Download Sympathetic activity does/does not influence cerebral blood flow

J Appl Physiol 290: 1364–1368, 2008;
doi:10.1152/japplphysiol.90597.2008.
Point:Counterpoint
Point:Counterpoint: Sympathetic activity does/does not influence cerebral
blood flow
POINT: SYMPATHETIC ACTIVITY DOES INFLUENCE
CEREBRAL BLOOD FLOW
1364
8750-7587/08 $8.00 Copyright © 2008 the American Physiological Society
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Cerebral arteries are abundantly innervated by sympathetic
fibers, but their influence on cerebral vessels was held unimportant for almost a century (2, 20). Whether there is sympathetic
influence on cerebral blood flow (CBF) is important in the
management of hypotensive patients. If there is no ␣-adrenergic
influence on CBF, a low mean arterial pressure (MAP) can be
increased to the cerebral autoregulation (CA) range by ␣-adrenergic receptor agonists and secure CBF and cerebral oxygenation
(ScO2). On the other hand, if CBF is influenced by cerebral
␣-adrenergic stimulation, CBF and ScO2 decline while MAP
increases in response to administration of the ␣-adrenergic agonist. In this context it is important that in humans, middle cerebral
artery (MCA) mean blood velocity (Vmean) decreases in response
to trigeminal ganglion stimulation (27) and CBF increases after
stellate ganglion blockade (24).
Studies performed in erect and exercising healthy subjects as
in patients with heart failure provide further direct and indirect
support for modulation of cerebral perfusion by sympathetically mediated vasoconstriction consequent to a reduced cardiac output (CO). A relationship between CBF and CO is
established when standing up as both MCA Vmean and ScO2
decrease together with CO (25). This reduction in cerebral
perfusion manifests although MAP increases, indicating a role
for sympathetic activation in cerebrovascular resistance control. Alternatively, the orthostatic reduction in cerebral perfusion
is alleged to be caused by the postural decrease in end-tidal carbon
dioxide tension (PETCO2) (3). The reduction in arterial CO2 tension
(PaCO2) accounts, however, for only one-half of the orthostatic
influence on MCA Vmean (13, 23). In support, both MCA Vmean
and ScO2 increase when the standing position is supplemented by
leg-muscle tensing, attenuating sympathetic activity by enhancing
CO (25). This observation might be related to an effect of stroke
volume on the arterial baroreceptors where dynamic input from
stroke volume is important in the regulation of sympathetic
activity in humans (5).
During dynamic exercise, MCA Vmean and ScO2 increase
(14). However, when exercise with ␤-adrenergic blockade
attenuates the increase in CO, e.g., from 19 to 15 l/min (19),
the increase in MCA Vmean is also reduced (12). Yet the usual
25% increase in MCA Vmean is reestablished if sympathetic
activity to the brain is eliminated by stellate ganglion blockade
(10). Similarly, in patients with heart failure the patient’s
ability to increase CO during exercise relates to the increase in
MCA Vmean (11). When comparing one- with two-legged
exercise, heart failure patients demonstrate a normal increase
in MCA Vmean that is attenuated, or eliminated, during twolegged exercise (7, 8, 16).
An increment in CO with volume expansion increases MCA
Vmean as a reduction in CO with application of negative
pressure to the lower parts of the body (LBNP) decreases MCA
Vmean at a maintained MAP (18). This takes place with no
change in PaCO2 and, therefore, cerebral vasoconstriction indicates increased sympathetic drive.
The orthostatic decrease in MAP at brain level is within
the CA range, but the reduction in CO is by ⬃20%.
Lowering MAP using trimethaphan and subsequently restoring it with phenylephrine evaluates sympathetic influence in
the control of CBF during moderate LBNP (29). The similarity of reductions in mean, systolic, and pulse arterial
pressures in addition to pulsatile change in MCA Vmean and
PETCO2 before vs. during ganglionic blockade was taken to
suggest that sympathetic vasoconstriction is not the mechanism underlying the reduction in CBF during central hypovolemia. An implicit assumption was that phenylephrine
does not affect the cerebral vasculature. However, phenylephrine may lower CBF while increasing MAP (22).
