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Themed Issue Papers |
1 The Department of Integrative Physiology, University of North Texas, Health Science Center, Fort Worth, TX 76107, USA
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(Received 14 September 2005;
accepted after revision 6 October 2005; first published online 6 October 2005)
Corresponding author P. B. Raven: 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA. Email: praven{at}hsc.unt.edu
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Introduction |
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TopAbstractIntroductionReferences |
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T. H. Huxley (1894) states that ‘The tragedy of science. The slaying of beautiful hypotheses by ugly fact.’ Subsequently this hase proven to be correct in light of the following review of current information. Coote & Dodds (1976) identified baroreflex resetting during sustained contraction of the hindlimb in decerebrate unanaesthetized cats. Subsequently, beginning in 1980, a series of landmark studies by Donald and coworkers (Stephenson & Donald, 1980; Melcher & Donald, 1981; Walgenbach & Donald, 1983), using an isolated carotid sinus technique in chronically instrumented exercising dogs, identified an upward shift from rest to exercise of the baroreflex stimulus–response curve of both HR and ABP without a change in maximal gain (Gmax). Another key study identifying the importance of the arterial baroreflex during exercise was performed by Sheriff et al. (1990). Using chronically instrumented exercising dogs, these investigators demonstrated that the increase in arterial pressure evoked by activation of the exercise pressor reflex became unrestrained following sino-aortic baroreceptor denervation. Collectively, these data clearly indicated that arterial baroreflex control of ABP was indeed functional during exercise and was in fact necessary for the normal cardiovascular response to exercise.
Methodological considerations for investigating the arterial baroreflexes
The early recognition of an inverse relationship between changes in ABP and changes in HR (Marey, 1863) suggested a negative feedback control system (Rowell et al. 1996). Over the course of many years and many experiments, elegantly reviewed by Sagawa (1983) and concisely presented by Rowell et al. (1996), the engineering concepts of the arterial baroreceptor's sigmoidal stimulus–response curve were described. This stimulus–response curve has been shown to conform to a logistic function model (Kent et al. 1972) from which several baroreflex parameters can be derived, see Fig. 1.
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The introduction of the variable pressure neck collar (Ernsting & Perry, 1957) and its subsequent mechanical modification (Eckberg et al. 1975) and customized computer-controlled operation (Pawelczyk & Raven, 1989) provided the ability to obtain stimulus–response logistic function curves of the carotid baroreflex (CBR) control of HR and mean arterial pressure (MAP) in humans at rest and during exercise. However, the initial NP/NS protocol, which used rapid pulses of 500 ms duration of NP and NS of approximately 40, 40, 40, 40, 25, 10, 0–5, –20, –35, –50 and –65 mmHg during an end-expiratory breath hold, was technically and physiologically impractical during exercise when the R–R interval approached 500 ms (i.e. HR of 120 beats min–1). Additionally, a 12–15 s end-expiratory breath hold during moderate to high intensity exercise can result in activation of the autonomic nervous system via chemoreceptor reflex activation. Therefore, in order to overcome these technical complications, Potts et al. (1993) developed a protocol using more sustained pulses of NP and NS (5 s pulses), which were brief enough to establish reflex responses via the parasympathetic and the sympathetic arms of the CBR without resulting in counteractive responses from the aortic baroreceptors. During the application of these techniques, recording peak HR and ABP responses and developing the best-fit linear or logistic regression model of the response data to assess Gmax or sensitivity of the reflex was the method of choice (Potts et al. 1993; Papelier et al. 1994).
The development of two dynamic measurement techniques: (i) the sequence technique (Iellamo et al. 1997); and (ii) the estimate of a transfer function gain using linear dynamic analysis of HR and ABP variability (Zhang et al. 2001), have added to the complexity of interpretation of data with regards to baroreflex function during exercise. A point to consider is that these dynamic techniques only determine the gain around the operating point of the reflex, which is very different from the maximal gain obtained from logistic modelling of the full stimulus–response curve. This is an important distinction, considering that the operating point of the reflex moves during exercise. As such, the reduced gain reported during exercise in studies using dynamic analyses probably reflects the movement of the operating point away from the centring point and closer to the threshold of the reflex, and so to a locus of lesser gain. Therefore, it is the gain around the operating point that is reduced during exercise, while the maximal gain of the stimulus–response curve is well preserved. Another complexity involved in assessing baroreflex function is the physiological interpretation of representing changes in heart period as the R–R interval (RRI) or as changes in HR because of the inverse exponential relationship between HR and RRI. This is of particular importance when baseline heart rates are different, such as between rest and exercise as described in detail previously (O'Leary, 1996; Raven et al. 1997).
