Delivery of oxygen to the tissues of the body at rest and during dynamic exercise is accomplished by the proportional increase in cardiac output to meet the metabolic demand. This proportional distribution of the circulation is accomplished by modulating the central and baroreflex-mediated sympathetic control of the vasculature insuring adequate perfusion of the tissues by maintaining control of arterial blood pressure (ABP) (64,65). For example, if maximal vasodilation were to occur in response to whole-body maximal exercise, the consequent ABP would be insufficient to maintain an individual conscious during exercise (7,65). The loss of consciousness would occur as a result of inadequate cerebral perfusion and oxygen delivery. However, due to the complexity involved in cerebral blood flow (CBF) regulation by cerebral autoregulation (CA) and arterial carbon dioxide tension (PaCO2), the mechanism of CBF regulation in the maintenance of cerebral perfusion during dynamic exercise remains controversial.
Numerous human and animal experiments have established that, during dynamic exercise, the arterial baroreflexes are reset to a higher pressure (operating point) in direct relation to the work intensity (15-17,39,57,62,64,68). This enables the heart rate and cardiac output to increase in parallel with the increase in arterial pressure necessary to perfuse the active tissues of the skeletal muscle, heart, lung, and brain. Activation of the feed-forward mechanism of "central command" is the primary mechanism involved in resetting the arterial baroreflex (15,17,39,57,62), whereas the feedback mechanism of the "exercise pressor reflex" plays a major modulatory role in this resetting by activation of the sympathetic nervous system (15,39,57,68). The arterial baroreflex regulation of sympathetic activity and its effect on the peripheral vasculature are the means by which the arterial baroreflexes regulate ABP from rest up to maximal dynamic exercise (46,52,61). Also, the operating point of arterial pressure around which the arterial baroreflexes regulate the pressure at rest and during exercise is related to central blood volume and its influence on sympathetic activity (11,55,56,73).
Despite the evidence from animal studies that cerebral arteries are richly innervated with sympathetic nerve fibers connected to α-adrenergic receptors (9,44,45) and that stellate ganglion and superior cervical ganglion stimulation results in cerebral vessel vasoconstriction (40),evidence regarding the role of arterial baroreflex control of the cerebral vasculature in humans during exercise is minimal. However, with the development of new methodologies in estimating regional and total CBF at rest and during exercise, the role of the arterial baroreflex in regulating the cerebral vasculature is being identified.
CBF DURING EXERCISE
The Kety-Schmidt method (N2O method) of measuring CBF requires assessing the uptake or elimination of nitric oxide and/or xenon (133Xe) from arteriovenous oxygen differences across the brain during steady-state conditions. Unfortunately, the comparison between two different steady-state conditions resulting from an acute perturbation eliminates any assessment of the dynamic regulation of CBF and any changes that may occur (67). The earliest studies used the Kety-Schmidt method to measure the average total blood flow of the brain and demonstrated that it is unaffected by dynamic exercise (18,37,66). These reports concluded that, in contrast to other organs, total CBF remains relatively constant under a variety of conditions including exercise.
Recently, it has been demonstrated using measures of cortical flow that CBF increases during dynamic exercise (35,71). The disagreement between the Kety-Schmidt method and the more modern methods of measurement may be explained by different experimental protocols and measurement methods (71) and by differences in the prevailing PaCO2 of the different workloads used (31). Scheinberg et al. (66) compared global CBF during upright exercise with supine rest. Thus, their results included the influence of the upright posture-induced decrease in CBF (75). Globus et al. (18) failed to show an increase in CBF during light exercise; however, this exercise decreased PaCO2 and resulted in a consequent vasoconstriction. Madsen et al. (37) also found a drop in PaCO2 during moderate cycling exercise; however, when they normalized the effect of exercise-induced decreases in PaCO2 on CBF for changes in cerebral vessel CO2 reactivity, they identified that there was no change in CBF from rest to exercise. The CO2 reactivity (30%·kPa−1) during the exercise was the same as that observed at rest. More recently, the cerebral CO2 reactivity was reported to be enhanced during exercise (63); thus, the work of Madsen et al. (37) may have underestimated the influence of the PaCO2 on the CBF during exercise.
