable to reproduce the magnitude of postexercise vasodilatation in skeletal muscle (Halliwill et al. 2000). Second, despite evidence in support of vascular -adrenergic hyporesponsiveness in rats (Rao et al. 2002), 1- and 2-adrenergic vascular responsiveness is intact in humans (Halliwill et al. 2003). Several likely vasodilators have been studied in humans. Although nitric oxide contributes to postexercise vasodilatation in rats (Patil et al. 1993), inhibition of nitric oxide synthase does not reduce the postexercise vasodilatation in humans (Halliwill et al. 2000). Inhibition of cyclooxygenase also does not reduce the postexercise vasodilatation in humans (Lockwood et al. 2005). Therefore prostaglandins and nitric oxide do not seem to independently mediate postexercise hypotension in humans. The question remains, what is the identity of this unknown vasodilator in humans
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Histamine is stored and released by mast cells in most tissues and basophils in blood. Histamine levels have been shown to increase during and after exercise (Duner & Pernow, 1958; Harries et al. 1979; Campos et al. 1999), but it is unclear if histamine contributes to exercise hyperaemia or if there is a role for histamine to act as a vasodilatory signal after exercise. Physical stimuli such as vibration and heat have been suggested to cause histamine release from mast cells (Atkinson et al. 1992). Exercise might elicit histamine release via these stimuli. There is also evidence that sympathetic withdrawal can lead to histamine release (Beck, 1965; Brody, 1966; Powell & Brody, 1976; Rengo et al. 1978), and sympathetic withdrawal is a component of postexercise hypotension (Floras et al. 1989; Halliwill et al. 1996a; Kulics et al. 1999). Thus, there are several potential scenarios that could lead to histamine release during or after exercise. When released, histamine binds to histamine-1 receptors (H1) located on vascular endothelial cells and causes vasodilatation by the formation of local vasodilator substances, such as nitric oxide and prostacyclin (Hill, 1990; Brown & Roberts, 2001). Prior studies have independently assessed the role of nitric oxide (Halliwill et al. 2000) and prostaglandins (Lockwood et al. 2005) in postexercise hypotension in humans, but failed to provide evidence for the activation of either pathway. Histamine activates multiple pathways to cause vasodilatation, suggesting that there are redundant pathways leading to vasodilatation. With blockade of one pathway, vasodilatation would still be elicited through the other pathway; this would be consistent with our prior observations and is similar to what was recently reported during exercise hyperaemia (Schrage et al. 2004). A classic study by Morganroth et al. (1977) found that after exercise in dogs, an H1 receptor antagonist restores vascular resistance back to baseline values more rapidly than control. This suggests that H1 receptors might play a role in the immediate postexercise vasodilatation. Thus, it seems likely that histamine acting via H1 receptors might contribute to postexercise hypotension.
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Therefore, the goal of this study was to determine the potential contribution of H1 receptor-mediated vasodilatation to postexercise hypotension in humans. We tested the hypothesis that the regional vasodilatation in the leg vasculature during postexercise hypotension would be partially reversed by administration of fexofenadine hydrochloride, a substance that selectively blocks H1 receptors.
Methods
This study was approved by the Institutional Review Board of the University of Oregon, and each subject gave informed, written consent before participation. All studies were performed according to the Declaration of Helsinki.
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Subjects
A total of 14 healthy, non-smoking, normotensive subjects between the ages of 19 and 28 years participated in this study (7 men; 7 women). On the basis of their exercise habits over the prior 12 months, subjects were classified as ‘normally active’ (no regular endurance activity). These subjects participated in <2 h of aerobic exercise per week. Subjects were taking no medication other than oral contraceptives. Female subjects had a negative pregnancy test on both the screening and study days.
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Screening visit
Subjects reported to the laboratory for a screening visit and cycle ergometer test at least 2 h postprandially, and abstained from caffeine, alcohol and exercise for 24 h prior to the screening visit. Subjects performed an incremental cycle exercise test (Lode Excaliber, Groningen, the Netherlands) consisting of 1 min workload increments to determine peak O2 uptake . Specifically, after a 2-min warm-up period of easy cycling (20–30 W), workload increased at 20, 25, or 30 W every minute. 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, USA) integrated with a mass spectrometry system (Marquette MGA 1100, MA Tech Services, St. Louis, MO, USA). All subjects reached subjective exhaustion (rating of perceived exertion on the Borg (Borg, 1970) scale of 19–20) within the 8–12 min period. After the subjects rested for 15–20 min, they returned to the cycle ergometer for assessment of the workload corresponding to a steady state of 60% of . This workload was used on the two study days for the 60-min exercise bout. Subjects self-reported activity levels on two questionnaires (Baecke et al. 1982; Kohl et al. 1988).
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Study visits
For all study days, subjects reported for the study at least 2 h postprandially and abstained from caffeine for 12 h and from exercise and all medications for 24 h prior to the study. The second study day, for all male subjects, was at least 5 days and not more than 10 days after the first study day, providing more than adequate time for clearance of fexofenadine (half life 12 h (Russell et al. 1998)). Female subjects were studied during consecutive early follicular stages of the menstrual cycle or placebo phase of the oral contraceptive cycle.
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Experimental protocol
Subjects reported for parallel experiments on two separate days. The order of experiments was randomized between an H1 receptor antagonist and a control day. On study days, subjects were given water with or without fexofenadine 60 min before the start of exercise. The subjects were then laid in the supine position for instrumentation. A venous catheter was inserted into the right arm in the antecubital region, to obtain blood samples. Exercise consisted of a 60-min period of seated upright cycling at 60% . Exercise of this intensity and duration produces a sustained (2 h) postexercise hypotension (Halliwill, 2001). During exercise, subjects received 15 ml of water per kg of body weight to replace water loss due to sweating. Measurements were taken for 30 min before and through to 90 min after a 60-min bout of exercise. Baseline (pre-exercise), 30 min, 60 min, and 90 min postexercise measurements included cardiac output, heart rate, arterial pressure, leg blood flow, skin blood flow and a blood sample. During exercise, blood pressure and heart rate were measured every 10 min. At the end of the protocol, maximum skin blood flow values were obtained through local heating to 43°C. All pre- and postexercise measurements were made in the supine position.