Mechanisms by which the carotid baroreflex responds to changes in pressure
In order to establish that HR and MAP changes in response to NP and NS are indeed representative of the carotid–cardiac (CBR–HR) and carotid–vasomotor (CBR–MAP) reflexes, respectively, measurements of stroke volume (SV) and muscle sympathetic nerve activity (MSNA) and the calculation of changes in systemic vascular conductance at rest and during exercise have been obtained (Fadel et al. 2001; Ogoh et al. 2002a, 2003; Wray et al. 2004). At rest, measures of SV, using Doppler ultrasound technology, were found to be unchanged during both the rapid pulse train protocol and the 5 s pulses of NP and NS (Levine et al. 1990; Ogoh et al. 2002a). More importantly, during cycling exercise up to heart rates of 150 beats min–1 estimations of changes in SV from the impedance changes of the arterial blood flow velocity curve obtained from beat-to-beat measurements of arterial pressure (Modelflow method) were not different during the 5 s NP/NS protocol (Ogoh et al. 2003). Identification of an unchanged SV during the NP/NS stimuli of the carotid baroreceptors demonstrated that the reflex changes in HR (CBR–HR) represent the carotid baroreflex control of cardiac output (i.e. the carotid–cardiac arm of the CBR).
The determination of SV during the application of NP and NS permitted the calculation of percentage contributions of cardiac output 
and systemic vascular conductance (SVC) to the CBR-mediated change in MAP at rest and during exercise (Ogoh et al. 2002a, 2003). Considering that peak changes in HR occur early in response to neck pressure and suction (i.e. 3–4 s, when MAP only changes (2–3 mmHg) and return to baseline at the time of the peak MAP response (Raven et al. 1997; Fadel et al. 2003), the percentage contributions of CO and SVC have been calculated not only at the time of the peak MAP response, but also at the time of the peak HR response. These data calculations have indicated that the rapid changes in HR cause subsequent changes in 
that are solely responsible for the initial reflex-mediated change in MAP (i.e. at the time of the peak HR response). At the same time, SVC changed minimally during these first few seconds, but changed dramatically at the time of the peak MAP response (i.e. 6–8 s from initiation of the stimulus), when the change in MAP evoked by NP and NS was primarily the consequence of alterations in SVC (see Fig. 2). These data demonstrated that alterations in SVC predominate over 
in mediating CBR changes in MAP.
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arm cycling exercise (Fadel et al. 2001). More recent work directly measuring blood flow using Doppler ultrasound technology has identified the dominant effect that the CBR has on leg vascular conductance (LVC). Using one legged knee extension exercise, Keller et al. (2003, 2004) measured CBR-mediated changes in LVC in both a non-exercising and an exercising leg. Although LVC responses were attenuated in the exercising leg compared to the non-exercising leg, it was clear from these data that the capacity of the CBR to regulate blood pressure depends critically on its ability to alter vascular tone both at rest and during exercise. Subsequent work using dynamic linear analysis of the HR, MAP, MSNA, femoral blood velocity and tissue oxygenation responses to 0.1 Hz NP stimuli of the CBR over a 5 min period confirmed the importance of vascular changes in CBR function (Wray et al. 2004). Perhaps more importantly, these data also demonstrated simultaneous entrainment of all CBR end-organ measurements, clearly linking the CBR-mediated alterations in MSNA to changes in the upstream (femoral blood velocity) and downstream (tissue oxygenation) vasculature. Collectively, these findings indicate that peak changes in MAP in response to NP and NS are a measure of vasomotor reflexes and confirm the basis of the carotid–vasomotor (CBR–MAP) arm of the CBR. Arterial baroreflex resetting during exercise
Several investigations have demonstrated resetting of the baroreflex stimulus–response curve during exercise, indicating a vertical upward shift on the response arm and a lateral rightward shift to higher operating pressures. Functionally this allows the baroreflex to operate at the prevailing ABP evoked by the exercise (Fig. 3).
