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1 The Copenhagen Muscle Research Centre, Departments of Anaesthesia, Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark2 The Copenhagen Muscle Research Centre, Departments of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark 3 Department of Medical Physiology, The Panum Institute, University of Copenhagen, Denmark 4 School of Sport and Education, Brunel University, Middlesex, UK
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(Received 27 January 2006;
accepted after revision 27 April 2006; first published online 4 May 2006)
Corresponding author S. Volianitis: Department of Anaesthesia, AN 2041, Rigshospitalet, Blegdamsvej 9, Copenhagen Ø, 2100 Denmark. Email: stefanos.volianitis{at}excite.com
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Introduction |
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This investigation evaluated the effect of A, L and A + L, in both upright and supine postures, on atrial natriuretic peptide (ANP). This peptide is synthesized in the atria secondary to atrial stretch and provides a potent defence mechanism against volume overload by promoting natriuresis, diuresis, vasodilatation and suppression of the renin–angiotensin–aldosterone system (Davidson & Struthers, 1994; Stein & Levin, 1998). Plasma ANP increases during exercise (Freund et al. 1988) and, even though its concentration may be affected by, for instance, angiotensin II, sympathetic stimulation, endothelin-1 and heart rate, its correlation with atrial filling allows for an indirect evaluation of CBV (Freund et al. 1988; Ray et al. 1990; Matzen et al. 1990; Perko et al. 1994; Perrault et al. 1998).
Supine exercise was used to manipulate CBV because it enhances venous return and atrial filling (Thadani & Parker, 1978). We hypothesized that plasma ANP would remain low during upright A, in which the leg muscle pump is considered not to enhance CBV, while CBV would increase during upright L and A + L and supine exercise, including supine A. In order to evaluate changes in CBV, central venous pressure (CVP) was determined during A, L and A + L exercise in both the upright seated and supine positions. We also evaluated whether brain natriuretic peptide (BNP) and arginine vasopressin (AVP), which are released in response to central hypervolaemia (Vanderheyden et al. 2004) and hypovolaemia, respectively, are sensitive to exercise and to a change in posture.
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Methods |
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Experimental design
On each of the two experimental days, separated by at least 3 days, the subjects performed in random order upright or supine A, L and A + L lasting 15–20 min, each separated by 
30 min so that plasma volume (Mack et al. 1998), plasma ANP values (Ray et al. 1990) and heart rate (HR) could return to pre-exercise levels. The order of the experimental days, i.e. upright or supine trials, was also randomized. The A was performed on an arm-cranking ergometer (Monark, Varberg, Sweden), and a similar ergometer was used for L when the subject was upright. In the supine position, L was carried out on an electrically braked cycle (Bosch, Berlin, Germany). The workloads for A (38.4 ± 11.2 W) and L (65.9 ± 16.6 W) were determined during a pretest, in which 5 min trials of upright A or L with increasing workloads were performed so that HR during A and L reached 110 and 120 beats min–1, respectively. These target HRs were chosen so that a direct comparison with the workloads used in previous evaluation of baroreflex function during arm and leg exercise can be made (Volianitis et al. 2004b). These workloads were maintained for A + L and for the supine trials.
A catheter (1.1 mm i.d., 20 gauge) was inserted into the radial artery of the non-dominant arm and kept patent by infusion of isotonic saline at 3 ml min–1 through a pressure-monitoring kit (Baxter, Uden, The Netherlands). The transducer was positioned at the level of the heart and pressure registered on a monitor (Dialogue 2000, Copenhagen, Denmark). Heart rate was obtained from a three-lead ECG (Medicotest Q-10-A, Copenhagen, Denmark) with the electrodes placed on the sternum and the cervical vertebrae to minimize noise from the working muscles.
Blood samples were drawn at rest, after 1 min and at the end of each exercise bout into tubes containing EDTA and aprotinin (Trasylol®, Bayer, Leverkusen, Germany). The samples were centrifuged at 10 000 r.p.m. for 10 min, and plasma was transferred to polyethylene tubes, immediately frozen and kept at –20°C until analysed. Plasma ANP was measured by a radioimmunoassay (RIA) of plasma extracted by means of C18 Sep-Pak cartridges (Schütten et al. 1987). The sensitivity of the assay was 3.1 pg ml–1, and the intra- and interassay coefficients of variation were 4 and 5%, respectively. Plasma BNP was measured by an automated two-site sandwich immunoassay technique using chemiluminescent technology (ADVIA Centaur, Bayer) to assess the C-terminal peptide (77–108). The sensitivity of the assay was 2 pg ml–1, and the intra- and interassay coefficients of variation were 1.2 and 2.3%, respectively, with a recovery in spiked samples of 93–98%. Plasma AVP was measured by a RIA of plasma extracted by means of C18 Sep-Pak cartridges with coefficients of variation and recovery similar to the assay used for plasma ANP (Kjær et al. 1995).