Against that background, the study (29) indicates that phenylephrine balances ␣-blockade for the brain. Among the
mechanisms by which changes in stroke volume may affect
CBF, altered shear stress related to changes in pulsatile flow
is proposed through flow-mediated regulatory mechanisms
like nitric oxide (NO) (29). NO is involved in the regulation
of CBF in both animals and humans. Endothelial dysfunction is proposed to affect cerebral artery myogenic tone and
CA, but its role in the regulation of CBF during central
hypovolemia is not established. CA may be NO mediated
(28), but in healthy subjects an exogenous NO donor does
not affect the control of CBF. Similarly, inhibition of NO
production does not impair dynamic CA (30) and neither
affects MCA Vmean in healthy subjects (9). Thus, in humans,
the role of NO in the control of CBF remains elusive.
The observation that steady-state CBF, MCA Vmean, and
ScO2 decrease on standing seems to be at odds with CA, i.e.,
that CBF is relatively stable within a wide range of perfusion
pressures (21, 25). Comparable to what happens to skeletal
muscle blood flow during exercise, regional flow is allowed to
increase for as long as it does not affect MAP. However, when
CO is restricted and challenges MAP, flow to exercising
muscles and to the brain becomes limited (22). Stimulation of
sympathetic nerves to the brain may cause a marked reduction
in CBF, whereas under conditions where MAP is not challenged by a restricted CO, the influence of sympathetic stimulation on CBF is abolished (1). Or, according to Bill and
Linder (1), under certain conditions stimulation of the sympathetic nerves to the brain causes a marked reduction in CBF,
whereas under normal conditions the effect of such stimulation
is practically nil.
An influence of the sympathetic activity on CBF is likely to
explain the discrepancy between the lack of influence of MAP
on CBF and ScO2 as long as the central blood volume (CBV)
is maintained during anesthesia (lowest level 37 mmHg) (17),
and the decrease in CBF and Vmean when MAP declines below
⬃80 mmHg in response to deliberate reduction in central blood
volume by LBNP, head-up tilt, or hemorrhage (Fig. 1).
When considering the stimulus to the arterial baroreceptors against a background of different effects of steady vs.
pulsatile pressure on baroreceptor discharge, we accept that
the influence of CO on CBF may be through the pulse
pressure generated by the stroke volume and detected by the
Point:Counterpoint
1365
arterial baroreceptors where data from animal studies support that baroreceptors detect flow as well as pressure (4).
Nevertheless, in animals the separate effects of different
components of arterial pressure have not been identified (6)
and also parasympathetic influence of CBF needs to be
established.
Taken together, an inability to maintain, or to increase, CO
adequately induces peripheral vasoconstriction not only in
working skeletal muscle (19) but also in the brain (26). We
take it that ␣-adrenergic influence on CBF is important and that
administration of ␣-adrenergic agonists affects CBF and ScO2.
As long as CBV is adequate, such an effect is masked to
become evident with central hypovolemia. The exception to
that rule is the patient with significant arteriosclerosis in the
arteries serving the brain. For such a patient, CBF is pressure
dependent but that distracts from the notion that recording
of MAP does not provide information on whether CBF and
ScO2 are maintained. The implication of these observations
is that for the unconscious patient, routine monitoring of
CBF or ScO2 needs to be established because recording of
blood pressure can not in itself predict whether CBF is
maintained.
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Fig. 1. Cerebral oxygenation (ScO2) related to mean arterial pressure (MAP)
including the data obtained with a maintained central blood volume (CBV)
during anesthesia (broken line) and data from subjects for whom the central
blood volume was reduced deliberately during head-up tilt [solid line (15)].
Nomogram illustrates distribution of the lowest MAP in anesthetized patients
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COUNTERPOINT: SYMPATHETIC NERVE ACTIVITY DOES
NOT INFLUENCE CEREBRAL BLOOD FLOW
It is intuitively clear that the cerebral circulation cannot take
part in general cardiovascular regulation. During states of shock,
where the sympathetic nervous system is activated, leading to a
decrease in the perfusion of kidneys and mesenteric vascular bed,
the cerebral circulation is kept functioning as long as possible and
experiences only a modulating effect on autoregulation by sympathetic perivascular nerves.
