Resetting of the arterial baroreflex increases orthostatic sympathetic activation and prevents postural hypotension in rabbits
1 Department of Cardiovascular Dynamics, National Cardiovascular Centre Research Institute, Osaka, Japan
2 Department of Cardiovascular Medicine, Kyusyu University Graduate School of Medical Sciences, Fukuoka, Japan
Abstract
Since humans are under ceaseless orthostatic stress, the mechanism to maintain arterial pressure (AP) under orthostatic stress against gravitational fluid shift is of great importance. We hypothesized that (1) orthostatic stress resets the arterial baroreflex control of sympathetic nerve activity (SNA) to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension. Renal SNA and AP were recorded in eight anaesthetized, vagotomized and aortic-denervated rabbits. Isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg (60 s for each CSP level) while the animal was placed supine and at 60 deg upright tilt. Upright tilt shifted the CSP–SNA relationship (the baroreflex neural arc) to a higher SNA, shifted the SNA–AP relationship (the baroreflex peripheral arc) to a lower AP, and consequently moved the operating point to marked high SNA while maintaining AP. A simulation study suggests that resetting in the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg, compared with the absence of resetting. In addition, upright tilt did not change the CSP–AP relationship (the baroreflex total arc). A simulation study suggests that although a downward shift of the peripheral arc could shift the total arc downward, resetting in the neural arc would compensate this fall and prevent the total arc from shifting downward to a lower AP. In conclusion, upright tilt increases SNA by resetting the baroreflex neural arc. This resetting may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system and contribute to preventing postural hypotension.
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Introduction
The maintenance of arterial pressure (AP) under orthostatic stress against gravitational fluid shift is of great importance, but the mechanisms remain unknown. During standing, a gravitational fluid shift directed toward the lower part of the body (such as the abdominal vascular bed and lower limbs) will cause severe postural hypotension if not counteracted by compensatory mechanisms (Rowell, 1993). Arterial baroreflexes have been considered to be the major compensatory mechanism (Persson & Kirchheim, 1991; Eckberg & Sleight, 1992; Rowell, 1993) since denervation of baroreceptor afferents causes profound postural hypotension (Sato et al. 2002). Earlier studies have characterized baroreflexes and their control of sympathetic nerve activity (SNA) and heart rate (Rea & Eckberg, 1987; Persson & Kirchheim, 1991; Eckberg & Sleight, 1992; Rudas et al. 1999; DiCarlo & Bishop, 2001; Kawada et al. 2003). However, the role of baroreflexes in orthostatic posture is little known. What determines AP and SNA in response to orthostatic stress remains unclear.
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The baroreflex is a negative feedback control system functioning physiologically to attenuate perturbations in AP (Eckberg & Sleight, 1992; Sato et al. 1999). Baroreflex equilibrium diagram analysis is, to our knowledge, the best method to define the operating point (operating SNA and AP) of baroreflex (Sato et al. 1999). The equilibrium diagram consists of the neural and peripheral arcs. The neural arc represents the static input–output relationship between baroreceptor pressure and SNA, whereas the peripheral arc represents the relationship between SNA and systemic AP. The intersection of the neural and peripheral arcs defines the operating point of AP regulation in the baroreflex closed-loop condition (for details, see Methods, Theoretical considerations: coupling of neural and peripheral arcs) (Sato et al. 1999; Yamamoto et al. 2004).
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In contrast to supine posture, in orthostatic posture a gravitational body fluid shift directed toward the lower part of the body (Rowell, 1993) decreases the effective circulatory blood volume (Sagawa et al. 1988; Rowell, 1993). Therefore, orthostatic stress probably attenuates the pressor response to SNA in the cardiovascular system (i.e. the baroreflex peripheral arc). If orthostatic stress resets the baroreflex neural arc to augment SNA, the resetting would compensate for the attenuated pressor response of the baroreflex peripheral arc and prevent AP falling under orthostatic stress. We hypothesized that (1) orthostatic stress resets the baroreflex neural arc to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension.
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Methods
Theoretical considerations: coupling of neural and peripheral arcs (Fig. 1)
The arterial baroreflex is a negative feedback control system that senses AP (strictly, transmural pressure; Angell James, 1971) by baroreceptors and regulates it. When the baroreflex feedback loop is closed, baroreceptor input pressure (i.e. carotid sinus pressure; CSP) equals AP. This situation makes it difficult to analyse the behaviour of the arterial baroreflex. In this study, we used a baroreflex open-loop equilibrium diagram analysis. We opened the baroreflex loop by isolating the baroreceptor element from the systemic circulation, and changed the input baroreceptor pressure independently of systemic AP. Moreover, we measured the efferent SNA, and divided the baroreflex system into the neural arc (from baroreceptor pressure input to efferent SNA) and the peripheral arc (from SNA to AP) (Fig. 1A, middle panel). The neural arc is a reverse sigmoid relation and the peripheral arc is a sigmoid relation (Fig. 1A, top and bottom panels). Importantly, baroreceptor pressure equals AP in the baroreflex closed-loop condition. Accordingly, when the two relationships are superimposed (Fig. 1B), the intersection of these arcs defines the operating point of the baroreflex feedback system. The validity of this framework has been confirmed in earlier studies showing that the AP and SNA estimated from the intersection agree with those measured in the closed-loop condition (Sato et al. 1999; Yamamoto et al. 2004).
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Although the baroreflex is a negative feedback control system that senses arterial pressure (AP) by baroreceptors and regulates AP, we opened the loop by changing baroreceptor pressure independently of AP (A). By measuring sympathetic nerve activity (SNA), we divided the baroreflex system into the neural arc (from baroreceptor pressure input to efferent SNA) and the peripheral arc (from SNA to AP) (A, middle panel). Both arcs show sigmoidal input–output relationships (A, top and bottom panels). Since baroreceptor pressure is equilibrated with AP under the baroreflex closed-loop condition, the intersection when these two arcs are superimposed defines the operating point of the baroreflex feedback system (B).
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Surgical preparations
Animals were cared for in strict accordance with the Guiding Principles for the Care and Use of Animals in the Field of Physiological Science of the Physiological Society of Japan. Eight Japanese White rabbits weighing 2.4–3.3 kg were initially anaesthetized by intravenous injection (2 ml kg–1) of a mixture of urethane (250 mg ml–1) and -chloralose (40 mg ml–1). Anaesthesia level were maintained by continuously infusing the anaesthetics at a rate of 0.33 ml kg–1 h–1 using a syringe pump (CFV-3200, Nihon Kohden, Tokyo). The rabbits were mechanically ventilated with oxygen-enriched room air. The bilateral carotid sinuses were isolated vascularly from systemic circulation by ligating the internal and external carotid arteries and other small branches originating from the carotid sinus regions. The isolated carotid sinuses were filled with warm physiological saline through catheters inserted via the common carotid arteries. The CSP was measured using a fluid-filled pressure transducer (AP-630G, Nihon Kohden, Tokyo) at the level of the carotid sinus throughout the experiment, and controlled by a servo-controlled piston pump (model ET-126 A; Labworks, Costa Mesa, CA, USA). In this condition, changes in carotid artery dimension are proportional to changes in carotid artery pressure. Bilateral vagal and aortic depressor nerves were sectioned at the middle of the neck to eliminate reflexes from the cardiopulmonary region and the aortic arch. Systemic AP was measured using a high-fidelity pressure transducer (Millar Instruments; Houston, TX, USA) inserted retrograde from the right common carotid artery below the isolated carotid sinus region. Body temperature was maintained at around 38°C with a heating pad. Additional injection of anaesthetics were never required as judged from haemodynamics (AP) in supine posture that were stable in the course of experiments.