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H1 receptor blockade and biochemical analyses
H1 receptors were blocked with 540 mg fexofenadine HCL (brand name: Allegra; Aventis Pharmaceuticals, Inc, Kansas City, MO, USA). 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) (Russell et al. 1998) and as a second-generation H1 receptor antagonist, fexofenadine does not cross into the central nervous system (Tashiro et al. 2004). Blockade of H1 receptors prevents the formation of local vasodilator substances such as nitric oxide and prostaglandins in response to histamine administration (Hill, 1990; Brown & Roberts, 2001). Blockade of H1 receptors does not alter histamine release and should not affect histamine concentrations. To assess histamine concentrations during the study, blood samples were taken via an intravenous catheter before exercise, during the last minute of exercise and postexercise at 30, 60, and 90 min. Whole-blood samples were centrifuged, separated, and stored at –80°C until analysis. The concentration of histamine was assessed by measuring plasma concentrations with a commercially available enzyme immunoassay kit, and was expressed in nanograms per millilitre (IBL-America, Minneapolis, MN, USA) (Duda et al. 1998). The reported lower limit for detection of histamine is 0.3 ng ml–1. Across the range of values in this study, interassay and intra-assay coefficients of variation are 11.5 and 7.8%.
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Sham study. To determine if fexofenadine might cause a non-specific vasoconstriction that could be superimposed on postexercise hypotension (masking the normal physiological response); we conducted a sham protocol on four of the male subjects. Subjects ingested the H1 receptor antagonist and then lay supine for instrumentation. Measurements were taken for 30 min before and through to 90 min after a 60-min bout of sham exercise (upright sitting). Baseline (pre-exercise), 30 min, 60 min, and 90 min post-sham measurements included cardiac output, heart rate, arterial pressure, leg blood flow, and skin blood flow. At the end of the protocol maximum skin blood flow values were obtained through local heating to 43°C. All pre- and post-sham measurements were made in the supine position.
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Measurements
Heart rate and arterial pressure. Heart rate and arterial pressure were monitored throughout all experimental procedures. Heart rate was monitored using a five-lead electrocardiogram (Q710, Quinton Instruments, Bothell, WA, USA). Arterial pressure was measured in the arm by using an automated auscultometric device (Dinamap Pro100 vital signs monitor, Critikon, Inc., Tampa, FL, USA).
Cardiac output. Cardiac output was estimated using an open-circuit acetylene washin method as developed by Stout et al. (Stout et al. 1975), modified by Gan et al. (1993), and validated in humans versus the direct Fick approach (Johnson et al. 2000). This method allows the non-invasive 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 rebreathing 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 non-rebreathing valve. During the washin phase, breath-by-breath acetylene and helium uptake were measured by a respiratory mass spectrometer (Marquette MGA 1100), and tidal volume was measured via a pneumotach (model 3700, Hans Rudolph, Kansas City, MO, USA) linearized by the technique of Yeh et al. (1982) and calibrated by using test gas before each study. The pneumotach and valve system had a combined dead space of 24 ml. Cardiac output calculations have been previously described (Johnson et al. 2000). Stroke volume was determined from cardiac output/heart rate. Systemic vascular conductance was calculated as cardiac output/mean arterial pressure, and expressed as ml min–1 mmHg–1.
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Leg blood flow. Femoral artery diameter and velocity were measured using an ultrasound probe (10 MHz linear-array vascular probe, GE Vingmed System 5, Horton, Norway). The entire width of the artery was insonated with an angle of 60 deg. Velocity measurements were taken immediately before diameter measurements. Leg blood flow was calculated as artery cross-sectional area multiplied by femoral mean blood velocity, doubled to represent both legs, and reported as ml min–1. Femoral vascular conductance was calculated as flow for both legs/mean arterial pressure and expressed as ml min–1 mmHg–1.
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Skin 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 one each on the forearm and thigh. 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 local heating to 43°C (Kellogg et al. 1998).
Plasma volume. In five subjects, the percentage changes in plasma and blood volume from pre-exercise were calculated from changes in haemoglobin and haematocrit by the method of Dill & Costill (1974).
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Data analysis
The individual analysing the data was blind regarding drug condition for each study day.
Statistics. Because there were no discernible differences between men and women, data from the two groups were combined for statistical analysis. The results were analysed with a repeated-measures two-way ANOVA (drug versus time). Significant effects were further tested with Fischer's LSD test, and differences were considered significant when P < 0.05. All values are reported as means ± S.E.M.
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Results
Subject characteristics are shown in Table 1. values were within the normal range for this population (39.5 ± 7.6 ml kg–1 min–1 (mean ± S.D)).
Pre-exercise haemodynamics
Supine resting heart rate was 53.8 ± 2.2 beats min–1 on the control day and 57.0 ± 4.3 beats min–1 on the H1-receptor antagonist day (fexofenadine day) (Table 2). Resting mean arterial pressure was 76.3 ± 1.3 mmHg on control day and 76.9 ± 1.9 mmHg on the fexofenadine day. There were no differences in resting heart rate and mean arterial pressure values between study days (P > 0.50).
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Exercise
The goal was to have subjects exercise for 60 min at 60% . On both days, the average workload was 129.5 ± 12.6 W. On the control day, heart rate was 138.0 ± 3.5 beats min–1 during exercise. This represented on average, 62.9 ± 1.9% heart rate reserve (heart rate reserve is defined as maximal heart rate achieved during testing minus the resting supine heart rate) and is consistent with the target workload. On the fexofenadine day, heart rate was 140.0 ± 4.4 beats min–1 during exercise. This represented on average, 63.4 ± 2.7% heart rate reserve and is consistent with the target workload. There were no differences in percentage heart rate reserve (P = 0.8) or the arterial pressure response to exercise (control 92.3 ± 1.7 mmHg; fexofenadine 92.7 ± 1.7 mmHg; P = 0.7) between the two study days.
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Postexercise haemodynamics
control day; fexofenadine day. *P < 0.05 versus pre-exercise; P < 0.05 versus control day at same time point. Values are means ± S.E.M.; n = 14.
Figure 2 shows the reduction in mean arterial pressure and the rise in systemic and femoral vascular conductances from baseline to 30 min postexercise. Mean arterial pressure was reduced 5–6 mmHg after exercise on the control day. This response was blunted on the fexofenadine day (P < 0.05 versus control day; Fig. 2A and B). Systemic vascular conductance was increased 20% after exercise on the control day. There was a tendency for this response to be blunted on the fexofenadine day (P < 0.08 versus control day; Fig. 2C and D). Femoral vascular conductance was increased 40% after exercise on control day. This response was blunted on the fexofenadine day (P < 0.05 versus control; Fig. 2E and F).