In 1992, Jorgensen et al. (35) suggested that the increase in CBF that occurred during exercise reflected an increase in brain activation that was independent of ABP, central command and muscle metaboreceptors. However, they went on to suggest that the increase in CBF was more likely to be dependent on the influence of mechanoreceptors. In contrast, Williamson et al. (74) used a unique experimental paradigm in which they eliminated afferent input to the brain from activation of both the mechanoreceptors and metaboreceptors using hypnotic suggestion of isometric handgrip exercise. Measures of regional CBF using single-photon emission computed tomography (SPECT) during the imagined exercise indicated increases in blood flow to the insular and anterior cingulate cortex that could only be related to the activation of central command. Interestingly, Gross et al. (20) demonstrated in a dog model that local dilator influences, which presumably result from increases in the brain's metabolism, predominate over a variety of potent cerebral vasoconstrictor stimuli in the regulation of cerebral vascular resistance associated with exercise (Fig. 1). During exercise, the blood flow increased in regions of the brain associated with motor control. After doxapram, the amount of hypocapnia, hypertension, and sympathetic nerve activities were similar to those observed during exercise, yet the CBF was reduced. This finding suggests that the vasodilatory effects of the exercise-induced increase in brain metabolism overrode the vasoconstrictor effects of hypocapnia, hypertension, and sympathetic nerves on the cerebral vasculature.
In the absence of any decreases in regional CBF to those areas of the brain supporting basal metabolic activity, any increases in regional CBF associated with the exercise increase in the brain's regional metabolic activity would increase global CBF. Hence, the more traditional measurement techniques of CBF that indicate no increases in CBF during exercise must be questioned. In 1989, Thomas et al. (71) used 133Xe clearance technique and reported an increase in CBF during dynamic exercise in humans. In addition, Jorgensen et al. (35) used transcranial Doppler (TCD) and 133Xe clearance technique (Fig. 2), and Hellstrom et al. (24) used TCD and internal carotid artery blood flow measurements in humans and demonstrated that the middle cerebral artery mean blood velocity (MCA V) was increased during dynamic exercise by all measurements of CBF. Furthermore, as the arteriovenous (jugular) O2 difference was found to be unchanged during moderate exercise (30), an increase in CBF would be needed to increase O2 delivery to those areas of the brain with an increase in metabolism associated with the exercise. In contrast, during heavy exercise, the arteriovenous O2 difference increased (30). This phenomenon was probably related to the hyperventilation-induced decrease in CBF observed during heavy exercise (50).
In conclusion, it seems that, during exercise, the CBF is determined by the integration of the balance between increases in metabolism and increases in vascular tone in those areas of the brain associated with the execution of the motor activity.
ABP AND CONTROL OF CBF
Despite the presence of pulsatile fluctuations in ABP related to beat-to-beat changes in pulse pressure associated with stroke volume and compliance and the slower fluctuations related to respiratory sinus arrhythmias, the steady-state measurements of CBF remain relatively constant as expressed by CA. CA is a homeostatic mechanism that buffers fluctuations in CBF when cerebral perfusion pressure changes and acts through vasomotor effectors that control cerebral vascular resistance (1). In humans, CA has a defined static autoregulatory range from 60 to 150 mm Hg (58,69). In the early 1990s, Tiecks et al. (72) used pulsed Doppler ultrasound measurements of the middle cerebral artery blood velocity (MCA V) in humans and demonstrated that CA maintained MCA V constant during pharmacologically induced slow increases in arterial blood pressure (ABP; Fig. 3). When the data were obtained using more dynamic measurements of MCA V, the presence of a static CA, measured by the steady-state measurement methods, was confirmed.
However, when an acute (or dynamic) change in cerebral perfusion pressure is imposed, CBF is not maintained. For example, in humans, after thigh cuff occlusion, the release of the cuff induces an acute drop in ABP (Fig. 8). The CA response results in cerebral vasodilation in an attempt to return the MCA V to its prehypotensive flow and provides evidence that CA was functional. However, the acute drop in perfusion pressure resulted in a sharp decrease in MCA V, indicating that CA was unable to provide dynamic (or rapid) adjustments to the changes in pressure. Therefore, control of arterial pressure is also an important factor for CBF regulation. In order for CA to be effective, the cerebral perfusion pressure must lie within an autoregulatory range of perfusion pressures. Indeed, patients with syncope have an impaired arterial baroreflex function (3,12,14).
In evaluating the regulation of CBF, there is a need to use more dynamic assessments of the relationship between CBF and ABP. These assessments have been accomplished using frequency domain analysis techniques of the beat-to-beat pulses of CBF velocity and ABP and using the outcomes of transfer function gain, phase, and coherence in probing dynamic CA. Using these frequency domain techniques, Brys et al. (5) evaluated dynamic CA during steady-state cycling exercise at heart rates of 90, 120, and 150 beats·min−1. The transfer function analysis of spontaneous oscillations in blood pressure and MCA V in the low-frequency range of 0.04 to 0.14 Hz indicated that the phase shift and transfer function gain remained stable. They suggested that progressive increases in exercise intensity did not alter CA, despite the increases in HR, ABP, and PaCO2. These findings were confirmed (50,53), although there was some indication that dynamic CA was compromised at the higher work intensities, especially during the diastolic phase of MCA V and ABP.