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We exposed the left renal sympathetic nerve retroperitoneally and attached a pair of stainless steel wire electrodes (Bioflex wire AS633; Cooner Wire, Chatworth, CA, USA) to record renal SNA. The nerve fibres peripheral to the electrodes were tightly ligated and crushed to eliminate afferent signals from the kidney. The nerve and electrodes were covered with a mixture of silicone gel (Silicon Low Viscosity, KWIK-SIL; World Precision Instrument, Inc., FL, USA) to insulate and immobilize the electrodes. The preamplified nerve signal was band-pass filtered at 150–1000 Hz, full-wave rectified and low-pass filtered with a cut-off frequency of 30 Hz to quantify the nerve activity. Pancuronium bromide (0.1 mg kg–1) was administered to prevent contamination of muscular activity in the SNA recording. After all protocols were finished, animals were killed by intravenous infusion of hexamethonium bromide (6 mg kg–1).
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Protocols
After the surgical preparation, the animal was maintained in the supine position (0 deg) on a tilt bed. To stabilize the posture, the head was fixed full-frontal to the bed by strings, and the body and legs were rigged up in a clothes-like bag. In protocol 1, the static non-linear characteristics of the sympathetic baroreflex system were estimated in the supine position. CSP was decreased to 40 mmHg, and then increased stepwise from 40 to 160 mmHg with increments of 20 mmHg. Each CSP step was maintained for 60 s.
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In protocol 2, to obtain the actual operating pressure in the baroreflex closed-loop condition in both supine and 60 deg upright positions, CSP was matched with systemic AP via the servo-controlled piston pump. The animal was kept supine for 10 min, and then tilted upright to 60 deg within 10 s by inclining the tilt bed to 60 deg and dropping the lower regions of rabbit with the fulcrum set at the level of the carotid sinus. The 60 deg upright posture was maintained for 10 min. Since the clothes-like bag stabilized the posture of the animals, there was no additional mechanical movement that reduced the quality of measurements. The position of the head remained almost fixed during the tilt to minimize vestibular stimulation.
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In protocol 3, the static non-linear characteristics of the sympathetic baroreflex system were estimated during the 60 deg upright tilt. CSP was increased stepwise from 40 to 160 mmHg similar to protocol 1.
Data analysis
In protocols 1 and 3, AP and SNA were averaged during the last 10 s of each CSP level. For normalization of SNA, the noise level when animals were killed after experiments was assigned 0 arbitrary units (a.u). The mean SNA at CSP of 40 mmHg in the supine position were assigned 100 arbitrary units (a.u). Other SNA signals in both postures were normalized to these units.
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The relationship between the input (CSP in the neural arc, SNA in the peripheral arc, CSP in the total arc) and output (SNA in the neural arc, AP in the peripheral arc, AP in the total arc) is parametrically characterized by a four-parameter logistic equation model as follows (Kent et al. 1972):
where y is the output and x the input, P1 is the response range of change in y, P2 is the coefficient for calculating gain, P3 is the value of x corresponding to the mid-point of operation, and P4 is the minimum value of y. Instantaneous gain was calculated from the first derivative of the logistic function (the maximum gain equals –P1P4/4 at x = P3). The intersection of the neural and peripheral arc curves on the equilibrium diagram was defined as the estimated operating point (Fig. 1), in supine and upright tilt positions. The hypothetical operating point during upright tilt (in which tilt changes the peripheral arc, but not the neural arc), was simulated by using the intersections of the supine neural arc and the upright tilt peripheral arc.
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The measured operating AP and SNA of the baroreflex were obtained in protocol 2. AP and SNA were averaged during the last 3 min in the baroreflex closed-loop condition both in the supine position and with 60 deg upright tilt.
Statistic analysis
All data are presented as means ± S.D. Student's paired t test was used to compare the parameters of the neural and peripheral arcs and operating points between postures (Glantz, 1997). Differences were considered significant when P < 0.05. A linear regression analysis was used to compare the operating points estimated from the equilibrium diagram with those measured (Glantz, 1997).
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Results
Figures 2–4 show examples of data derived from the same animal. In the baroreflex closed-loop condition, 60 deg upright tilt rapidly decreased and then increased AP, and transiently decreased and then increased SNA (Fig. 2). Both AP and SNA reached nearly steady states within 3 min (Fig. 2).
Data were resampled at 10 Hz. The SNA and AP reach a steady state within 3 min.
In the baroreflex open-loop condition, SNA and AP decreased in response to stepwise increase in CSP both in the supine position (Fig. 3A) and at 60 deg upright tilt (Fig. 3B). In the neural arc, SNA was higher during upright tilt than supine at all CSP levels (Fig. 4A). The upright tilt shifted the CSP–SNA curve rightward to a higher SNA. Meanwhile, in the peripheral arc, the upright tilt shifted the SNA–AP curve downward to a lower AP (Fig. 4B). Consequently, as the animal was changed from supine to upright tilt, the operating point estimated from the intersection of the two arcs shifted from point S to point U with a marked increase in SNA and a slight increase in AP (Fig. 4C). In the total arc, the upright tilt slightly steepened the CSP–AP curve, and also slightly increased the operating AP from point St to point Ut (Fig. 4E).
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Each CSP step was maintained for 1 min. The same animal in Fig. 2 was used in this study. Data were resampled at 10 Hz. In the middle panels, the fine vertical spikes indicate SNA signals resampled at 10 Hz, while the continuous bold line indicates data averaged over 1 min. SNA and AP decrease in response to increments in CSP for both postures. Upright tilt increases SNA at all CSP levels.
Data were obtained from the same animal as in Figs 2 and 3. The upright tilt shifts the neural arc to a higher SNA (A), shifts the peripheral arc to a lower AP (B), and moves the operating point from point S to point U (C). In the baroreflex equilibrium diagram (E), point S and U indicate the estimated operating points in supine and upright tilt positions, respectively. Point A (grey circle) indicates the estimated operating point in upright tilt position in the absence of neural arc shift (simulation) (C). The upright tilt slightly steepens the total arc and moves the operating AP from point St to point Ut (D and E). In the total arc (E), points St and Ut indicate the estimated operating points in supine and upright tilt positions, respectively.