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Open bars denote control day; filled bars denote fexofenadine day. A, the absolute decrease in mean arterial pressure. B, the percentage decrease in mean arterial pressure. C, the absolute rise in systemic vascular conductance. D, the percentage rise in systemic vascular conductance. E, the absolute rise in femoral vascular conductance. F, the percentage rise in femoral vascular conductance. P-values are fexofenadine versus control day. Values are means ± S.E.M.;n = 14.
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Skin blood flow
Plasma and blood volume
During exercise both plasma volume ( –13.8 ± 2.7% control and –12.2 ± 3.8% fexofenadine; both P < 0.05) and blood volume ( –13.7 ± 3.8% control and –12.1 ± 3.8% fexofenadine; both P < 0.05) decreased from baseline. However, at 30 min postexercise, both plasma volume ( +0.2 ± 6.9% control and –0.5 ± 2.9% fexofenadine; both P = 0.95) and blood volume ( +0.2 ± 7.0% control and –0.5 ± 2.9% fexofenadine; both P = 0.74) had returned to pre-exercise levels. There were no differences in plasma or blood volume changes between the two study days (P > 0.57).
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Histamine concentration
The values of histamine concentrations did not differ between pre-exercise (control 0.36 ± 0.12 ng ml–1; fexofenadine 0.33 ± 0.18 ng ml–1), exercise (control 0.34 ± 0.11 ng ml–1; fexofenadine 0.33 ± 0.18 ng ml–1), or any of the postexercise measurements (control 0.40 ± 0.15 ng ml–1; fexofenadine 0.48 ± 0.20 ng ml–1; all time points P > 0.37 versus pre-exercise). There were no differences between study days (P = 0.97).
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Sham study
The four subjects that completed the sham protocol showed no differences in mean arterial pressure (P = 0.49), systemic (P = 0.79) and femoral vascular conductances (P = 0.92) throughout the sham protocol (Table 3).
Discussion
Postexercise hypotension after a single bout of aerobic exercise is due to an unexplained peripheral vasodilatation. The goal of this study was to determine the potential contribution of an H1 receptor-mediated vasodilatation to postexercise hypotension in humans. In agreement with our hypothesis, we found that administering the selective antagonist of H1 receptors, fexofenadine, resulted in a reduction in the vasodilatation after exercise and markedly blunted the magnitude of postexercise hypotension.
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Postexercise hypotension is characterized by a persistent rise in systemic vascular conductance that is not completely offset by increases in cardiac output (Halliwill, 2001). Forearm and calf vascular conductances are increased in parallel with systemic vascular conductance; thus the vasodilatation that underlies postexercise hypotension is not restricted to the sites of active skeletal muscles (Halliwill et al. 2000), however, this vasodilatation is not extended to the skin (Wilkins et al. 2004). This peripheral vasodilatation includes both a neural and a vascular component. Previously, Halliwill et al. (1996a) have shown in humans that the baroreflex is reset to a lower pressure after exercise, creating a reduction in sympathetic vasoconstrictor outflow. In addition, vascular responsiveness to sympathetic vasoconstrictor outflow is impaired so that vascular resistance is reduced for a given level of sympathetic nerve activity, independent of changes in -adrenergic receptor responsiveness (Halliwill et al. 2003). This suggests a presynaptic inhibition of noradrenaline (norepinephrine) release from sympathetic vasoconstrictor nerves following exercise. However, in another study by Halliwill et al. (2000) the increase in vascular conductance after exercise was greater than that observed after -adrenergic receptor blockade, suggesting the existence of a superimposed vasodilator signal. Prior studies have independently assessed the role of nitric oxide (Halliwill et al. 2000) and prostaglandins (Lockwood et al. 2005) in postexercise hypotension in humans, but failed to provide evidence for the activation of either pathway. This study considers the possibility that H1 receptors could mediate this vasodilator signal.
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Histamine is stored and released by mast cells within most tissues and by basophils in the blood. It can also be synthesized in non-mast cell tissues such as cells of the epidermis, cells in the gastric mucosa, neurones within the central nervous system, and cells in regenerating tissues, by the actions of L-histidine decarboxylase (Brown & Roberts, 2001). Once released, histamine binds to several histamine receptor subtypes. H1 receptors are predominately located on vascular endothelial cells and cause vasodilatation via formation of local vasodilators, such as nitric oxide and prostacyclin. H2 receptors are located predominately on smooth muscle cells and cause vasodilatation by decreasing intracellular calcium levels (Hill, 1990; Brown & Roberts, 2001). H3 receptors have been suggested to be located throughout tissues on presynaptic nerve terminals, and may cause vasodilatation by inhibiting noradrenaline (norepinephrine) release (Molderings et al. 1992) and/or by decreasing intracellular calcium levels (Brown & Roberts, 2001).
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Numerous substances and certain conditions have been suggested to cause mast cells and basophils to release histamine (Atkinson et al. 1992). It has been suggested that exercise causes histamine release; however, this is difficult to assess in humans as red blood cells actively take up histamine (Campos et al. 1999). Histamine levels have been measured in arterial and venous whole blood as well as venous plasma during and after high-intensity exercise (Duner & Pernow, 1958; Harries et al. 1979; Hartley et al. 1981; Morgan et al. 1983; Campos et al. 1999). However, these studies do not agree on an adequate method for collecting and analysing the concentration of histamine. In the present study, we measured venous plasma histamine concentration and found no changes in response to exercise. It is possible that systemic changes in histamine levels are masked by red blood cell uptake of histamine. In other words, plasma histamine concentration would be unchanged, yet whole-blood histamine concentration (which we did not measure) would be elevated. Another possibility is that histamine release is regional (i.e. in the legs) and is not elevated in the upper limbs. It is not yet known if the vasodilator signal in active and inactive muscles during recovery from exercise is the same. Next, it is possible that there is not an increase in histamine after exercise, but that exercise increases the sensitivity of the H1 receptors to histamine. Finally, it is possible that histamine is released locally and cleared before significant spillover into the circulation. With these last three scenarios, one would not suspect changes in histamine concentration in plasma or whole blood. Nonetheless, reduction of the peripheral vasodilatation during recovery from exercise with the H1 receptor antagonist would suggest a role for histamine, regardless of a measurable increase in histamine concentration. At this time, we are unable to determine if histamine is working in a paracrine or endocrine fashion.
