Middle cerebral artery blood velocity during exercise

with b-1 adrenergic and unilateral stellate ganglion

blockade in humans

K . I D E , R . B O U S H E L , H . M . S é R E N S E N , A . F E R N A N D E S , Y . C A I , F . P O T T

and N . H . S E C H E R

Department of Anaesthesia, The Copenhagen Muscle Research Centre, University of Copenhagen, Rigshospitalet, Denmark

ABSTRACT

A reduced ability to increase cardiac output (CO) during exercise limits blood flow by vasoconstriction

even in active skeletal muscle. Such a flow limitation may also take place in the brain as an increase in

the transcranial Doppler determined middle cerebral artery blood velocity (MCA Vmean) is attenuated

during cycling with b-1 adrenergic blockade and in patients with heart insuf®ciency. We studied

whether sympathetic blockade at the level of the neck (0.1% lidocain; 8 mL; n � 8) affects the

attenuated exercise ± MCA Vmean following cardio-selective b-1 adrenergic blockade (0.15 mg kg)1

metoprolol i.v.) during cycling. Cardiac output determined by indocyanine green dye dilution, heart

rate (HR), mean arterial pressure (MAP) and MCA Vmean were obtained during moderate intensity

cycling before and after pharmacological intervention. During control cycling the right and left MCA

Vmean increased to the same extent (11.4 � 1.9 vs. 11.1 � 1.9 cm s)1). With the pharmacological

intervention the exercise CO (10 � 1 vs. 12 � 1 L min)1; n � 5), HR (115 � 4 vs.

134 � 4 beats min)1) and DMCA Vmean (8.7 � 2.2 vs. 11.4 � 1.9 cm s)1) were reduced, and MAP

was increased (100 � 5 vs. 86 � 2 mmHg; P < 0.05). However, sympathetic blockade at the level of

the neck eliminated the b-1 blockade induced attenuation in DMCA Vmean (10.2 � 2.5 cm s)1). These

results indicate that a reduced ability to increase CO during exercise limits blood ¯ow to a vital organ

like the brain and that this ¯ow limitation is likely to be by way of the sympathetic nervous system.

Keywords b-1 blockade, cerebral blood ¯ow, exercise.

Received 17 February 2000, accepted 19 June 2000

During dynamic exercise cardiac output (CO) increases

in proportion to workrate and metabolism, and an

increasing fraction of CO is directed to the working

muscle at the expense of ¯ow to, e.g. the splanchnic

organs (Perko et al. 1998). However, when the ability to

increase CO is reduced following cardio-selective b-1

blockade, the increase in muscle blood ¯ow is restricted

by vasoconstriction in the working muscle re¯ected in a

magni®ed noradrenaline spillover (Pawelczyk et al.

1992). Similarly, the exercise leg blood ¯ow is low in

patients with cardiac insuf®ciency (Isnar et al. 1996,

Magnusson et al. 1997). Conversely, in the cardiac

insuf®cient patient, the increase in muscle blood ¯ow is

improved following digoxin medication that allows for

an increase in CO during exercise (Schmidt et al. 1995).

During dynamic exercise, middle cerebral artery

blood velocity (MCA Vmean) increases by ~25% (Jùr-

gensen et al. 1992). However, this increase is attenuated

in patients with cardiac insuf®ciency (HellstroÈm et al.

1997) and in patients with atrial ®brillation (Ide et al.

1999a). When the ability to increase CO is impaired

during cycling by cardio-selective b-1 adrenergic

blockade (metoprolol) in healthy subjects, the increase

in MCA Vmean is also reduced to only 12% compared

with 22% during control exercise (Ide et al. 1998) and

the near-infrared spectroscopy determined increase

in cerebral oxygenation is attenuated (Ide et al. 1999b).

In contrast, b-1 blockade does not affect the increase in

MCA Vmean during rhythmic handgrip where the

demand for an elevated CO is minimal.

Taken together, these observations indicated to us

that a reduced ability to increase CO induces peripheral

vasoconstriction not only in the splanchnic organs and

in working skeletal muscle but also in the brain. To test

this hypothesis, we determined the MCA Vmean during

exercise with unilateral sympathetic block at the level of

Correspondence: Kojiro Ide, Department of Anaesthesia, Rigshospitalet 2041, Blegdamsvej 9, DK-2100 Copenhagen é, Denmark.

Acta Physiol Scand 2000, 170, 33±38

Ó 2000 Scandinavian Physiological Society 33

the neck before and after b-1 adrenergic blockade. In

humans, a stellate ganglion blockade increases hemi-

spheric cerebral blood ¯ow (Umeyama et al. 1995) and

we considered that it would eliminate, or at least

attenuate, the reduction in MCA Vmean that is estab-

lished during exercise with b-1 adrenergic blockade. In

addition to MCA Vmean, the CO response to cycling

with cardio-selective b-1 adrenergic blockade was

determined.

MATERIALS AND METHODS

Eight healthy volunteers (age 22 � 4 years [mean �

standard error (SE)], body weight 74 � 4 kg and height

181 � 4 cm) participated in the study after informed

consent to the protocol as approved by the Ethics

Committee of Copenhagen (KF 01-038/98).

Before the main study, the subjects performed an

incremental exercise test until exhaustion to determine

maximal O2 uptake ( _V O2) on a modi®ed Krogh

ergometer (Galbo et al. 1987), and expired air was

obtained with an oxyscreen apparatus (Medical

Graphics, Spiropharma, Denmark). On the day of the

main study, the subjects accessed the laboratory after

having a light breakfast. The subjects were studied in a

semisupine position with the head resting on a pillow,

similar to the usage in the preliminary study.