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Group-averaged data show that the 60 deg upright tilt shifted the neural arc to higher SNA (Fig. 5A), shifted the peripheral arc to lower AP (Fig. 5B), and moved the operating point to markedly higher SNA (25 ± 5 a.u) while maintaining AP (Fig. 5C). In a simulation where 60 deg upright tilt produces no shift in the neural arc (i.e. no resetting), then the operating point during the tilt would be the intersection between the neural arc at supine and the peripheral arc at upright tilt (point A). The upright tilt would shift the operating point to a SNA (13 ± 5 a.u., Table 1) only half of that compared with when there is a neural arc shift, while the operating AP at upright tilt would decrease by 10 ± 2 mmHg.
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Data were averaged from all animals (n = 8) and presented as means ± S.D. Dotted and continuous lines are four-parameter logistic functions fitted to the averaged data. In the baroreflex equilibrium diagram (C), point S and U indicate the estimated operating points in supine and upright tilt positions, respectively. Point A (grey circle) indicates the estimated operating point in upright tilt position in the absence of neural arc shift (C). In the total arc (E), points St and Ut indicate the estimated operating points in supine and upright tilt positions, respectively. The two points are superimposed. The line joining the crosses and point At (grey circle) indicate the estimated total arc curve and operating point, respectively, in the absence of neural arc shift (simulation) (E).
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Group-averaged data show that the 60 deg upright tilt did not change the total arc curve (Fig. 5D). The operating AP point in the total arc was constant during the postural change (point St overlapped with point Ut, in Fig. 5E). In a simulation where 60 deg upright tilt produces no shift in the neural arc (i.e. no resetting), then the tilt would shift the total arc curve downward to a lower AP (line joining crosses) and decrease the operating AP from point St to point At (Fig. 5E).
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Group-averaged data of P1 (the range of SNA response to CSP) and P4 (the minimum value of SNA) in the neural arc were larger at 60 deg upright tilt than supine (Table 2). In the peripheral arc, P1 (the range of AP response to SNA) was smaller while P3 (midpoint of the SNA operating range) was higher at 60 deg upright tilt (Table 1). In both the neural and peripheral arcs, the maximal gains (at the mid-point of the arc) and operating gains (at the intersection of arcs) were similar in supine and upright tilt positions. All parameters (P1-4) and the maximal gain of the total arc were similar in supine and upright tilt positions (Table 3).
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Using the data from all animals, the operating AP estimated from the baroreflex open-loop equilibrium diagram (protocols 1 and 3) agreed with those measured in the baroreflex closed-loop condition (protocol 2) for both postures (Fig. 6A). The operating SNA values estimated from the equilibrium diagram also agreed with those measured for both postures (Fig. 6B).
A and B show the operating AP and SNA, respectively. Each animal provided two data points obtained in supine (open circles) and upright tilt positions (filled circles). Both the operating AP and SNA estimated by the equilibrium diagram match the values actually measured under the baroreflex closed-loop condition. RMS: root mean square.
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Discussion
The maintenance of AP in upright posture against gravitational fluid shift is of great importance, but the mechanisms remain unknown. We applied baroreflex equilibrium diagram analysis (Yamamoto et al. 2004) to the baroreflex system both in supine and 60 deg upright tilt positions. Our new major findings are that upright tilt shifts the CSP–SNA relationship (the baroreflex neural arc) to a higher SNA, whereas it shifts the SNA–AP relationship (the baroreflex peripheral arc) to a lower AP (Fig. 5). These data support our first hypothesis that orthostatic stress resets the baroreflex neural arc to a higher SNA.
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Our data indicate that resetting of the baroreflex neural arc in an upright posture doubles the orthostatic activation of SNA and increases the operating AP by 10 mmHg. In our experiments, 60 deg upright tilt reset the neural arc to a higher SNA, shifted the peripheral arc to a lower AP (Fig. 5A and B), and consequently moved the estimated operating point from point S (SNA, 66 a.u.; AP, 102 mmHg) to point U at a higher SNA (91 a.u) and similar AP (102 mmHg) (Fig. 5C). In a simulation where the resetting in the neural arc is absent, 60 deg upright tilt would move the operating point from point S to point A (the intersection of the supine neural arc and the upright-tilt peripheral arc: SNA, 79 a.u.; AP, 92 mmHg), halving the orthostatic activation of SNA (13 a.u. versus 25 a.u) and decreasing the operating AP at upright tilt by 10 mmHg compared with when the resetting is in operation. These findings support our second hypothesis that resetting of the arterial baroreflex contributes to preventing postural hypotension.
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Our data indicate that resetting of the baroreflex neural arc contributes to preserving the baroreflex total arc function in an upright posture. In a simulation where resetting in the neural arc is absent, 60 deg upright tilt would shift the total arc downward to a lower AP (Fig. 5D and E) by a downward shift of the peripheral arc. However, in our experiments, 60 deg upright tilt maintained the total arc (Fig. 5D and E) by orthostatic resetting of the neural arc. These findings indicate that resetting of the neural arc has an important role in maintaining the total baroreflex function in an upright posture.
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Little is known about the arterial baroreflex system under orthostatic stress. Although earlier studies addressed the baroreflex in relation to AP regulation under orthostatic stress, most of them evaluated the baroreflex in a supine, not orthostatic, position (Mosqueda-Garcia et al. 1997). In addition, although earlier studies investigated the gains of baroreflex control of SNA (Mosqueda-Garcia et al. 1997), vascular resistance (Cooper & Hainsworth, 2001) and R–R interval (Cooke et al. 1999), these gains were part of the total baroreflex system, and thus could not explain the operating points of the baroreflex. In the present study, we determined the neural and peripheral arcs independently in an upright position using the baroreflex open-loop equilibrium diagram. We found that upright tilt shifted the baroreflex neural arc to a higher SNA, while it shifted the baroreflex peripheral arc to a lower AP. Our data confirmed the accuracy of the equilibrium diagram in defining the operating point, since in both supine and upright tilt positions, the operating points estimated from the diagram agreed well with those measured in the baroreflex closed-loop condition (Fig. 6). This is consistent with earlier studies addressing haemorrhage (Sato et al. 1999) and muscle stretch (Yamamoto et al. 2004).
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The mechanism responsible for the resetting of baroreflex neural arc with upright tilt remains unclear. The most likely mechanism is recruitment of other sympathoexcitatory systems than the baroreflex during orthostatic stress. In particular, the vestibular system is stimulated by upright tilt, and has been reported to increase SNA (vestibulosympathetic reflex) (Yates, 1992) and assist AP regulation during orthostatic stress in humans (Ray & Carter, 2003) and rats (Gotoh et al. 2004). In addition, contractions of the antigravity muscles during upright tilt stimulate the muscle reflexes that increase SNA (Potts & Mitchell, 1998; Yamamoto et al. 2004). Thus recruitments of other systems may shift the CSP–SNA relationship to a higher SNA.