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We have shown that the H1 receptor antagonist fexofenadine markedly reduced postexercise vasodilatation in the legs and blunted postexercise hypotension. However, we would be remiss if we did not also indicate that postexercise hypotension is a complex response mediated by multiple and redundant mechanisms. For example, we have shown that the leg vasculature only accounts for 34% of the rise in systemic vascular conductance (Pricher et al. 2004). As such, it is not surprising that blocking vasodilatation in the legs did not abolish the rise in systemic vascular conductance. Along these lines, the arterial baroreflex control of the skeletal muscle (Halliwill et al. 1996a), renal (Miki et al. 2003; Pricher et al. 2004), and splanchnic (Pricher et al. 2004) vascular beds appears to be reset to maintain a lower pressure during postexercise hypotension. As such, it is likely that these vascular beds undergo baroreflex-mediated sympathetic withdrawal in response to the reversal of vasodilatation in the leg. Thus, it is possible, or even likely, that failure of fexodenadine to blunt the postexercise rise in systemic vascular conductance is due to an increased vasodilatation in vascular beds other than the legs.
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The present study examined the role of H1 receptors; however, all three histamine receptors could be involved in postexercise hypotension. When H1 receptors are stimulated, the vasodilatation produced has a rapid onset and is short-lived; however, H2 receptors produce an extended period of vasodilatation after a slow onset (Brown & Roberts, 2001). It could be that both H1 and H2 receptors mediate postexercise hypotension. The stimulation of H1 receptors could play a more significant role in the early postexercise hypotension (30–60 min), whereas H2 receptors would become involved in the later stages of postexercise hypotension (60–120 min). This would be consistent with the present study where we show a striking difference in the mean arterial pressure response at 30 min after exercise between the two study days, but a less marked difference between the fexofenadine and control days at 60 and 90 min after exercise. H3 receptors could also play a role by inhibiting presynaptic release of noradrenaline (norepinephrine) (Molderings et al. 1992). Along these lines, Halliwill et al. (1996a) showed that vascular responsiveness to sympathetic vasoconstrictor outflow is impaired postexercise, so that vascular resistance is reduced for a given level of sympathetic nerve activity, independent of changes in -adrenergic receptor responsiveness. Thus, if H3 receptors are stimulated during and after exercise, they could explain this observation of impaired vascular transduction. We can only speculate at this time regarding the roles of H2 and H3 receptors, but it seems plausible that the release of histamine would also affect these receptors.
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Alternative interpretations
Have we identified the unknown vasodilator underlying postexercise hypotension Fexofenadine is a second-generation H1 receptor antagonist and highly selective for H1 receptors (Brown & Roberts, 2001). Histamine is the most likely candidate to bind to H1 receptors; however, other compounds might be able to bind and activate H1 receptors. Therefore, we cannot say with certainty that histamine is the unknown vasodilator. Confirmation might depend on quantifying changes in histamine levels or demonstrating the involvement of other histamine receptor subtypes. Nonetheless, histamine appears to be the most likely candidate at this time.
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Wong et al. (2004) recently found that H1 receptors contribute to the rise in skin blood flow during whole-body heating. However, our lab has previously shown that skin blood flow does not contribute to postexercise hypotension (Wilkins et al. 2004). Nonetheless, we have considered the possibility that a reduction in cutaneous vascular conductance contributes to the decrease in femoral vascular conductance with fexofenadine. In the current study, we found no differences in skin blood flow between the two study days, despite a reduction in femoral artery blood flow with the H1 receptor antagonist. These results suggest the reduction in the magnitude of postexercise hypotension, with fexofenadine, is not due to decreased cutaneous vasodilatation, but results from a decrease in skeletal muscle vasodilatation.
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We have also considered the possibility that fexofenadine caused vasoconstriction that is superimposed on the postexercise hypotension response. To address this concern, we conducted a time control study (sham exercise) in four of the subjects, and found no differences in mean arterial pressure, or systemic vascular conductance, or femoral vascular conductance across time. Thus, it seems unlikely that the effect on postexercise hypotension is due to the H1 receptor antagonist causing non-specific vasoconstriction.
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We also considered the possibility that fexofenadine altered plasma volume dynamics or changed cardiac haemodynamics. For example, the blunting of postexercise hypotension from fexofenadine might be due to a decrease in plasma volume recovery instead of a decrease in peripheral vasodilatation. However, we found plasma volume recovery after exercise, and cardiac haemodynamics to be unaltered by fexofenadine. Clearly, these alternative explanations are not the reason postexercise hypotension was blunted.
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Clinical significance
Our findings suggest that H1 receptors play an important role in the postexercise response. Thus, over-the-counter and prescription drug treatments for allergies could challenge the antihypertensive benefits of exercise by altering the normal blood pressure response to exercise.
Conclusion
In conclusion, ingestion of an H1 receptor antagonist markedly reduces vasodilatation after exercise and blunts postexercise hypotension. These data suggest an H1 receptor-mediated vasodilatation contributes to postexercise hypotension in humans.
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Abstract
In normally active individuals, postexercise hypotension after a single bout of aerobic exercise is due to an unexplained peripheral vasodilatation. Histamine has been shown to be released during exercise and could contribute to postexercise vasodilatation via H1 receptors in the peripheral vasculature. The purpose of this study was to determine the potential contribution of an H1 receptor-mediated vasodilatation to postexercise hypotension. We studied 14 healthy normotensive men and women (ages 21.9 ± 2.1 years) before and through to 90 min after a 60 min bout of cycling at 60% on randomized control and H1 receptor antagonist days (540 mg oral fexofenadine hydrochloride; Allegra). Arterial blood pressure (automated auscultation) and femoral blood flow (Doppler ultrasound) were measured in the supine position. Femoral vascular conductance was calculated as flow/pressure. Fexofenadine had no effect on pre-exercise femoral vascular conductance or mean arterial pressure (P > 0.5). At 30 min postexercise on the control day, femoral vascular conductance was increased ( +33.7 ± 7.8%; P < 0.05 versus pre-exercise) while mean arterial pressure was reduced ( –6.5 ± 1.6 mmHg; P < 0.05 versus pre-exercise). In contrast, at 30 min postexercise on the fexofenadine day, femoral vascular conductance was not elevated ( +10.7 ± 9.8%; P = 0.7 versus pre-exercise) and mean arterial pressure was not reduced ( –1.7 ± 1.2 mmHg; P = 0.2 versus pre-exercise). Thus, ingestion of an H1 receptor antagonist markedly reduces vasodilatation after exercise and blunts postexercise hypotension. These data suggest H1 receptor-mediated vasodilatation contributes to postexercise hypotension.