On a third experimental day, CVP was measured in eight of the 11 subjects at rest and during the last minute of A, L and A + L in the upright seated and supine positions in random order and with the same recovery between trials as in previous experimental days. For this purpose, a catheter was advanced from an antecubital vein into the vena cava, and the pressure transducer was placed at the level of the mid-chest in both postures. During all the experimental days, the subjects were allowed water consumption in order to minimize any body mass losses.
Statistical analyses
Data are presented as means ±
S.D. Main effects of body position, exercise mode and time (at rest and during exercise) on MAP, CVP, HR and plasma ANP, BNP and AVP were evaluated by a three-way analysis of variance with repeated measures followed by a Fisher test for post hoc evaluation. Also, the influence of HR and MAP (at rest and end of exercise) on plasma ANP, BNP and AVP, with the product of HR and MAP expressing the strain on the heart (Clausen & Trap-Jensen, 1976), was evaluated with regression analysis. An 
level of P < 0.05 was considered statistically significant.
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Results |
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In the seated position, CVP during A was not different from the resting values (–1.3 ± 0.4 and –1.5 ± 0.6 mmHg, respectively), while it increased during L (–0.2 ± 1.0 mmHg, P < 0.05) and A + L (–0.1 ± 0.9 mmHg, P < 0.05). There was a marked postural effect on the CVP in that the supine position caused higher values at rest (2.8 ± 1.2 mmHg, P < 0.05) but without any further significant rise during A (2.4 ± 1.1 mmHg), L (2.6 ± 1.3 mmHg) and A + L (2.7 ± 1.0 mmHg).
The change in posture also had a marked effect on the plasma ANP levels (Fig. 2). While seated on the cycle, plasma ANP was lower than during supine rest (34.6 ± 14.3 versus 47.2 ± 15.9 pg ml–1, P < 0.01), and only the end-exercise values during seated L and A + L (42.7 ± 12.2 and 43.3 ± 17.1 pg ml–1, respectively) reached the supine value. Thus, during L and A + L, plasma ANP was higher than during seated rest, but with A there was no significant change (P > 0.20). In spite of the higher resting values, plasma ANP increased during all three trials of supine exercise (P < 0.01). Also, in the supine position, plasma ANP during A and L was lower than during A + L (73.1 ± 22.5, 67.4 ± 18.3 and 78.1 ± 25.0 pg ml–1, respectively, P < 0.05). Plasma levels of ANP did not correlate significantly with HR (r = 0.13, P > 0.10, n = 11), MAP (r = 0.19, P > 0.10, n = 11) or to the HR x MAP product (r = 0.15, P > 0.05, n = 11). However, plasma ANP correlated with CVP values (r = 0.83, P < 0.05, n = 8).
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Discussion |
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25% increase in plasma ANP from rest to leg and combined arm with leg exercise. The other major findings are that, in contrast to the plasma ANP, there was no significant postural influence on plasma BNP either at rest or during exercise and that the plasma AVP was higher in the seated compared to the supine position with no influence of exercise.
Plasma ANP was 36% higher in the supine position than when seated at rest, a difference that can be eliminated by application of an antigravity suit (Guezennec et al. 1989). During supine exercise, the plasma ANP level increased by 50% from the supine resting value, compared to a 25% increase during seated exercise from seated rest. Upright A did not increase plasma ANP, suggesting that arm activity does not enhance CBV similarly to the leg blood volume shift during L. Even though moderate leg activity can enhance CVP when the legs are used to stabilize the body, CBV is not affected (Van Lieshout et al. 2001).
The increase in plasma ANP during supine exercise, despite the enhanced resting value, demonstrates the effect of the muscle pump in enhancing CBV. In addition, the increase in plasma ANP during supine A highlights the effect of gravity on CBV during upright exercise, independent of the effect of the muscle pump. The effect of CBV during exercise on plasma ANP is supported when the time course is considered. In the upright position, there was no increase in mean plasma ANP within 1 min of both L and A + L (–1 ± 2%), while for supine exercise there was an immediate increase of 33%. It seems reasonable that, in the upright position, some time is required for the muscle pump to overcome gravity and enhance CBV, while in the supine position, where the total blood volume is more equally distributed between upper and lower body, there is an immediate increase.
Although the predominant signal for ANP release is atrial wall stretch due to volume expansion, ANP is also considered to be affected by a number of other factors, including angiotenin II, endothelin-1, sympathetic stimulation and heart rate, all of which change during exercise. Also, one of the main considerations is the standardization of exercise intensity performed in two postures at different submaximal heart rates.