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However, the resetting of the baroreflex neural arc during upright tilt may not result from simple summation of SNA activation by the arterial baroreflex and by other systems. Theoretically, if the recruitments of other systems only offset SNA, it increases P4 (the minimum value of SNA) but not P1 (the range of SNA response to CSP) of the neural arc, and causes a parallel shift of the CSP–SNA relationship to a higher SNA without transforming the inverse sigmoid curve. In contrast, our results showed that 60 deg upright tilt increased not only P4 but also P1 (Table 2), and widened the inverse sigmoid curve. These findings suggest an interaction between baroreflex and other systems in upright tilt posture. Indeed, the vestibular system has been considered to interact with the baroreflex (Yates, 1992; Kaufmann et al. 2002; Monahan & Ray, 2002; Ray & Carter, 2003; Gotoh et al. 2004). In addition, the muscle reflex has been reported to interact with the baroreflex (Potts & Mitchell, 1998), and contribute to the central resetting of the baroreflex during exercise (DiCarlo & Bishop, 2001; Miki et al. 2003). We have recently reported that passive stretch of the triceps surae muscles shifts the CSP–SNA relationship to a higher SNA using the baroreflex equilibrium diagram analysis (Yamamoto et al. 2004). Further studies are necessary to address the mechanism for the resetting during upright tilt.
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Our data indicate that 60 deg upright tilt reduces the pressor response to SNA in the peripheral cardiovascular system. We observed that upright tilt down-shifted the baroreflex peripheral arc to a lower AP. For all SNA levels, AP was lower in the upright than supine position (Figs 4 and 5). This change may be attributed to the gravitational fluid shift toward the lower part of the body (i.e. abdominal vascular bed, lower limbs), which decreases the preload and effective circulatory blood volume (Sagawa et al. 1988; Rowell, 1993).
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Our data suggest that upright tilt yields a different effect on the baroreflex system compared with haemorrhage. Haemorrhage decreases effective circulatory blood volume and preload (Sagawa et al. 1988; Rowell, 1993). Earlier study in rats demonstrated that haemorrhage (blood loss in the range of 0.5–2% of body weight) reduced AP in a prevailing level of SNA in the baroreflex peripheral arc (Sato et al. 1999), similar to our upright tilt. Therefore, both upright tilt and haemorrhage reduce the pressor response to SNA in the peripheral cardiovascular system. In contrast to upright tilt, haemorrhage did not affect the baroreflex neural arc (Sato et al. 1999). In short, upright tilt resets the baroreflex neural arc to a higher SNA whereas haemorrhage does not.
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Since we focused on arterial baroreflex dynamics in response to an acute orthostatic stress, our findings could not relate long-term pressure regulation by arterial and cardiopulmonary baroreflexes and the renin–angiotensin system. Early study showed that chronic sino-aortic and cardiopulmonary denervations increased AP and activated the renin–angiotensin system in the conscious dog (Persson et al. 1988). Further study is needed to address long-term orthostatic physiology.
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As we investigated the role of the arterial baroreflex in AP control under orthostatic stress while AP was well maintained, our findings could not explain the pathophysiology of orthostatic vasovagal syncope. Interestingly, the final trigger of human orthostatic syncope appears to be the abrupt disappearance of SNA (Morillo et al. 1997). Given the present findings, we speculate that some changes in the baroreflex neural arc can decrease SNA and trigger orthostatic syncope.
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Limitations
The present study has several limitations. First, we excluded the efferent effect of vagally mediated arterial baroreflex, which could affect the properties of the two arcs. Second, we used an anaesthetic agent (intravenous injection of a mixture of urethane and -chloralose) that could flatten the baroreflex peripheral arc by reducing the cardiac pumping function.
Third, since we measured only renal SNA, our findings have limited applicability to other SNA, including cardiac SNA. Although static regulation of the baroreflex neural arc over SNA is similar in renal and cardiac SNAs in supine posture (Kawada et al. 2001), whether this holds true during orthostatic stress remains to be verified.
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Fourth, we were not able to quantify the contribution of cardiac function (i.e. cardiac output) to AP regulation. Since the baroreflex peripheral arc represents the static relation from SNA input to AP, it includes the effects of SNA on cardiac function, stressed blood volume and vascular resistance. We were not able to isolate these factors because of complexity and experimental difficulties.
Fifth, we eliminated cardiopulmonary baroreflex by cutting bilateral vagal nerves. Earlier human studies have indicated that non-hypotensive hypovolaemic perturbations do not change AP, but reduce central venous, right heart and pulmonary pressures, and cause vasoconstriction. These observations have been interpreted as reflexes triggered by cardiopulmonary baroreceptors (Johnson et al. 1974; Pawelczyk & Raven, 1989). However, Taylor et al. (1995) showed that small reductions of effective blood volume reduce aortic baroreceptive areas and trigger haemodynamic adjustments which are so efficient that alterations in AP escape detection by conventional means. Accordingly, further studies are needed to understand the relative importance and mutual cooperation of arterial and cardiopulmonary baroreflexes in AP control during orthostatic stress.
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Lastly, we used rabbits, which are quadrupeds. Since humans spend most of their time in nearly 90 deg upright postures whereas rabbits do not, our findings have limited applicability to humans. However, Japanese White rabbits spend most of their time in 10–40 deg head-up posture, and frequently stand up to nearly 70 deg. This suggests that rabbits have an ability to maintain arterial pressure against gravity-induced pressure perturbation under orthostatic stress. Additionally, in our preliminary experiments in rabbits, we observed that denervation of both carotid and aortic arterial baroreflexes caused postural hypotension of approximately 50 mmHg during 60 deg upright tilt, consistent with a previous study in rats (Sato et al. 2002). This suggests that even in quadrupeds, the arterial baroreflex has a very important role in the maintenance of AP under orthostatic stress. Accordingly, we speculate that our findings may reflect, at least, the qualitative aspects of orthostatic baroreflex physiology in humans. Indeed, recent human studies have suggested that orthostatic stress (lower body negative pressure) enhances the SNA response to arterial pressure change in the baroreflex closed-loop condition (Ichinose et al. 2004a; Ichinose et al. 2004b)
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In conclusion, baroreflex open-loop equilibrium analysis demonstrated that 60 deg upright tilt shifted the baroreflex neural arc to a higher SNA and shifted the peripheral arc to a lower AP. Consequently, the upright tilt markedly increased the operating SNA and maintained the operating AP. Simulation study suggests that resetting of the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg compared with the absence of resetting. These data suggest that orthostatic stress increases SNA by resetting the baroreflex neural arc. The resetting of the neural arc may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system, and contribute to preventing postural hypotension.