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exercise, it was clearly demonstrated that both the carotid–cardiac (CBR–HR) and the carotid–vasomotor (CBR–MAP) reflex function curves had been ‘reset’ (Potts et al. 1993; Papelier et al. 1994). An additional investigation, using a combination of leg and arm exercise, identified that this resetting of the CBR–HR and CBR–MAP function curves was maintained up to 100%
(Norton et al. 1999a). Collectively, these investigations identified that the upward and rightward resetting of the CBR function curves occurred in direct relation to the intensity of dynamic exercise without a change in Gmax or sensitivity (see Fig. 3) (Potts et al. 1993; Papelier et al. 1994; Norton et al. 1999a). This resetting of the CBR without a change in sensitivity has also been reported during isometric (static) exercise (Ebert, 1986). The importance of this resetting of the arterial baroreflex during exercise has been demonstrated using the instrumented exercising rabbit model. In these experiments ABP was maintained at resting values using nitroprusside infusions during the first 60 s of treadmill exercise. Both HR and renal sympathetic nerve activity were immediately increased above that of control exercise conditions, indicating that the ABR normally buffers these responses to adequately control ABP during exercise (DiCarlo & Bishop, 1992). Similar findings have been reported in humans, in that HR and MSNA responses to static handgrip exercise were greatly elevated when nitroprusside was infused to prevent the exercise-induced increase in ABP (Scherrer et al. 1990). Another fundamental alteration associated with baroreflex resetting during exercise is the movement of the operating point away from the centring point and closer to the threshold of the reflex (see Fig. 3). This is an important change with regard to baroreflex control because it places the baroreflex in a more optimal position to counteract hypertensive stimuli. However, once the operating point moves away from the centring point (i.e. its point of maximal sensitivity, or Gmax) the reflex operates at a lower MAP and a reduced gain. Most studies employing the NP/NS protocol have reported this movement of the operating point away from the centring point, with the exception of one investigation that was only able to fit response data to a linear regression model (Papelier et al. 1994) instead of the typical logistic function model (Potts et al. 1993; Norton et al. 1999a). It is important to note that this relocation of the operating point to a position of reduced gain occurs in direct relation to the exercise intensity. We believe this movement of the operating point provides both a physiological and a mathematical basis for the differences in interpretation of data from those studies which suggest that the arterial baroreceptors are ‘switched off’ or are working with a reduced gain compared to those that suggest they are ‘reset’ and functioning with a similar gain as at rest. In this regard, if a study only examines the gain at the operating point, for example when using dynamic analyses, then the results will indicate a reduced baroreflex gain during exercise. However, if a study incorporates full stimulus–response curves than the ability to identify the maximal gain at the centring point will indicate a preserved baroreflex gain.
Dynamic analysis techniques such as the sequence technique have been used to gain an understanding of the vagal withdrawal associated with the transition from rest to progressive increases in exercise workload (Ogoh et al. 2005). Interpretation of data from these studies has indicated that vagal control of the heart was virtually absent at heart rates > 120 beats min–1 and therefore the cardiac arterial baroreflex appeared to be ‘switched off’. In contrast, linear transfer function analysis between HR variability and SBP variability in the low frequency domain identified a gradual reduction in baroreflex sensitivity to heart rates > 150 beats min–1, reflective of the progressive reduction in vagally mediated reflex control of the heart as workload increased (Ogoh et al. 2005). An elegant animal experiment verified the presence of a decreasing vagal influence on the heart up to maximal exercise (O'Leary & Seamans, 1993). Recently, CBR resetting from rest to bicycle exercise at heart rates of 90, 120 and 150 beats min–1, along with the documented relocation of the CBR–HR operating point and reduced HR responding range with increasing exercise intensity, was found to result from vagal withdrawal. Furthermore, the sensitivity at the operating point obtained from the logistic modelling of the HR responses to NP and NS was similar to the sensitivity of the cardiac baroreflex assessed by the two methods of dynamic analysis (Ogoh et al. 2005). Importantly, the sensitivity at the centreing point (Gmax) of the CBR–HR curve was not different from rest. Nevertheless, of physiological importance is that the relocation of the operating point to a position of reduced gain on the modelled CBR–HR function curve reflects the intensity-related decreases in vagal tone, which leads to a progressive operational reduction in the baroreflex control of the heart from rest to maximal exercise.