Based on the findings that arterial baroreflex regulation of ABP (64) and dynamic CA (5) are well maintained during progressive increases in exercise intensity, the regulation of CBF should be preserved during dynamic exercise. However, during exercise, CBF regulation is not always perfect because large fluctuations of ABP seem to impair CBF control. For example, during rowing, when the perfusion pressure to the brain changes rapidly with each rowing stroke, there is a parallel change in the MCA V (60). In addition, fluctuations in MAP during resistance exercise have been found to be too brisk to be dampened efficiently by the brain vasculature (10). Furthermore, high-intensity dynamic exercise presents a challenge to CA due to the rapid and large increases in pulse pressure. For example, in humans, Ogoh et al. (53) considered the potential differences that may be established between the two distinct (systolic and diastolic) phases of the MCA V profile, where increases in systolic blood pressure (SBP) can exceed the range of pressure counteracted by CA. In this same study (53), the authors identified that the normalized low-frequency transfer function gain between MAP and MCA V and between SBP and systolic MCA V (MCA V) remained unchanged from rest to exercise, whereas that between diastolic blood pressure (DBP) and diastolic MCA V (MCA V) increased from rest to heavy exercise (P < 0.05; Fig. 4) indicating a loss of control in the diastolic phase.
Although the data in Figure 4 indicate that, during exercise, dynamic CA was challenged by increases in pulse pressure, the ability of the cerebral vasculature to modulate blood flow around the exercise-induced increase in MCA V was maintained. This finding may explain why previous investigations into static CA during exercise using steady-state measures of CBF were unable to identify differences. However, the data suggest that the regulatory mechanisms involved in controlling the cerebral circulation are less effective in responding to rapid decreases than they are to increases in blood pressure. These findings seem to confirm the hypothesis that the static CA function curve may be shifted rightward to allow the operating point of regulation of the CBF to function around the sympathetically mediated increased blood pressure associated with the intensity of the exercise. However, Ogoh et al. (50) demonstrated in humans that the normalized low-frequency gain between MAP and MCA V was increased (P < 0.05), whereas the phase shift tended to decrease, indicating that dynamic CA was impaired during exhaustive exercise when the pulse pressures exceeded the range of static CA despite a hyperventilation-induced reduction in PaCO2 (Fig. 5).
CARDIAC OUTPUT CONTROL AND CBF
The contribution of arterial baroreflex regulation of HR (i.e., cardiac output) to the control of ABP is small (25%) at rest and virtually zero during exercise (51,52). In contrast, the regulation of cardiac output during exercise has an important role in establishing the CBF (27,48,49). For example, when healthy subjects performed one-legged exercise, MCA V was increased by 20% and was maintained when they performed two-legged exercise (25). However, in patients with heart failure, performance of one-legged exercise did not increase MCA V and two-legged exercise resulted in a decreased MCA V (25). In addition, when cardiac output was reduced by β1-blockade (27,29), or atrial fibrillation (28), the increase in MCA V during bicycling exercise was reduced. These findings indicate that cardiac output is an important factor in the establishment of the CBF. This finding was confirmed in healthy subjects by altering central blood volume and cardiac output at rest and during exercise and by demonstrating a linear relationship between cardiac output and MCA V, which was statistically significant at rest (P < 0.001) and during exercise (P = 0.035). However, the MCA V response to the changes in cardiac output was greater at rest compared with that during exercise (Fig. 6).
These results indicate that any regulation of the cardiac output via the cardiac baroreflex would directly influence dynamic CBF regulation at rest and during exercise. Furthermore, this study (48) demonstrated that the phase and gain between MCA V and MAP in the low-frequency range were not altered from rest to exercise, indicating that the CA was well maintained during changes in cardiac output or MCA V. The sensitivity of the cardiac baroreflex is reduced at its operating point in association with an increase in exercise intensity, and the contribution of the variations in cardiac output to beat-to-beat MCA V remains stable during exercise (54). Hence, we hypothesized that the reduction of cardiac arterial baroreflex function would result in a loss of control of the beat-to-beat changes in MCA V during rapid changes in arterial pressure. These questions were addressed in healthy human subjects at rest and while performing moderate- and heavy-intensity cycling exercise with and without cardiac β1-adrenergic blockade (49). Both moderate and heavy exercise intensities decreased the low-frequency transfer function gain between cardiac output and MCA V with no significant influence of β1-blockade. In contrast, the low-frequency transfer function gain between MAP and MCA V remained stable with or without β1-adrenergic blockade. These findings suggest that the exercise intensity-related reduction in cardiac-arterial baroreflex function that occurs at its operating point does not influence the dynamic control of MCA V, even when the exercise-induced increase in cardiac output is reduced by cardiac β1-adrenergic blockade (Fig. 7). Therefore, the arterial baroreflex regulation of blood pressure via reflex regulation of the systemic vasculature becomes more involved in maintaining CBF during exercise.