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2 Department of Cardiovascular Medicine, Kyusyu University Graduate School of Medical Sciences, Fukuoka, Japan
Abstract
Since humans are under ceaseless orthostatic stress, the mechanism to maintain arterial pressure (AP) under orthostatic stress against gravitational fluid shift is of great importance. We hypothesized that (1) orthostatic stress resets the arterial baroreflex control of sympathetic nerve activity (SNA) to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension. Renal SNA and AP were recorded in eight anaesthetized, vagotomized and aortic-denervated rabbits. Isolated intracarotid sinus pressure (CSP) was increased stepwise from 40 to 160 mmHg with increments of 20 mmHg (60 s for each CSP level) while the animal was placed supine and at 60 deg upright tilt. Upright tilt shifted the CSP–SNA relationship (the baroreflex neural arc) to a higher SNA, shifted the SNA–AP relationship (the baroreflex peripheral arc) to a lower AP, and consequently moved the operating point to marked high SNA while maintaining AP. A simulation study suggests that resetting in the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg, compared with the absence of resetting. In addition, upright tilt did not change the CSP–AP relationship (the baroreflex total arc). A simulation study suggests that although a downward shift of the peripheral arc could shift the total arc downward, resetting in the neural arc would compensate this fall and prevent the total arc from shifting downward to a lower AP. In conclusion, upright tilt increases SNA by resetting the baroreflex neural arc. This resetting may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system and contribute to preventing postural hypotension.
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Introduction
The maintenance of arterial pressure (AP) under orthostatic stress against gravitational fluid shift is of great importance, but the mechanisms remain unknown. During standing, a gravitational fluid shift directed toward the lower part of the body (such as the abdominal vascular bed and lower limbs) will cause severe postural hypotension if not counteracted by compensatory mechanisms (Rowell, 1993). Arterial baroreflexes have been considered to be the major compensatory mechanism (Persson & Kirchheim, 1991; Eckberg & Sleight, 1992; Rowell, 1993) since denervation of baroreceptor afferents causes profound postural hypotension (Sato et al. 2002). Earlier studies have characterized baroreflexes and their control of sympathetic nerve activity (SNA) and heart rate (Rea & Eckberg, 1987; Persson & Kirchheim, 1991; Eckberg & Sleight, 1992; Rudas et al. 1999; DiCarlo & Bishop, 2001; Kawada et al. 2003). However, the role of baroreflexes in orthostatic posture is little known. What determines AP and SNA in response to orthostatic stress remains unclear.
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The baroreflex is a negative feedback control system functioning physiologically to attenuate perturbations in AP (Eckberg & Sleight, 1992; Sato et al. 1999). Baroreflex equilibrium diagram analysis is, to our knowledge, the best method to define the operating point (operating SNA and AP) of baroreflex (Sato et al. 1999). The equilibrium diagram consists of the neural and peripheral arcs. The neural arc represents the static input–output relationship between baroreceptor pressure and SNA, whereas the peripheral arc represents the relationship between SNA and systemic AP. The intersection of the neural and peripheral arcs defines the operating point of AP regulation in the baroreflex closed-loop condition (for details, see Methods, Theoretical considerations: coupling of neural and peripheral arcs) (Sato et al. 1999; Yamamoto et al. 2004).
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In contrast to supine posture, in orthostatic posture a gravitational body fluid shift directed toward the lower part of the body (Rowell, 1993) decreases the effective circulatory blood volume (Sagawa et al. 1988; Rowell, 1993). Therefore, orthostatic stress probably attenuates the pressor response to SNA in the cardiovascular system (i.e. the baroreflex peripheral arc). If orthostatic stress resets the baroreflex neural arc to augment SNA, the resetting would compensate for the attenuated pressor response of the baroreflex peripheral arc and prevent AP falling under orthostatic stress. We hypothesized that (1) orthostatic stress resets the baroreflex neural arc to a higher SNA, and (2) resetting of the arterial baroreflex contributes to preventing postural hypotension.
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Methods
Theoretical considerations: coupling of neural and peripheral arcs (Fig. 1)
The arterial baroreflex is a negative feedback control system that senses AP (strictly, transmural pressure; Angell James, 1971) by baroreceptors and regulates it. When the baroreflex feedback loop is closed, baroreceptor input pressure (i.e. carotid sinus pressure; CSP) equals AP. This situation makes it difficult to analyse the behaviour of the arterial baroreflex. In this study, we used a baroreflex open-loop equilibrium diagram analysis. We opened the baroreflex loop by isolating the baroreceptor element from the systemic circulation, and changed the input baroreceptor pressure independently of systemic AP. Moreover, we measured the efferent SNA, and divided the baroreflex system into the neural arc (from baroreceptor pressure input to efferent SNA) and the peripheral arc (from SNA to AP) (Fig. 1A, middle panel). The neural arc is a reverse sigmoid relation and the peripheral arc is a sigmoid relation (Fig. 1A, top and bottom panels). Importantly, baroreceptor pressure equals AP in the baroreflex closed-loop condition. Accordingly, when the two relationships are superimposed (Fig. 1B), the intersection of these arcs defines the operating point of the baroreflex feedback system. The validity of this framework has been confirmed in earlier studies showing that the AP and SNA estimated from the intersection agree with those measured in the closed-loop condition (Sato et al. 1999; Yamamoto et al. 2004).
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Although the baroreflex is a negative feedback control system that senses arterial pressure (AP) by baroreceptors and regulates AP, we opened the loop by changing baroreceptor pressure independently of AP (A). By measuring sympathetic nerve activity (SNA), we divided the baroreflex system into the neural arc (from baroreceptor pressure input to efferent SNA) and the peripheral arc (from SNA to AP) (A, middle panel). Both arcs show sigmoidal input–output relationships (A, top and bottom panels). Since baroreceptor pressure is equilibrated with AP under the baroreflex closed-loop condition, the intersection when these two arcs are superimposed defines the operating point of the baroreflex feedback system (B).
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Surgical preparations
Animals were cared for in strict accordance with the Guiding Principles for the Care and Use of Animals in the Field of Physiological Science of the Physiological Society of Japan. Eight Japanese White rabbits weighing 2.4–3.3 kg were initially anaesthetized by intravenous injection (2 ml kg–1) of a mixture of urethane (250 mg ml–1) and -chloralose (40 mg ml–1). Anaesthesia level were maintained by continuously infusing the anaesthetics at a rate of 0.33 ml kg–1 h–1 using a syringe pump (CFV-3200, Nihon Kohden, Tokyo). The rabbits were mechanically ventilated with oxygen-enriched room air. The bilateral carotid sinuses were isolated vascularly from systemic circulation by ligating the internal and external carotid arteries and other small branches originating from the carotid sinus regions. The isolated carotid sinuses were filled with warm physiological saline through catheters inserted via the common carotid arteries. The CSP was measured using a fluid-filled pressure transducer (AP-630G, Nihon Kohden, Tokyo) at the level of the carotid sinus throughout the experiment, and controlled by a servo-controlled piston pump (model ET-126 A; Labworks, Costa Mesa, CA, USA). In this condition, changes in carotid artery dimension are proportional to changes in carotid artery pressure. Bilateral vagal and aortic depressor nerves were sectioned at the middle of the neck to eliminate reflexes from the cardiopulmonary region and the aortic arch. Systemic AP was measured using a high-fidelity pressure transducer (Millar Instruments; Houston, TX, USA) inserted retrograde from the right common carotid artery below the isolated carotid sinus region. Body temperature was maintained at around 38°C with a heating pad. Additional injection of anaesthetics were never required as judged from haemodynamics (AP) in supine posture that were stable in the course of experiments.