With regard to the baroreflex control of the vasculature (CBR–MAP (vasomotor) curve), a consistent relocation of the operating point of the CBR–MAP function curve away from the centring point and closer to the threshold to a point of lesser gain is not present for all of the NP/NS modelling investigations (Potts et al. 1993; Norton et al. 1999a; Gallagher et al. 2001b; Ogoh et al. 2003, 2005). Furthermore, there is no evidence of a reduction in the response range of the CBR–MAP function curve from rest to maximal exercise (Norton et al. 1999a; Ogoh et al. 2003, 2005). However, in subsequent investigations, in which arm exercise was added to leg exercise, the operating point of regulated ABP was either increased above or was maintained at the ABP of the leg exercise (Secher et al. 1977; Norton et al. 1999a). In contrast, when leg exercise was added to arm exercise the operating point of ABP was reduced below that of the arm exercise alone (Volianitis et al. 2003). These data suggest that the amount of central blood volume and its consequent cardiopulmonary baroreceptor load provides modulatory neural information to the establishment of the operating carotid ABP. This concept has been preliminarily confirmed by assessing CBR function during rest, arm exercise only, leg exercise only and the combination of arm and leg exercise (Volianitis et al. 2004). The importance of a modulatory role of central blood volume in establishing the ABP to be regulated during exercise in healthy humans remains unknown. However, this interaction may provide an explanation for the lack of consistency in observing a relocation of the operating point of the CBR–MAP function curve. In these studies, exercise protocols consisted of cycling exercise in the 70 deg-back supported semirecumbent position (Potts et al. 1993), upright and supine cycling (Volianitis et al. 2004) or seated leg kicking (Keller et al. 2004; Wray et al. 2004). Therefore, the differences in the movement of the operating point on the CBR–MAP curve may be due to the substantial differences in subject positioning and its subsequent effect on central blood volume and cardiopulmonary baroreceptor loading.
Neural mechanisms involved in baroreflex resetting during exercise
Having established that the CBR is reset during dynamic exercise to functionally operate around the prevailing ABP elicited by the exercise workload, investigation of the integrated neural mechanisms involved in accomplishing this resetting required the a priori establishment of a hypothetical model. Based upon the extensive background of investigation of muscle chemoreflex activation of the sympathetic nervous system in animal and human models, Rowell & O'Leary (1990) formulated a working hypothesis of arterial baroreflex resetting during exercise and its regulation of sympathetic nerve activity. They proposed that central command and the muscle metaboreflex (i.e. the chemical component of the exercise pressor reflex) mediate the resetting of the arterial baroreflex during exercise. Using hypothetical baroreflex function curves, they suggested that central command was responsible for relocating the initial operating point of the CBR (i.e. the prevailing blood pressure) to higher arterial blood pressures, the consequence being a resetting of the entire stimulus–response curve around the newly established operating pressure. In addition, vertical shifts in the stimulus–response curves could be produced via activation of the muscle metaboreflex to raise the dependent variable (e.g. MAP or MSNA), without changing the initial operating point of the reflex. Together, the concerted actions of both central command and the muscle metaboreflex would produce a rightward and upward relocation of the baroreflex curve during exercise, thereby preserving the functionality of the reflex during exercise. As illustrated in Fig. 3, both the CBR–HR and the CBR–MAP function curves were reset in a similar fashion, suggesting to us that both central command and the exercise pressor reflex independently or in combination were involved in resetting the carotid–cardiac and carotid–vasomotor reflex function curves during exercise; see Fig. 4.