Without a maximal HR test in each modality, a description of each intensity in terms of specific relative HR responses is uncertain; nevertheless, responses to the same absolute workload in each modality were compared across the two postures. Furthermore, plasma levels of ANP did not correlate significantly with HR, MAP or to the HR x MAP product. Indeed, ANP responses (across exercise modalities) appear not to be different (Fig. 2A), despite large differences in HR, suggesting that plasma ANP was independent of HR, which therefore rules out any concerns regarding different heart rates and allows for an evaluation of CBV shift across experimental conditions.
Sympathetic stimulation may also have enhanced the ANP response, but then it would be expected that plasma ANP would be higher in the upright than in the supine position, as was the case for plasma AVP; however, plasma ANP was highest in the supine position. Equally, plasma endothelin-1, even though it correlates with plasma AVP and angiotensin II, is markedly increased during head-up tilt when plasma ANP is reduced (Matzen et al. 1991). Another consideration that could have affected repetitive evaluations is the effect of exercise-induced haemoconcentration on plasma ANP and its restitution to baseline values. However, since (a) plasma volume returns to baseline within 30 min (Mack et al. 1998); (b) half-life of the plasma ANP is 3 min (Atlas, 1986); and (c) ANP returns to resting values by 15 min postexercise (Ray et al. 1990), the increases in ANP during the present study can be attributed to enhanced secretion. Thus, plasma ANP did depend on posture, and its variation may offer some insight into how exercise affects CBV, as illustrated with plasma expansion (Grant et al. 1996). Even though CVP was measured in order to evaluate changes in CVB, during supine exercise the CVP data did not follow the ANP data, confirming that the secretion of ANP is determined by changes in CBV rather than CVP (Matzen et al. 1990).
The differences in MAP between A and A + L were marginal in both postures. In the upright posture, MAP did not rise when L was added to A, as would be expected owing to the increase in active muscle mass; this was presumably a muscle pump effect, attenuating MAP by raising CBV. These data suggest that a low CBV may contribute to the MAP response during exercise.
Since there was no significant influence of posture on plasma BNP, it is unlikely that changes in CBV, which is enhanced in the supine position (Harms et al. 2003), would have an effect. However, plasma BNP did increase during exercise as we varied the strain on the heart by including three types of exercise that elicit different blood pressure responses. Even though cardiac afterload is described by MAP, we also used HR and the product of HR and MAP (Clausen & Trap-Jensen, 1976), which best describe oxygen demand as additional indices of the cardiac strain. The L and A + L require a large increase in cardiac output, while A tends to elicit a relatively large increase in MAP (Secher et al. 1977). However, there was no significant correlation of MAP, HR or the HR and MAP product with the plasma level of BNP. Therefore, we suggest that its plasma level increases with distension of the ventricles rather than in response to the magnitude or the frequency of the pressure developed. If so, there may be a relationship between plasma BNP and stroke volume of the heart, as indicated by the correlation to left ventricular dimensions (Barletta et al. 1998). Even though the release of secretory granules is somewhat temperature dependent (Bilder et al. 1986), the increase in core temperature with exercise does not seem to have an effect (Melin et al. 1997). Thus, the plasma level of BNP does not appear to be related either to changes in CBV or to the cardiac afterload, but it may be related to the systolic and/or diastolic distension of the ventricular myocytes. The implication of the present results is that when plasma BNP is used to identify patients with congestive heart failure (Azzazy & Christenson, 2003), it is an evaluation of ventricular distension (Barletta et al. 1998) rather than of CBV.
We did not address the consequence of the elevated plasma levels of ANP and BNP during exercise, both of which increase natriuresis and diuresis as well as exhibiting a tendency to lower MAP (Van der Zander et al. 2003). During exercise, however, urine production is small, and the effect of the elevated plasma ANP and BNP levels is likely to be counteracted by sympathetic-mediated reduction in kidney blood flow and, during intense exercise, also by the elevated plasma AVP (Hanel et al. 1997). Urine production is also low after exercise, which is likely to reflect the reduced CBV as blood accumulates in the previously exercising muscles. Thus, after rowing, plasma ANP falls below the resting level (Hanel et al. 1997), while it may remain elevated in a supine position (Ray et al. 1990).
The plasma AVP demonstrated quite a different profile from the two other hormonal responses, with the highest values in the upright position and no significant change during moderate exercise. Plasma expansion lowers plasma AVP during exercise (Grant et al. 1996), while AVP appears to be released in parallel with sympathetic activation induced either by CBV reduction (Bie et al. 1986) or exercise (Hanel et al. 1997). Thus, plasma AVP values were responsive to the CBV changes induced by posture change but they were insensitive to the rather small increase in sympathetic activity induced by moderate exercise.
In conclusion, as suggested by plasma ANP, during upright exercise, with the exception of arm exercise, CBV is enhanced by the action of the active leg muscle pump that counteracts the gravitational pooling of blood in the capacitance leg veins. Thus, low central blood volume during arm exercise may contribute to elevated mean arterial pressure observed during upper body exercise.
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different from upright posture; a different from A, b different from L; all at P < 0.05.