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We exposed the left renal sympathetic nerve retroperitoneally and attached a pair of stainless steel wire electrodes (Bioflex wire AS633; Cooner Wire, Chatworth, CA, USA) to record renal SNA. The nerve fibres peripheral to the electrodes were tightly ligated and crushed to eliminate afferent signals from the kidney. The nerve and electrodes were covered with a mixture of silicone gel (Silicon Low Viscosity, KWIK-SIL; World Precision Instrument, Inc., FL, USA) to insulate and immobilize the electrodes. The preamplified nerve signal was band-pass filtered at 150–1000 Hz, full-wave rectified and low-pass filtered with a cut-off frequency of 30 Hz to quantify the nerve activity. Pancuronium bromide (0.1 mg kg–1) was administered to prevent contamination of muscular activity in the SNA recording. After all protocols were finished, animals were killed by intravenous infusion of hexamethonium bromide (6 mg kg–1).
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Protocols
After the surgical preparation, the animal was maintained in the supine position (0 deg) on a tilt bed. To stabilize the posture, the head was fixed full-frontal to the bed by strings, and the body and legs were rigged up in a clothes-like bag. In protocol 1, the static non-linear characteristics of the sympathetic baroreflex system were estimated in the supine position. CSP was decreased to 40 mmHg, and then increased stepwise from 40 to 160 mmHg with increments of 20 mmHg. Each CSP step was maintained for 60 s.
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In protocol 2, to obtain the actual operating pressure in the baroreflex closed-loop condition in both supine and 60 deg upright positions, CSP was matched with systemic AP via the servo-controlled piston pump. The animal was kept supine for 10 min, and then tilted upright to 60 deg within 10 s by inclining the tilt bed to 60 deg and dropping the lower regions of rabbit with the fulcrum set at the level of the carotid sinus. The 60 deg upright posture was maintained for 10 min. Since the clothes-like bag stabilized the posture of the animals, there was no additional mechanical movement that reduced the quality of measurements. The position of the head remained almost fixed during the tilt to minimize vestibular stimulation.
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In protocol 3, the static non-linear characteristics of the sympathetic baroreflex system were estimated during the 60 deg upright tilt. CSP was increased stepwise from 40 to 160 mmHg similar to protocol 1.
Data analysis
In protocols 1 and 3, AP and SNA were averaged during the last 10 s of each CSP level. For normalization of SNA, the noise level when animals were killed after experiments was assigned 0 arbitrary units (a.u). The mean SNA at CSP of 40 mmHg in the supine position were assigned 100 arbitrary units (a.u). Other SNA signals in both postures were normalized to these units.
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The relationship between the input (CSP in the neural arc, SNA in the peripheral arc, CSP in the total arc) and output (SNA in the neural arc, AP in the peripheral arc, AP in the total arc) is parametrically characterized by a four-parameter logistic equation model as follows (Kent et al. 1972):
where y is the output and x the input, P1 is the response range of change in y, P2 is the coefficient for calculating gain, P3 is the value of x corresponding to the mid-point of operation, and P4 is the minimum value of y. Instantaneous gain was calculated from the first derivative of the logistic function (the maximum gain equals –P1P4/4 at x = P3). The intersection of the neural and peripheral arc curves on the equilibrium diagram was defined as the estimated operating point (Fig. 1), in supine and upright tilt positions. The hypothetical operating point during upright tilt (in which tilt changes the peripheral arc, but not the neural arc), was simulated by using the intersections of the supine neural arc and the upright tilt peripheral arc.
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The measured operating AP and SNA of the baroreflex were obtained in protocol 2. AP and SNA were averaged during the last 3 min in the baroreflex closed-loop condition both in the supine position and with 60 deg upright tilt.
Statistic analysis
All data are presented as means ± S.D. Student's paired t test was used to compare the parameters of the neural and peripheral arcs and operating points between postures (Glantz, 1997). Differences were considered significant when P < 0.05. A linear regression analysis was used to compare the operating points estimated from the equilibrium diagram with those measured (Glantz, 1997).
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Results
Figures 2–4 show examples of data derived from the same animal. In the baroreflex closed-loop condition, 60 deg upright tilt rapidly decreased and then increased AP, and transiently decreased and then increased SNA (Fig. 2). Both AP and SNA reached nearly steady states within 3 min (Fig. 2).
Data were resampled at 10 Hz. The SNA and AP reach a steady state within 3 min.
In the baroreflex open-loop condition, SNA and AP decreased in response to stepwise increase in CSP both in the supine position (Fig. 3A) and at 60 deg upright tilt (Fig. 3B). In the neural arc, SNA was higher during upright tilt than supine at all CSP levels (Fig. 4A). The upright tilt shifted the CSP–SNA curve rightward to a higher SNA. Meanwhile, in the peripheral arc, the upright tilt shifted the SNA–AP curve downward to a lower AP (Fig. 4B). Consequently, as the animal was changed from supine to upright tilt, the operating point estimated from the intersection of the two arcs shifted from point S to point U with a marked increase in SNA and a slight increase in AP (Fig. 4C). In the total arc, the upright tilt slightly steepened the CSP–AP curve, and also slightly increased the operating AP from point St to point Ut (Fig. 4E).
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Each CSP step was maintained for 1 min. The same animal in Fig. 2 was used in this study. Data were resampled at 10 Hz. In the middle panels, the fine vertical spikes indicate SNA signals resampled at 10 Hz, while the continuous bold line indicates data averaged over 1 min. SNA and AP decrease in response to increments in CSP for both postures. Upright tilt increases SNA at all CSP levels.
Data were obtained from the same animal as in Figs 2 and 3. The upright tilt shifts the neural arc to a higher SNA (A), shifts the peripheral arc to a lower AP (B), and moves the operating point from point S to point U (C). In the baroreflex equilibrium diagram (E), point S and U indicate the estimated operating points in supine and upright tilt positions, respectively. Point A (grey circle) indicates the estimated operating point in upright tilt position in the absence of neural arc shift (simulation) (C). The upright tilt slightly steepens the total arc and moves the operating AP from point St to point Ut (D and E). In the total arc (E), points St and Ut indicate the estimated operating points in supine and upright tilt positions, respectively.