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Central command activation
The experiments that have demonstrated CBR resetting using NP and NS were generally performed during 20 min steady-state dynamic exercise in attempts to establish a constant central command and EPR input into the cardiovascular control centres (Potts et al. 1993; Norton et al. 1999a; Ogoh et al. 2002b). However, during prolonged (60 min) cycling exercise cardiovascular drift occurs and results in progressive increases in HR, oxygen uptake and ratings of perceived exertion (RPE), indicating progressive increases in central command activation (Norton et al. 1999b). The importance of this progressive increase in central command was the finding that the CBR was progressively reset in direct relation to the increased activation of central command (as mainly determined from increases in RPE and HR). The elevation in central command input was presumably related to increases in muscle fibre recruitment in order to maintain the same power output throughout 60 min of exercise. However, as an increasing number of single muscle fibres became fatigued, skeletal muscle afferents were probably activated, and so increases in the EPR input to the cardiovascular centres may also have contributed to this progressive resetting of the CBR during prolonged exercise.
To address the question of the influence of central command on baroreflex resetting during exercise more specifically, several studies have attempted to manipulate central command input directly by either reducing or increasing central command activation during exercise. In order to minimize central command input, Iellamo et al. (1997) assessed baroreflex function during involuntary muscle contraction. During electrically induced exercise the sensitivity of the relationship between systolic arterial pressure and R–R interval was decreased, suggesting that central command was necessary to preserve baroreflex sensitivity. However, it should be noted that these findings were unable to be reproduced by Carrington & White (2002). A plausible explanation for these contradictory findings may be the use of dynamic analyses techniques to assess baroreflex sensitivity. Moreover, these procedures do not allow the full baroreflex function curve to be determined.
In an attempt to address this concern, Querry et al. (2001) constructed full baroreflex function curves during static and dynamic handgrip exercise performed before and after partial axillary blockade (2% lignocaine) to block motor fibres and increase central command input. Under blockade conditions, dynamic and static exercise relocated the CBR–HR and CBR–MAP function curves upward on the response arm and rightward to higher arterial pressures to a greater magnitude than during exercise without blockade (Fig. 5A). In addition, the operating point of the carotid–cardiac curve was shifted closer to the threshold of the reflex when central command was augmented. However, a limitation of this protocol was that, in addition to increasing central command activation, the 2% lignocaine may also have interrupted afferent neural information emanating from the exercising muscle (i.e. EPR input). Unfortunately, this compromised the interpretation of these data.
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50% caused a further resetting of the CBR–HR and CBR–MAP function curves upward on the response arm and rightward to higher arterial pressures in comparison to exercise without blockade (Fig. 5A). This augmentation in CBR resetting occurred without any change in the maximal gain of the reflex. In such experiments that produce muscle weakness, issues related to subject anxiety and possible activation of central neural pathways contributing to the elicited physiological responses remains a caveat of interpretation (see Williamson et al.'s review regarding this issue). Furthermore, because the muscle weakening experiments require volitional increases in central command, it is unclear whether the act of CBR resetting is a culmination of active physiological mechanisms or whether it results primarily from the active increase in arterial blood pressure. Involuntary manipulation of central command was achieved previously in a classical experimental protocol using agonist tendon vibration to assist in producing a given muscle tension and antagonist tendon vibration to inhibit the development of a given muscle tension (Goodwin et al. 1972). In this experimental protocol agonist tendon vibration reduces central command input and antagonist tendon vibration increases central command input, while the same static workload is performed. Recently, by reducing central command input with agonist tendon vibration during knee extension exercise, Ogoh et al. (2002b) reported a shifting of the CBR–HR and CBR–MAP function curves downward on the response arm and leftward to lower arterial pressures in comparison to the location of the curves during exercise without vibration (Fig. 5A). Conversely, increasing central command input with antagonist tendon vibration further reset the CBR function curves upward and rightward compared to exercise without vibration. Additional experiments in which the actual muscle contration was performed at the same rating of perceived exertion (i.e. equal central command input) observed during the agonist and antagonist protocols identified that the CBR–HR resetting was a result of 100% central command activation while CBR–MAP resetting resulted from a 50%:50% activation of central command and the exercise pressor reflex (Ogoh et al. 2002b).