The cerebral arteries are innervated like other vascular beds by
neurons arising in the peripheral nervous system and also by
intrinsic neurons (4, 9). Sympathetic nerves in contact with the
cerebral arteries originate from the superior cervical ganglion, but
peculiarly under normal conditions seem to have little influence
on cerebral blood flow (CBF). Already Fog (3) in his early studies
of pial arteries in cats found no effect of acute sympathetic, vagal,
or baroreceptor denervation on the autoregulatory responses.
Chronic sympathetic denervation in animals does not influence
CBF autoregulation (2, 15). Electric stimulation or acute sympathetic denervation in animals likewise has little effect on CBF if
blood pressure is kept stable. In humans, bladder distension
caused a powerful sympathetic activation with a 35% rise in blood
pressure with a rise in heart rate and papillary dilatation, but did
not influence CBF (11).
A weak modulatory effect of the sympathetic perivascular nerves
on CBF autoregulation can only be detected at extremes of blood
pressure. During hemorrhagic hypotension, the otherwise inactive
nerves constrict the larger cerebral resistance vessels, the “inflow
tract” of the brain, thereby counteracting the autoregulatory response
of the smaller arteries and arterioles (1, 5). This response is a weak
analog of the intense vasoconstriction seen in the peripheral and
visceral vascular beds. Likewise, during acutely induced hypertension, sympathetic activation, either endogenously or by electric stimulation, can constrict the inflow tract and hence contribute to autoregulation and exert a protective effect on the cerebral resistance
vessels (8, 12). The net effect is a shift of the autoregulation curve
toward higher blood pressure. Interestingly, during acutely induced
hypertension in the anesthetized rat an interaction between the sympathetic nervous system and the renin-angiotensin system can be
demonstrated. Blockade of the renin-angiotensin system with captopril causes a shift of the upper limit of autoregulation toward lower
J Appl Physiol • VOL
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Johannes J. van Lieshout1,2
Niels H. Secher3,4
Department of Internal Medicine,
Medium Care Unit, Human
Cardiovascular Physiology Unit,
AMC Center for Heart Failure Research,
Academic Medical Center,
University of Amsterdam
The Netherlands;
Department of Anaesthesiology,
The Copenhagen Muscle Research Center,
Rigshospitalet
University of Copenhagen,
Copenhagen, Denmark
e-mail: [email protected]
blood pressure, and this shift is abolished by concomitant electric
stimulation of the cervical sympathetic trunk (14).
In a study in normal humans, lower body negative pressure
was used to create a baroreflex-induced activation of the
sympathetic nervous system. Such activation did not alter
cerebrovascular reactivity to hypercapnia or hypocapnia, as
studied by medial cerebral artery velocity (7). Likewise, the
same group found no effect of ganglionic blockade on cerebrovascular CO2 reactivity (10). By contrast, in a related study,
where sympathetic activation was achieved by head-up tilt and
sympathetic tone was removed by ganglionic blockade, a slight
effect of sympathetic activation was found on CO2 reactivity
(6). These finding may have been influenced by methodological
errors, as discussed in detail by LeMarbre et al. (7). Interestingly,
ganglionic blockade with trimetaphan did not appear to influence
cerebrovascular CO2 reactivity in normotensive and hypertensive
humans (13). Lower body negative pressure induces a decrease in
cerebral blood flow velocity even if blood pressure is maintained
by infusion of a pressor drug. This cerebral vasoconstrictor response was preserved in healthy individuals under ganglionic
blockade with trimetaphan, excluding participation of the sympathetic nervous system (16).
Thus it may be concluded that the sympathetic perivascular
nerves have little or no effects on CBF and its regulation under
normal conditions, but may be activated to constrict the inflow
tract cerebral vessels at very high or very low blood pressure. It is
gratifying that this point of view was also expressed in a recent
review on perivascular nerves and the regulation of cerebrovascular tone (4).