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Introduction
Postexercise hypotension occurs after a single bout of dynamic exercise (Kenney & Seals, 1993; Halliwill, 2001; MacDonald, 2002). Although mechanisms behind postexercise hypotension have not been fully elucidated, this phenomenon, in most subjects, is due to a persistent rise in peripheral vascular conductance that is not completely offset by increases in cardiac output (Halliwill et al. 1996a, 1996b; Halliwill, 2001), although endurance-trained men are an exception (Senitko et al. 2002).
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The mechanisms of the vasodilatation underlying postexercise hypotension are poorly understood; several studies suggest an unknown vasodilator is largely responsible for the persistent vasodilatation. First, despite clear evidence of reduced sympathetic outflow to skeletal muscle vascular beds in humans (Floras et al. 1989; Halliwill et al. 1996a) and rats (Kulics et al. 1999), blockade of -adrenergic receptors was unable to reproduce the magnitude of postexercise vasodilatation in skeletal muscle (Halliwill et al. 2000). Second, despite evidence in support of vascular -adrenergic hyporesponsiveness in rats (Rao et al. 2002), 1- and 2-adrenergic vascular responsiveness is intact in humans (Halliwill et al. 2003). Several likely vasodilators have been studied in humans. Although nitric oxide contributes to postexercise vasodilatation in rats (Patil et al. 1993), inhibition of nitric oxide synthase does not reduce the postexercise vasodilatation in humans (Halliwill et al. 2000). Inhibition of cyclooxygenase also does not reduce the postexercise vasodilatation in humans (Lockwood et al. 2005). Therefore prostaglandins and nitric oxide do not seem to independently mediate postexercise hypotension in humans. The question remains, what is the identity of this unknown vasodilator in humans
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Histamine is stored and released by mast cells in most tissues and basophils in blood. Histamine levels have been shown to increase during and after exercise (Duner & Pernow, 1958; Harries et al. 1979; Campos et al. 1999), but it is unclear if histamine contributes to exercise hyperaemia or if there is a role for histamine to act as a vasodilatory signal after exercise. Physical stimuli such as vibration and heat have been suggested to cause histamine release from mast cells (Atkinson et al. 1992). Exercise might elicit histamine release via these stimuli. There is also evidence that sympathetic withdrawal can lead to histamine release (Beck, 1965; Brody, 1966; Powell & Brody, 1976; Rengo et al. 1978), and sympathetic withdrawal is a component of postexercise hypotension (Floras et al. 1989; Halliwill et al. 1996a; Kulics et al. 1999). Thus, there are several potential scenarios that could lead to histamine release during or after exercise. When released, histamine binds to histamine-1 receptors (H1) located on vascular endothelial cells and causes vasodilatation by the formation of local vasodilator substances, such as nitric oxide and prostacyclin (Hill, 1990; Brown & Roberts, 2001). Prior studies have independently assessed the role of nitric oxide (Halliwill et al. 2000) and prostaglandins (Lockwood et al. 2005) in postexercise hypotension in humans, but failed to provide evidence for the activation of either pathway. Histamine activates multiple pathways to cause vasodilatation, suggesting that there are redundant pathways leading to vasodilatation. With blockade of one pathway, vasodilatation would still be elicited through the other pathway; this would be consistent with our prior observations and is similar to what was recently reported during exercise hyperaemia (Schrage et al. 2004). A classic study by Morganroth et al. (1977) found that after exercise in dogs, an H1 receptor antagonist restores vascular resistance back to baseline values more rapidly than control. This suggests that H1 receptors might play a role in the immediate postexercise vasodilatation. Thus, it seems likely that histamine acting via H1 receptors might contribute to postexercise hypotension.
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Therefore, the goal of this study was to determine the potential contribution of H1 receptor-mediated vasodilatation to postexercise hypotension in humans. We tested the hypothesis that the regional vasodilatation in the leg vasculature during postexercise hypotension would be partially reversed by administration of fexofenadine hydrochloride, a substance that selectively blocks H1 receptors.
Methods
This study was approved by the Institutional Review Board of the University of Oregon, and each subject gave informed, written consent before participation. All studies were performed according to the Declaration of Helsinki.
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Subjects
A total of 14 healthy, non-smoking, normotensive subjects between the ages of 19 and 28 years participated in this study (7 men; 7 women). On the basis of their exercise habits over the prior 12 months, subjects were classified as ‘normally active’ (no regular endurance activity). These subjects participated in <2 h of aerobic exercise per week. Subjects were taking no medication other than oral contraceptives. Female subjects had a negative pregnancy test on both the screening and study days.
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Screening visit
Subjects reported to the laboratory for a screening visit and cycle ergometer test at least 2 h postprandially, and abstained from caffeine, alcohol and exercise for 24 h prior to the screening visit. Subjects performed an incremental cycle exercise test (Lode Excaliber, Groningen, the Netherlands) consisting of 1 min workload increments to determine peak O2 uptake . Specifically, after a 2-min warm-up period of easy cycling (20–30 W), workload increased at 20, 25, or 30 W every minute. 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, USA) integrated with a mass spectrometry system (Marquette MGA 1100, MA Tech Services, St. Louis, MO, USA). All subjects reached subjective exhaustion (rating of perceived exertion on the Borg (Borg, 1970) scale of 19–20) within the 8–12 min period. After the subjects rested for 15–20 min, they returned to the cycle ergometer for assessment of the workload corresponding to a steady state of 60% of . This workload was used on the two study days for the 60-min exercise bout. Subjects self-reported activity levels on two questionnaires (Baecke et al. 1982; Kohl et al. 1988).
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Study visits
For all study days, subjects reported for the study at least 2 h postprandially and abstained from caffeine for 12 h and from exercise and all medications for 24 h prior to the study. The second study day, for all male subjects, was at least 5 days and not more than 10 days after the first study day, providing more than adequate time for clearance of fexofenadine (half life 12 h (Russell et al. 1998)). Female subjects were studied during consecutive early follicular stages of the menstrual cycle or placebo phase of the oral contraceptive cycle.