In summary, these human investigations support the concept that CBR resetting occurs during exercise as a result of central command activation and are in agreement with the elegant animal work in which stimulation of the mesencephalic locomotor region (a brain anatomical site potentially involved in central command) was reported to reset the arterial baroreflex (Waldrop et al. 1996; McIlveen et al. 2001). The involvement of central command in resetting the CBR–HR reflex is not surprising and is consistent with previous work (Mitchell, 1990). Additionally, it is important to note that many of the human exercise experiments which used exercise intensities below 30% maximal intensity identified involvement of central command in the resetting of the CBR–MAP function curve (Gallagher et al. 2001a; Querry et al. 2001; Ogoh et al. 2002b). These data strongly suggest that central command regulates sympathetic nerve activity from rest to exercise without regard to exercise intensity. Finally, in contrast to the initial working hypothesis, in which activation of central command would selectively shift the CBR function curve to higher arterial blood pressures (Rowell & O'Leary, 1990), the findings from these studies indicate that central command produces not only a rightward relocation to higher pressures but also an upward relocation of the curve on the response arm. That is, central command activation results in the classic upward and rightward resetting of the baroreflex during exercise.
Exercise pressor reflex
The involvement of the exercise pressor reflex in the neural control of the circulation during exercise has been the subject of a number of excellent reviews (Mitchell et al. 1981; Rowell et al. 1996). Its postulated involvement in arterial baroreflex resetting was a result of experiments involving muscle chemoreflex activation (Rowell & O'Leary, 1990; Kaufman & Forster, 1996; Rowell et al. 1996; Carrington et al. 2001; Fisher & White, 2004) and sino-aortic baroreceptor denervation (Sheriff et al. 1990). As noted above (Page 6, Neural mechanisms involved in baroreflex resetting during exercize), activation of the muscle metaboreflex was hypothesized to result in vertical shifts in the baroreflex function curves which would raise the dependent variable (e.g. MAP), without changing the initial operating point of the reflex.
Several studies have attempted to examine the involvement of the exercise pressor reflex in baroreflex resetting during exercise. Papelier et al. (1997) reported that the selective activation of the muscle metaboreflex (metabolic component of the exercise pressor reflex) with postexercise ischaemia altered the sensitivity of the carotid–vasomotor arm of CBR without altering the sensitivity of the carotid–cardiac arm. Others have reported that activation of the exercise pressor reflex with lower-body positive pressure resets the cardiac component of the CBR and increases its sensitivity (Eiken et al. 1992). However, lower body positive pressure has also been shown to decrease the sensitivity of the CBR (Shi et al. 1993). Nevertheless, these studies clearly indicate that the exercise pressor reflex can modulate baroreflex function.
In a subsequent study, Gallagher et al. (2001b) used medical antishock trousers to stimulate both the mechanoreceptors and the metaboreceptors of the exercise pressor reflex and reported that the CBR–MAP function curve was reset upward on the response arm and rightward to higher carotid sinus pressures compared to control exercise (Fig. 5B). However, the carotid–cardiac reflex function curve was relocated rightward towards higher carotid sinus pressures only. These relocations of the CBR function curves occurred without any changes in maximal sensitivity or any relocation of the operating point when compared with control exercise (Gallagher et al. 2001b). The latter findings are in direct contrast to those when central command was selectively altered and indicate that the exercise pressor reflex is not involved in relocation of the operating point of either arm of the baroreflex.
Further studies using epidural anaesthesia to reduce EPR activation during static and dynamic exercise resulted in a relocation of the CBR–MAP function curve downward on the response arm and leftward to lower carotid sinus pressure compared to control exercise (Fig. 5B; Smith et al. 2003). During static exercise, the carotid–cardiac reflex curve was likewise relocated; however, it only exhibited a leftward shift on the response arm. These changes occurred without alterations in maximal sensitivity, the response range of the CBR, or the relocation of the operating point away from the centring point. Collectively, these studies indicate that the exercise pressor reflex is capable of actively resetting the CBR–MAP function curve during exercise, but it appears only to modulate the carotid–cardiac reflex function curve. Additionally, the exercise pressor reflex has little effect on the relocation of the operating point of the CBR during exercise.