AUTONOMIC CONTROL AND CBF
A multitude of animal studies have shown that cerebral arteries are richly innervated with sympathetic nerve fibers (9,44,45). However, the role of autonomic neural control of the cerebral circulation remains controversial. The traditional thinking is that, in the presence of normocapnia, changes in sympathetic tone seem to have a limited effect on CBF (2,21,23,36). Although sympathoexcitation has little effect on CBF at rest, several investigators have reported a direct effect of sympathoexcitation on CBF in pathophysiology (22,27,33,59). Sympathetic nerve activity influences CBF CO2 reactivity (8,34) and CA (76). In addition, there is a strong evidence that increases in sympathetically mediated vasoconstriction protects cerebral vessels during severe hypertension (4). In a cat model at high blood pressures, a breakdown of the blood-brain barrier was observed in the cerebrum; however, in this same model, electrically induced sympathetic stimulation at 10-20 Hz prevented this breakdown, indicating that disruption of the blood-brain barrier during hypertension is reduced by sympathetic stimulation (4). Furthermore, several studies (6,22) have demonstrated that sympathetic stimulation attenuated the increase in CBF that was observed in severe hypertension. Sympathetic stimulation during normotension did not decrease CBF significantly in cats, but during acute severe hypertension, decreases in CBF due to sympathetic stimulation were greatly augmented (−29% compared to −3%) (22). In addition, within a physiological pressure range, a sudden increase in ABP induced transient increases in CBF. This hypertensively induced transient increase in CBF was attenuated by sympathetic nerve stimulation (6). These findings suggest that a major function of sympathetic nerves attached to the cerebral vessels is to protect the cerebral vessels during increases in arterial pressure such as exercise. There is a lower distribution of α-adrenoreceptors in the cerebral circulation compared with other vascular beds, and the presence of the endothelial blood-brain barrier limits the access of many circulating vasoactive hormones to the vascular smooth muscle in the cerebral vessels (13).
Cerebral vessels are also innervated by parasympathetic nerves, and parasympathetic nerve stimulation caused a marked increase in CBF (41). Baroreflex deactivation increases efferent sympathetic activity (70) in the cervical sympathetic trunk, and electrical stimulation of the cervical trunk causes vasoconstriction in multiple regions of the brain (40). In addition, hemorrhage-induced baroreceptor deactivation causes mild cerebral vasoconstriction (19). Moreover, several animal studies (26,32,38,42,43) suggest that, in the medulla, the anatomical location of the site that controls cerebral circulation is mainly related to the same area that controls systemic circulation (cardiovascular center). Nakai (42) demonstrated that unilateral electrical stimulation of the nucleus tractus solitarius (NTS) increased CBF in rats with cervical cordotomy and vagotomy. In addition, lesions within the NTS impaired CA, indicating that the neural pathways originating or passing through the NTS can regulate CA (32). Therefore, the arterial baroreflex control of sympathetic nerve activity directly influences CBF. Recently, the effects of the α1-adrenoreceptor blocker, prazosin, on the regulation of CBF and cerebral vascular conductance index (CVCi) during a hypotensive-induced drop in cerebral perfusion pressure were investigated. It was identified that the prazosin-mediated α1-adrenoreceptor blockade impaired the control of CBF before and after the baroreflex-mediated restoration of ABP (Fig. 8). Furthermore, prazosin impaired the cerebral autoregulatory response to hypotension. These findings suggest that sympathoexcitation affects the mechanism of CA and identifies a role for the arterial baroreflex in the control of the cerebral vasculature in humans. However, the role of a centrally activated autonomic nervous system and its activation via the arterial baroreflex on CBF regulation that occurs during exercise remain unclear.
For CA to be effective, the cerebral perfusion pressure must lie within an autoregulatory range. In addition, the change in cardiac output influences static and dynamic CBF regulation. Therefore, the arterial baroreflex is an important mechanism for the regulation of ABP and CBF especially during heavy exercise when CA is impaired (50). The response of the cerebral vasculature to changes in sympathetic nerve activity protects against the disruption of the blood-brain barrier rather than regulating CBF. In addition, the cerebral vasoconstriction response to sympathetic stimulation is greater during acute hypertension than during normal conditions (22). Thus, autonomic control of the cerebral vasculature is very important for CBF regulation during exercise. However, the direct effect of the autonomic nervous system activation on dynamic CBF regulation during exercise remains unclear.
This work was supported in part by the American Heart Association grant no. 0465104Y and NIH grant no. HL045547. The results of this review paper do not constitute endorsement by ACSM.
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