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Experimental protocol
Subjects reported for parallel experiments on two separate days. The order of experiments was randomized between an H1 receptor antagonist and a control day. On study days, subjects were given water with or without fexofenadine 60 min before the start of exercise. The subjects were then laid in the supine position for instrumentation. A venous catheter was inserted into the right arm in the antecubital region, to obtain blood samples. Exercise consisted of a 60-min period of seated upright cycling at 60% . Exercise of this intensity and duration produces a sustained (2 h) postexercise hypotension (Halliwill, 2001). During exercise, subjects received 15 ml of water per kg of body weight to replace water loss due to sweating. Measurements were taken for 30 min before and through to 90 min after a 60-min bout of exercise. Baseline (pre-exercise), 30 min, 60 min, and 90 min postexercise measurements included cardiac output, heart rate, arterial pressure, leg blood flow, skin blood flow and a blood sample. During exercise, blood pressure and heart rate were measured every 10 min. At the end of the protocol, maximum skin blood flow values were obtained through local heating to 43°C. All pre- and postexercise measurements were made in the supine position.
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H1 receptor blockade and biochemical analyses
H1 receptors were blocked with 540 mg fexofenadine HCL (brand name: Allegra; Aventis Pharmaceuticals, Inc, Kansas City, MO, USA). 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) (Russell et al. 1998) and as a second-generation H1 receptor antagonist, fexofenadine does not cross into the central nervous system (Tashiro et al. 2004). Blockade of H1 receptors prevents the formation of local vasodilator substances such as nitric oxide and prostaglandins in response to histamine administration (Hill, 1990; Brown & Roberts, 2001). Blockade of H1 receptors does not alter histamine release and should not affect histamine concentrations. To assess histamine concentrations during the study, blood samples were taken via an intravenous catheter before exercise, during the last minute of exercise and postexercise at 30, 60, and 90 min. Whole-blood samples were centrifuged, separated, and stored at –80°C until analysis. The concentration of histamine was assessed by measuring plasma concentrations with a commercially available enzyme immunoassay kit, and was expressed in nanograms per millilitre (IBL-America, Minneapolis, MN, USA) (Duda et al. 1998). The reported lower limit for detection of histamine is 0.3 ng ml–1. Across the range of values in this study, interassay and intra-assay coefficients of variation are 11.5 and 7.8%.
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Sham study. To determine if fexofenadine might cause a non-specific vasoconstriction that could be superimposed on postexercise hypotension (masking the normal physiological response); we conducted a sham protocol on four of the male subjects. Subjects ingested the H1 receptor antagonist and then lay supine for instrumentation. Measurements were taken for 30 min before and through to 90 min after a 60-min bout of sham exercise (upright sitting). Baseline (pre-exercise), 30 min, 60 min, and 90 min post-sham measurements included cardiac output, heart rate, arterial pressure, leg blood flow, and skin blood flow. At the end of the protocol maximum skin blood flow values were obtained through local heating to 43°C. All pre- and post-sham measurements were made in the supine position.
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Measurements
Heart rate and arterial pressure. Heart rate and arterial pressure were monitored throughout all experimental procedures. Heart rate was monitored using a five-lead electrocardiogram (Q710, Quinton Instruments, Bothell, WA, USA). Arterial pressure was measured in the arm by using an automated auscultometric device (Dinamap Pro100 vital signs monitor, Critikon, Inc., Tampa, FL, USA).
Cardiac output. Cardiac output was estimated using an open-circuit acetylene washin method as developed by Stout et al. (Stout et al. 1975), modified by Gan et al. (1993), and validated in humans versus the direct Fick approach (Johnson et al. 2000). This method allows the non-invasive 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 rebreathing 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 non-rebreathing valve. During the washin phase, breath-by-breath acetylene and helium uptake were measured by a respiratory mass spectrometer (Marquette MGA 1100), and tidal volume was measured via a pneumotach (model 3700, Hans Rudolph, Kansas City, MO, USA) linearized by the technique of Yeh et al. (1982) and calibrated by using test gas before each study. The pneumotach and valve system had a combined dead space of 24 ml. Cardiac output calculations have been previously described (Johnson et al. 2000). Stroke volume was determined from cardiac output/heart rate. Systemic vascular conductance was calculated as cardiac output/mean arterial pressure, and expressed as ml min–1 mmHg–1.
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Leg blood flow. Femoral artery diameter and velocity were measured using an ultrasound probe (10 MHz linear-array vascular probe, GE Vingmed System 5, Horton, Norway). The entire width of the artery was insonated with an angle of 60 deg. Velocity measurements were taken immediately before diameter measurements. Leg blood flow was calculated as artery cross-sectional area multiplied by femoral mean blood velocity, doubled to represent both legs, and reported as ml min–1. Femoral vascular conductance was calculated as flow for both legs/mean arterial pressure and expressed as ml min–1 mmHg–1.
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Skin 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 one each on the forearm and thigh. 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 local heating to 43°C (Kellogg et al. 1998).
Plasma volume. In five subjects, the percentage changes in plasma and blood volume from pre-exercise were calculated from changes in haemoglobin and haematocrit by the method of Dill & Costill (1974).
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Data analysis
The individual analysing the data was blind regarding drug condition for each study day.
Statistics. Because there were no discernible differences between men and women, data from the two groups were combined for statistical analysis. The results were analysed with a repeated-measures two-way ANOVA (drug versus time). Significant effects were further tested with Fischer's LSD test, and differences were considered significant when P < 0.05. All values are reported as means ± S.E.M.
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Results
Subject characteristics are shown in Table 1. values were within the normal range for this population (39.5 ± 7.6 ml kg–1 min–1 (mean ± S.D)).
Pre-exercise haemodynamics
Supine resting heart rate was 53.8 ± 2.2 beats min–1 on the control day and 57.0 ± 4.3 beats min–1 on the H1-receptor antagonist day (fexofenadine day) (Table 2). Resting mean arterial pressure was 76.3 ± 1.3 mmHg on control day and 76.9 ± 1.9 mmHg on the fexofenadine day. There were no differences in resting heart rate and mean arterial pressure values between study days (P > 0.50).