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Group-averaged data show that the 60 deg upright tilt shifted the neural arc to higher SNA (Fig. 5A), shifted the peripheral arc to lower AP (Fig. 5B), and moved the operating point to markedly higher SNA (25 ± 5 a.u) while maintaining AP (Fig. 5C). In a simulation where 60 deg upright tilt produces no shift in the neural arc (i.e. no resetting), then the operating point during the tilt would be the intersection between the neural arc at supine and the peripheral arc at upright tilt (point A). The upright tilt would shift the operating point to a SNA (13 ± 5 a.u., Table 1) only half of that compared with when there is a neural arc shift, while the operating AP at upright tilt would decrease by 10 ± 2 mmHg.
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Data were averaged from all animals (n = 8) and presented as means ± S.D. Dotted and continuous lines are four-parameter logistic functions fitted to the averaged data. In the baroreflex equilibrium diagram (C), point S and U indicate the estimated operating points in supine and upright tilt positions, respectively. Point A (grey circle) indicates the estimated operating point in upright tilt position in the absence of neural arc shift (C). In the total arc (E), points St and Ut indicate the estimated operating points in supine and upright tilt positions, respectively. The two points are superimposed. The line joining the crosses and point At (grey circle) indicate the estimated total arc curve and operating point, respectively, in the absence of neural arc shift (simulation) (E).
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Group-averaged data show that the 60 deg upright tilt did not change the total arc curve (Fig. 5D). The operating AP point in the total arc was constant during the postural change (point St overlapped with point Ut, in Fig. 5E). In a simulation where 60 deg upright tilt produces no shift in the neural arc (i.e. no resetting), then the tilt would shift the total arc curve downward to a lower AP (line joining crosses) and decrease the operating AP from point St to point At (Fig. 5E).
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Group-averaged data of P1 (the range of SNA response to CSP) and P4 (the minimum value of SNA) in the neural arc were larger at 60 deg upright tilt than supine (Table 2). In the peripheral arc, P1 (the range of AP response to SNA) was smaller while P3 (midpoint of the SNA operating range) was higher at 60 deg upright tilt (Table 1). In both the neural and peripheral arcs, the maximal gains (at the mid-point of the arc) and operating gains (at the intersection of arcs) were similar in supine and upright tilt positions. All parameters (P1-4) and the maximal gain of the total arc were similar in supine and upright tilt positions (Table 3).
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Using the data from all animals, the operating AP estimated from the baroreflex open-loop equilibrium diagram (protocols 1 and 3) agreed with those measured in the baroreflex closed-loop condition (protocol 2) for both postures (Fig. 6A). The operating SNA values estimated from the equilibrium diagram also agreed with those measured for both postures (Fig. 6B).
A and B show the operating AP and SNA, respectively. Each animal provided two data points obtained in supine (open circles) and upright tilt positions (filled circles). Both the operating AP and SNA estimated by the equilibrium diagram match the values actually measured under the baroreflex closed-loop condition. RMS: root mean square.
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Discussion
The maintenance of AP in upright posture against gravitational fluid shift is of great importance, but the mechanisms remain unknown. We applied baroreflex equilibrium diagram analysis (Yamamoto et al. 2004) to the baroreflex system both in supine and 60 deg upright tilt positions. Our new major findings are that upright tilt shifts the CSP–SNA relationship (the baroreflex neural arc) to a higher SNA, whereas it shifts the SNA–AP relationship (the baroreflex peripheral arc) to a lower AP (Fig. 5). These data support our first hypothesis that orthostatic stress resets the baroreflex neural arc to a higher SNA.
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Our data indicate that resetting of the baroreflex neural arc in an upright posture doubles the orthostatic activation of SNA and increases the operating AP by 10 mmHg. In our experiments, 60 deg upright tilt reset the neural arc to a higher SNA, shifted the peripheral arc to a lower AP (Fig. 5A and B), and consequently moved the estimated operating point from point S (SNA, 66 a.u.; AP, 102 mmHg) to point U at a higher SNA (91 a.u) and similar AP (102 mmHg) (Fig. 5C). In a simulation where the resetting in the neural arc is absent, 60 deg upright tilt would move the operating point from point S to point A (the intersection of the supine neural arc and the upright-tilt peripheral arc: SNA, 79 a.u.; AP, 92 mmHg), halving the orthostatic activation of SNA (13 a.u. versus 25 a.u) and decreasing the operating AP at upright tilt by 10 mmHg compared with when the resetting is in operation. These findings support our second hypothesis that resetting of the arterial baroreflex contributes to preventing postural hypotension.
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Our data indicate that resetting of the baroreflex neural arc contributes to preserving the baroreflex total arc function in an upright posture. In a simulation where resetting in the neural arc is absent, 60 deg upright tilt would shift the total arc downward to a lower AP (Fig. 5D and E) by a downward shift of the peripheral arc. However, in our experiments, 60 deg upright tilt maintained the total arc (Fig. 5D and E) by orthostatic resetting of the neural arc. These findings indicate that resetting of the neural arc has an important role in maintaining the total baroreflex function in an upright posture.
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Little is known about the arterial baroreflex system under orthostatic stress. Although earlier studies addressed the baroreflex in relation to AP regulation under orthostatic stress, most of them evaluated the baroreflex in a supine, not orthostatic, position (Mosqueda-Garcia et al. 1997). In addition, although earlier studies investigated the gains of baroreflex control of SNA (Mosqueda-Garcia et al. 1997), vascular resistance (Cooper & Hainsworth, 2001) and R–R interval (Cooke et al. 1999), these gains were part of the total baroreflex system, and thus could not explain the operating points of the baroreflex. In the present study, we determined the neural and peripheral arcs independently in an upright position using the baroreflex open-loop equilibrium diagram. We found that upright tilt shifted the baroreflex neural arc to a higher SNA, while it shifted the baroreflex peripheral arc to a lower AP. Our data confirmed the accuracy of the equilibrium diagram in defining the operating point, since in both supine and upright tilt positions, the operating points estimated from the diagram agreed well with those measured in the baroreflex closed-loop condition (Fig. 6). This is consistent with earlier studies addressing haemorrhage (Sato et al. 1999) and muscle stretch (Yamamoto et al. 2004).
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The mechanism responsible for the resetting of baroreflex neural arc with upright tilt remains unclear. The most likely mechanism is recruitment of other sympathoexcitatory systems than the baroreflex during orthostatic stress. In particular, the vestibular system is stimulated by upright tilt, and has been reported to increase SNA (vestibulosympathetic reflex) (Yates, 1992) and assist AP regulation during orthostatic stress in humans (Ray & Carter, 2003) and rats (Gotoh et al. 2004). In addition, contractions of the antigravity muscles during upright tilt stimulate the muscle reflexes that increase SNA (Potts & Mitchell, 1998; Yamamoto et al. 2004). Thus recruitments of other systems may shift the CSP–SNA relationship to a higher SNA.