Animal experiments have provided invaluable information regarding exercise pressor reflex control, mainly using static muscle contraction protocols as well as infusions of chemical substances into the vasculature of locomotor muscles and passive muscle stretch to activate the metabolic and mechanical components of the EPR, respectively (Wildenthal et al. 1968; Kaufman et al. 1982; Tallarida et al. 1982; Rybicki et al. 1984; Stebbins & Longhurst, 1985; Stebbins et al. 1988; Sinoway et al. 1994; Hanna et al. 2002; Li & Sinoway, 2002). In a recent study, McIlveen et al. (2001) provided clear evidence that the exercise pressor reflex is capable of resetting the CBR in decerebrate unanaesthetized cats. Similar results were originally reported by Coote & Dodds (1976). Furthermore, using techniques of nerve degeneration and markers of synaptic stimulation, such as c-fos oncoprotein and antergrade staining (Waldrop et al. 1996; Potts et al. 1998), both baroreceptor and skeletal muscle somatosensory afferents have been demonstrated to colocate within the nucleus tractus solitarii, an essential cardiovascular regulatory centre within the central nervous system (Fig. 6). Collectively, these animal investigations establish the anatomical and physiological foundation of baroreflex resetting associated with activation of the exercise pressor reflex.
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Over the past 25 years both animal and human experimentation have verified that the arterial baroreflex is reset from rest to exercise in direct relation to the work intensity. In addition, more recent studies have indicated that activation of central command or the exercise pressor reflex, independently or in combination, is required for the arterial baroreflex to be reset with exercise. Perhaps more importantly, input from all three neural mechanisms (central command, the exercise pressor reflex and the arterial baroreflex) are requisite for the normal physiological responses to exercise. For example, in experiments in which simulated exercise was performed using electrical stimulation (no central command) with the afferent sensing pathways from the exercise pressor reflex blocked pharmacologically or absent due to spinal injury, blood pressure did not increase (Strange et al. 1993; Winchester et al. 2000). This occurred even though a functioning arterial baroreflex was present.
Selective activation of central command has been shown to relocate CBR–HR and CBR–MAP function curves upward on the response arm and rightward to higher arterial pressures without any change in maximal sensitivity. Furthermore, reductions in central command relocated both arms of the CBR downward on the response arm and leftward to lower arterial pressures without any change in maximal sensitivity. Several studies have indicated that the progressive vagal withdrawal accompanying increases in exercise intensity was the primary mechanism responsible for this central command-induced CBR–HR resetting, as well as the relocation of the operating point away from the centring point and the reduction in the response range of the carotid–cardiac baroreflex. With regard to exercise pressor reflex involvement in baroreflex resetting, the EPR has been shown to reset the CBR–MAP function curve upward on the response arm and rightward to higher arterial pressures, whereas it resets the CBR–HR curve only rightward to higher arterial pressures. The use of epidural anaesthesia to reduce exercise pressor reflex activation during exercise resulted in a relocation of the CBR–MAP function curve downward on the response arm and leftward to lower carotid sinus pressures compared to control exercise. Finally, differences in exercise posture, and so differences in central blood volume and its consequent load on the cardiopulmonary baroreceptors, appear to modulate sympathetic nerve activity during exercise. These postural alterations in cardiopulmonary baroreceptor load may also be responsible for the inconsistency of reports concerning the relocation of the operating point of the CBR–MAP function curve.
Overall, our current understanding of the mechanisms for baroreflex resetting during exercise is that the feedforward mechanism of central command is probably the primary regulator of baroreflex resetting, while the negative feedback mechanism of the exercise pressor reflex is more of a modulator of resetting. In summarizing the findings reported in this review, we present a hypothetical model in Fig. 6, depicting the neural integration associated with the resetting of the arterial baroreflex that occurs from rest to exercise.
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Author's present address
P. J. Fadel: Department of Medical Pharmacology and Physiology, University of Missouri, One Hospital Drive, MA 516, Columbia, MO 65212, USA.
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and systemic vascular conductance (SVC) to the CBR-mediated changes in MAP at rest and during cycling exercise at heart rates of 90 (Ex 90), 120 (Ex 120) and 150 beats min–1 (Ex 150) 
) away from the centring point (•) to a position of reduced gain results from the integration within the NTS and subsequent modulation of efferent sympathetic and parasympathetic neural control to the vasculature and the heart, respectively. Importantly, the relocation of the operating point places the baroreflex in a more optimal position to counteract hypertensive stimuli during exercise, as indicated by the arrows within the inset boxes. MAP, mean arterial pressure; SNA, sympathetic nerve activity; PSNA, parasympathetic nerve activity.