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Exercise
The goal was to have subjects exercise for 60 min at 60% . On both days, the average workload was 129.5 ± 12.6 W. On the control day, heart rate was 138.0 ± 3.5 beats min–1 during exercise. This represented on average, 62.9 ± 1.9% heart rate reserve (heart rate reserve is defined as maximal heart rate achieved during testing minus the resting supine heart rate) and is consistent with the target workload. On the fexofenadine day, heart rate was 140.0 ± 4.4 beats min–1 during exercise. This represented on average, 63.4 ± 2.7% heart rate reserve and is consistent with the target workload. There were no differences in percentage heart rate reserve (P = 0.8) or the arterial pressure response to exercise (control 92.3 ± 1.7 mmHg; fexofenadine 92.7 ± 1.7 mmHg; P = 0.7) between the two study days.
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Postexercise haemodynamics
control day; fexofenadine day. *P < 0.05 versus pre-exercise; P < 0.05 versus control day at same time point. Values are means ± S.E.M.; n = 14.
Figure 2 shows the reduction in mean arterial pressure and the rise in systemic and femoral vascular conductances from baseline to 30 min postexercise. Mean arterial pressure was reduced 5–6 mmHg after exercise on the control day. This response was blunted on the fexofenadine day (P < 0.05 versus control day; Fig. 2A and B). Systemic vascular conductance was increased 20% after exercise on the control day. There was a tendency for this response to be blunted on the fexofenadine day (P < 0.08 versus control day; Fig. 2C and D). Femoral vascular conductance was increased 40% after exercise on control day. This response was blunted on the fexofenadine day (P < 0.05 versus control; Fig. 2E and F).
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Open bars denote control day; filled bars denote fexofenadine day. A, the absolute decrease in mean arterial pressure. B, the percentage decrease in mean arterial pressure. C, the absolute rise in systemic vascular conductance. D, the percentage rise in systemic vascular conductance. E, the absolute rise in femoral vascular conductance. F, the percentage rise in femoral vascular conductance. P-values are fexofenadine versus control day. Values are means ± S.E.M.;n = 14.
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Skin blood flow
Plasma and blood volume
During exercise both plasma volume ( –13.8 ± 2.7% control and –12.2 ± 3.8% fexofenadine; both P < 0.05) and blood volume ( –13.7 ± 3.8% control and –12.1 ± 3.8% fexofenadine; both P < 0.05) decreased from baseline. However, at 30 min postexercise, both plasma volume ( +0.2 ± 6.9% control and –0.5 ± 2.9% fexofenadine; both P = 0.95) and blood volume ( +0.2 ± 7.0% control and –0.5 ± 2.9% fexofenadine; both P = 0.74) had returned to pre-exercise levels. There were no differences in plasma or blood volume changes between the two study days (P > 0.57).
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Histamine concentration
The values of histamine concentrations did not differ between pre-exercise (control 0.36 ± 0.12 ng ml–1; fexofenadine 0.33 ± 0.18 ng ml–1), exercise (control 0.34 ± 0.11 ng ml–1; fexofenadine 0.33 ± 0.18 ng ml–1), or any of the postexercise measurements (control 0.40 ± 0.15 ng ml–1; fexofenadine 0.48 ± 0.20 ng ml–1; all time points P > 0.37 versus pre-exercise). There were no differences between study days (P = 0.97).
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Sham study
The four subjects that completed the sham protocol showed no differences in mean arterial pressure (P = 0.49), systemic (P = 0.79) and femoral vascular conductances (P = 0.92) throughout the sham protocol (Table 3).
Discussion
Postexercise hypotension after a single bout of aerobic exercise is due to an unexplained peripheral vasodilatation. The goal of this study was to determine the potential contribution of an H1 receptor-mediated vasodilatation to postexercise hypotension in humans. In agreement with our hypothesis, we found that administering the selective antagonist of H1 receptors, fexofenadine, resulted in a reduction in the vasodilatation after exercise and markedly blunted the magnitude of postexercise hypotension.
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Postexercise hypotension is characterized by a persistent rise in systemic vascular conductance that is not completely offset by increases in cardiac output (Halliwill, 2001). Forearm and calf vascular conductances are increased in parallel with systemic vascular conductance; thus the vasodilatation that underlies postexercise hypotension is not restricted to the sites of active skeletal muscles (Halliwill et al. 2000), however, this vasodilatation is not extended to the skin (Wilkins et al. 2004). This peripheral vasodilatation includes both a neural and a vascular component. Previously, Halliwill et al. (1996a) have shown in humans that the baroreflex is reset to a lower pressure after exercise, creating a reduction in sympathetic vasoconstrictor outflow. In addition, vascular responsiveness to sympathetic vasoconstrictor outflow is impaired so that vascular resistance is reduced for a given level of sympathetic nerve activity, independent of changes in -adrenergic receptor responsiveness (Halliwill et al. 2003). This suggests a presynaptic inhibition of noradrenaline (norepinephrine) release from sympathetic vasoconstrictor nerves following exercise. However, in another study by Halliwill et al. (2000) the increase in vascular conductance after exercise was greater than that observed after -adrenergic receptor blockade, suggesting the existence of a superimposed vasodilator signal. Prior studies have independently assessed the role of nitric oxide (Halliwill et al. 2000) and prostaglandins (Lockwood et al. 2005) in postexercise hypotension in humans, but failed to provide evidence for the activation of either pathway. This study considers the possibility that H1 receptors could mediate this vasodilator signal.
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Histamine is stored and released by mast cells within most tissues and by basophils in the blood. It can also be synthesized in non-mast cell tissues such as cells of the epidermis, cells in the gastric mucosa, neurones within the central nervous system, and cells in regenerating tissues, by the actions of L-histidine decarboxylase (Brown & Roberts, 2001). Once released, histamine binds to several histamine receptor subtypes. H1 receptors are predominately located on vascular endothelial cells and cause vasodilatation via formation of local vasodilators, such as nitric oxide and prostacyclin. H2 receptors are located predominately on smooth muscle cells and cause vasodilatation by decreasing intracellular calcium levels (Hill, 1990; Brown & Roberts, 2001). H3 receptors have been suggested to be located throughout tissues on presynaptic nerve terminals, and may cause vasodilatation by inhibiting noradrenaline (norepinephrine) release (Molderings et al. 1992) and/or by decreasing intracellular calcium levels (Brown & Roberts, 2001).