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However, the resetting of the baroreflex neural arc during upright tilt may not result from simple summation of SNA activation by the arterial baroreflex and by other systems. Theoretically, if the recruitments of other systems only offset SNA, it increases P4 (the minimum value of SNA) but not P1 (the range of SNA response to CSP) of the neural arc, and causes a parallel shift of the CSP–SNA relationship to a higher SNA without transforming the inverse sigmoid curve. In contrast, our results showed that 60 deg upright tilt increased not only P4 but also P1 (Table 2), and widened the inverse sigmoid curve. These findings suggest an interaction between baroreflex and other systems in upright tilt posture. Indeed, the vestibular system has been considered to interact with the baroreflex (Yates, 1992; Kaufmann et al. 2002; Monahan & Ray, 2002; Ray & Carter, 2003; Gotoh et al. 2004). In addition, the muscle reflex has been reported to interact with the baroreflex (Potts & Mitchell, 1998), and contribute to the central resetting of the baroreflex during exercise (DiCarlo & Bishop, 2001; Miki et al. 2003). We have recently reported that passive stretch of the triceps surae muscles shifts the CSP–SNA relationship to a higher SNA using the baroreflex equilibrium diagram analysis (Yamamoto et al. 2004). Further studies are necessary to address the mechanism for the resetting during upright tilt.
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Our data indicate that 60 deg upright tilt reduces the pressor response to SNA in the peripheral cardiovascular system. We observed that upright tilt down-shifted the baroreflex peripheral arc to a lower AP. For all SNA levels, AP was lower in the upright than supine position (Figs 4 and 5). This change may be attributed to the gravitational fluid shift toward the lower part of the body (i.e. abdominal vascular bed, lower limbs), which decreases the preload and effective circulatory blood volume (Sagawa et al. 1988; Rowell, 1993).
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Our data suggest that upright tilt yields a different effect on the baroreflex system compared with haemorrhage. Haemorrhage decreases effective circulatory blood volume and preload (Sagawa et al. 1988; Rowell, 1993). Earlier study in rats demonstrated that haemorrhage (blood loss in the range of 0.5–2% of body weight) reduced AP in a prevailing level of SNA in the baroreflex peripheral arc (Sato et al. 1999), similar to our upright tilt. Therefore, both upright tilt and haemorrhage reduce the pressor response to SNA in the peripheral cardiovascular system. In contrast to upright tilt, haemorrhage did not affect the baroreflex neural arc (Sato et al. 1999). In short, upright tilt resets the baroreflex neural arc to a higher SNA whereas haemorrhage does not.
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Since we focused on arterial baroreflex dynamics in response to an acute orthostatic stress, our findings could not relate long-term pressure regulation by arterial and cardiopulmonary baroreflexes and the renin–angiotensin system. Early study showed that chronic sino-aortic and cardiopulmonary denervations increased AP and activated the renin–angiotensin system in the conscious dog (Persson et al. 1988). Further study is needed to address long-term orthostatic physiology.
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As we investigated the role of the arterial baroreflex in AP control under orthostatic stress while AP was well maintained, our findings could not explain the pathophysiology of orthostatic vasovagal syncope. Interestingly, the final trigger of human orthostatic syncope appears to be the abrupt disappearance of SNA (Morillo et al. 1997). Given the present findings, we speculate that some changes in the baroreflex neural arc can decrease SNA and trigger orthostatic syncope.
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Limitations
The present study has several limitations. First, we excluded the efferent effect of vagally mediated arterial baroreflex, which could affect the properties of the two arcs. Second, we used an anaesthetic agent (intravenous injection of a mixture of urethane and -chloralose) that could flatten the baroreflex peripheral arc by reducing the cardiac pumping function.
Third, since we measured only renal SNA, our findings have limited applicability to other SNA, including cardiac SNA. Although static regulation of the baroreflex neural arc over SNA is similar in renal and cardiac SNAs in supine posture (Kawada et al. 2001), whether this holds true during orthostatic stress remains to be verified.
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Fourth, we were not able to quantify the contribution of cardiac function (i.e. cardiac output) to AP regulation. Since the baroreflex peripheral arc represents the static relation from SNA input to AP, it includes the effects of SNA on cardiac function, stressed blood volume and vascular resistance. We were not able to isolate these factors because of complexity and experimental difficulties.
Fifth, we eliminated cardiopulmonary baroreflex by cutting bilateral vagal nerves. Earlier human studies have indicated that non-hypotensive hypovolaemic perturbations do not change AP, but reduce central venous, right heart and pulmonary pressures, and cause vasoconstriction. These observations have been interpreted as reflexes triggered by cardiopulmonary baroreceptors (Johnson et al. 1974; Pawelczyk & Raven, 1989). However, Taylor et al. (1995) showed that small reductions of effective blood volume reduce aortic baroreceptive areas and trigger haemodynamic adjustments which are so efficient that alterations in AP escape detection by conventional means. Accordingly, further studies are needed to understand the relative importance and mutual cooperation of arterial and cardiopulmonary baroreflexes in AP control during orthostatic stress.
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Lastly, we used rabbits, which are quadrupeds. Since humans spend most of their time in nearly 90 deg upright postures whereas rabbits do not, our findings have limited applicability to humans. However, Japanese White rabbits spend most of their time in 10–40 deg head-up posture, and frequently stand up to nearly 70 deg. This suggests that rabbits have an ability to maintain arterial pressure against gravity-induced pressure perturbation under orthostatic stress. Additionally, in our preliminary experiments in rabbits, we observed that denervation of both carotid and aortic arterial baroreflexes caused postural hypotension of approximately 50 mmHg during 60 deg upright tilt, consistent with a previous study in rats (Sato et al. 2002). This suggests that even in quadrupeds, the arterial baroreflex has a very important role in the maintenance of AP under orthostatic stress. Accordingly, we speculate that our findings may reflect, at least, the qualitative aspects of orthostatic baroreflex physiology in humans. Indeed, recent human studies have suggested that orthostatic stress (lower body negative pressure) enhances the SNA response to arterial pressure change in the baroreflex closed-loop condition (Ichinose et al. 2004a; Ichinose et al. 2004b)
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In conclusion, baroreflex open-loop equilibrium analysis demonstrated that 60 deg upright tilt shifted the baroreflex neural arc to a higher SNA and shifted the peripheral arc to a lower AP. Consequently, the upright tilt markedly increased the operating SNA and maintained the operating AP. Simulation study suggests that resetting of the neural arc would double the orthostatic activation of SNA and increase the operating AP in upright tilt by 10 mmHg compared with the absence of resetting. These data suggest that orthostatic stress increases SNA by resetting the baroreflex neural arc. The resetting of the neural arc may compensate for the reduced pressor responses to SNA in the peripheral cardiovascular system, and contribute to preventing postural hypotension.
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