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Numerous substances and certain conditions have been suggested to cause mast cells and basophils to release histamine (Atkinson et al. 1992). It has been suggested that exercise causes histamine release; however, this is difficult to assess in humans as red blood cells actively take up histamine (Campos et al. 1999). Histamine levels have been measured in arterial and venous whole blood as well as venous plasma during and after high-intensity exercise (Duner & Pernow, 1958; Harries et al. 1979; Hartley et al. 1981; Morgan et al. 1983; Campos et al. 1999). However, these studies do not agree on an adequate method for collecting and analysing the concentration of histamine. In the present study, we measured venous plasma histamine concentration and found no changes in response to exercise. It is possible that systemic changes in histamine levels are masked by red blood cell uptake of histamine. In other words, plasma histamine concentration would be unchanged, yet whole-blood histamine concentration (which we did not measure) would be elevated. Another possibility is that histamine release is regional (i.e. in the legs) and is not elevated in the upper limbs. It is not yet known if the vasodilator signal in active and inactive muscles during recovery from exercise is the same. Next, it is possible that there is not an increase in histamine after exercise, but that exercise increases the sensitivity of the H1 receptors to histamine. Finally, it is possible that histamine is released locally and cleared before significant spillover into the circulation. With these last three scenarios, one would not suspect changes in histamine concentration in plasma or whole blood. Nonetheless, reduction of the peripheral vasodilatation during recovery from exercise with the H1 receptor antagonist would suggest a role for histamine, regardless of a measurable increase in histamine concentration. At this time, we are unable to determine if histamine is working in a paracrine or endocrine fashion.
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We have shown that the H1 receptor antagonist fexofenadine markedly reduced postexercise vasodilatation in the legs and blunted postexercise hypotension. However, we would be remiss if we did not also indicate that postexercise hypotension is a complex response mediated by multiple and redundant mechanisms. For example, we have shown that the leg vasculature only accounts for 34% of the rise in systemic vascular conductance (Pricher et al. 2004). As such, it is not surprising that blocking vasodilatation in the legs did not abolish the rise in systemic vascular conductance. Along these lines, the arterial baroreflex control of the skeletal muscle (Halliwill et al. 1996a), renal (Miki et al. 2003; Pricher et al. 2004), and splanchnic (Pricher et al. 2004) vascular beds appears to be reset to maintain a lower pressure during postexercise hypotension. As such, it is likely that these vascular beds undergo baroreflex-mediated sympathetic withdrawal in response to the reversal of vasodilatation in the leg. Thus, it is possible, or even likely, that failure of fexodenadine to blunt the postexercise rise in systemic vascular conductance is due to an increased vasodilatation in vascular beds other than the legs.
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The present study examined the role of H1 receptors; however, all three histamine receptors could be involved in postexercise hypotension. When H1 receptors are stimulated, the vasodilatation produced has a rapid onset and is short-lived; however, H2 receptors produce an extended period of vasodilatation after a slow onset (Brown & Roberts, 2001). It could be that both H1 and H2 receptors mediate postexercise hypotension. The stimulation of H1 receptors could play a more significant role in the early postexercise hypotension (30–60 min), whereas H2 receptors would become involved in the later stages of postexercise hypotension (60–120 min). This would be consistent with the present study where we show a striking difference in the mean arterial pressure response at 30 min after exercise between the two study days, but a less marked difference between the fexofenadine and control days at 60 and 90 min after exercise. H3 receptors could also play a role by inhibiting presynaptic release of noradrenaline (norepinephrine) (Molderings et al. 1992). Along these lines, Halliwill et al. (1996a) showed that vascular responsiveness to sympathetic vasoconstrictor outflow is impaired postexercise, so that vascular resistance is reduced for a given level of sympathetic nerve activity, independent of changes in -adrenergic receptor responsiveness. Thus, if H3 receptors are stimulated during and after exercise, they could explain this observation of impaired vascular transduction. We can only speculate at this time regarding the roles of H2 and H3 receptors, but it seems plausible that the release of histamine would also affect these receptors.
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Alternative interpretations
Have we identified the unknown vasodilator underlying postexercise hypotension Fexofenadine is a second-generation H1 receptor antagonist and highly selective for H1 receptors (Brown & Roberts, 2001). Histamine is the most likely candidate to bind to H1 receptors; however, other compounds might be able to bind and activate H1 receptors. Therefore, we cannot say with certainty that histamine is the unknown vasodilator. Confirmation might depend on quantifying changes in histamine levels or demonstrating the involvement of other histamine receptor subtypes. Nonetheless, histamine appears to be the most likely candidate at this time.
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Wong et al. (2004) recently found that H1 receptors contribute to the rise in skin blood flow during whole-body heating. However, our lab has previously shown that skin blood flow does not contribute to postexercise hypotension (Wilkins et al. 2004). Nonetheless, we have considered the possibility that a reduction in cutaneous vascular conductance contributes to the decrease in femoral vascular conductance with fexofenadine. In the current study, we found no differences in skin blood flow between the two study days, despite a reduction in femoral artery blood flow with the H1 receptor antagonist. These results suggest the reduction in the magnitude of postexercise hypotension, with fexofenadine, is not due to decreased cutaneous vasodilatation, but results from a decrease in skeletal muscle vasodilatation.
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We have also considered the possibility that fexofenadine caused vasoconstriction that is superimposed on the postexercise hypotension response. To address this concern, we conducted a time control study (sham exercise) in four of the subjects, and found no differences in mean arterial pressure, or systemic vascular conductance, or femoral vascular conductance across time. Thus, it seems unlikely that the effect on postexercise hypotension is due to the H1 receptor antagonist causing non-specific vasoconstriction.
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We also considered the possibility that fexofenadine altered plasma volume dynamics or changed cardiac haemodynamics. For example, the blunting of postexercise hypotension from fexofenadine might be due to a decrease in plasma volume recovery instead of a decrease in peripheral vasodilatation. However, we found plasma volume recovery after exercise, and cardiac haemodynamics to be unaltered by fexofenadine. Clearly, these alternative explanations are not the reason postexercise hypotension was blunted.
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Clinical significance
Our findings suggest that H1 receptors play an important role in the postexercise response. Thus, over-the-counter and prescription drug treatments for allergies could challenge the antihypertensive benefits of exercise by altering the normal blood pressure response to exercise.
Conclusion
In conclusion, ingestion of an H1 receptor antagonist markedly reduces vasodilatation after exercise and blunts postexercise hypotension. These data suggest an H1 receptor-mediated vasodilatation contributes to postexercise hypotension in humans.
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