Measurements were obtained during 5 min of rest and

during 20 min of moderate intensity cycling. The

exercise intensity aimed at ~60% of maximal _V O2

( _V O2max) and it resulted in a value corresponding to

57 � 3% of _V O2max. After termination of cycling, the

subjects rested for ~60 min. Fifteen minutes after the

administration of the blocking agents, the protocol was

repeated.

After the control study sympathetic blockade was

established. For the sympathetic block at the level of the

neck lidocain (8 mL, 0.1%; SAD, Denmark) was

administered at the transverse process of 6th left

cervical vertebra. Presence of miosis, ptosis, injection of

the conjunctiva and nasal stuf®ness indicated an

appropriate block. Cardio-selective b-1 adrenergic

blockade was Instituted by metoprolol (Seloken, Hassle,

Sweden) and administered intravenously (0.15 mg kg)1

body weight followed by a 10-mL saline ¯ush). An

additional dose of metoprolol (0.03 mg kg)1) was

administered during cycling at the 10th min in order to

maintain the adrenergic block in the face of increasing

levels of plasma catecholamines (Kjñr et al. 1987). This

dose of b-1 blockade was also used in other studies

where a reduced exercise CO and leg blood ¯ow were

demonstrated (Pawelczyk et al. 1992, Ide et al. 1998).

The proximal segment of the MCA was insonated

(Multidop X, DWL, Sipplingen, Germany) through the

posterior temporal `window'. To identify MCA the

Doppler signal is scanned deeper until a spectrum with

a ¯ow directed away from the probe was found. This

represents the bifurcation of MCA and the anterior

cerebral artery. The depth and the size of `volume' were

optimized from the depth of 50 mm and a volume of

8 mm, depending upon signal-to-noise ratio. Once the

optimal signal-to-noise ratio was obtained, the probe

was covered with adhesive ultrasonic gel (Tensive,

Parker Laboratories, Orange, NJ) and secured with a

headband. The Vmean in the MCA was computed as

the time-average of continuously sampled maximal

frequency Doppler shifts for each heart beat and

averaged for each minute.

Mean arterial pressure (MAP) was obtained from the

catheter in the brachial artery and integrated by a

monitor that also calculated heart rate (HR) from a

two-lead electrocardiogram (8000, Simonsen & Weel,

Copenhagen, Denmark). Blood samples were collected

anaerobically at rest and during each step of the cycling

protocols and immediately analysed for pH, haemo-

globin (Hb), O2 (PO2) and CO2 tensions (PCO2), O2

saturation (SO2), glucose and lactate (ABL-4, Radio-

meter, Copenhagen, Denmark). Separate blood samples

were placed in chilled tubes containing 100 lL of

EGTA/GSH solution and centrifuged at 600 ´ g for

10 min at 4 °C. The plasma was stored at ±80 °C for

analysis of catecholamines by High Performance

Liquid Chromatography1 (HPLC) using a radioenzy-

matic method (Christensen et al. 1980).

The CO was obtained by indicator-dilution tech-

nique with the use of indocyanine green dye (ICG,

Cardiogreen, Becton Dickison). A 5-mg dose of ICG

was injected rapidly into the vein followed by a 10-mL

¯ush of isotonic saline (Pawelczyk et al. 1992). Blood

from the artery was sampled at 30 mL min)1 by a

Harvard pump through a photodensitometer (Water

Intruments, Rochester, MN) and the dye dilution

curves were recorded. The arterial ICG concentrations

were calibrated using known concentrations of ICG in

whole blood.

Values are presented as mean � SE. The Friedman

test was used to determine whether signi®cant changes

occurred between circumstances and such changes

which were located with the Wilcoxon matched pairs

sign test by rank. A P-value <0.05 was considered to

indicate a statistically signi®cant difference.

RESULTS

At rest, the pharmacological interventions did not

signi®cantly affect blood gas variables (Table 1) or

MCA Vmean. The MAP increased (100 � 5 vs. 86 �

2 mmHg), and HR (62 � 4 vs. 65 � 5 beats min)1) and

CO became lower (4.6 � 0.2 vs. 5.2 � 0.4 L min)1;

Table 2).

34 Ó 2000 Scandinavian Physiological Society

Exercise MCA Vmean and sympathetic blockade � K Ide et al. Acta Physiol Scand 2000, 170, 33±38

During exercise, the pharmacological intervention

reduced HR (115 � 4 vs. 134 � 4 beats min)1) and

CO (10.4 � 0.7 vs. 12.0 � 1.1 L min)1; n � 5) and

they increased MAP (103 � 5 vs. 98 � 4 mmHg). For

MCA Vmean, the b-1 adrenergic blockade-induced

attenuation of the increase in Vmean was eliminated by

the stellate blockade (unblocked right side: 8.7 � 2.2

vs. 11.4 � 1.9 cm s)1 P < 0.05; blocked left side:

10.2 � 2.5 vs. 11.1 � 1.9 cm s)1 NS, Fig. 1).

During cycling blood variables including PCO2, pH

and Hb were not affected by the two types of block,

and PO2 was reduced (Table 1). Corresponding to the

right atrium SO2 decreased during cycling with the

block (63 � 3 vs. 70 � 2%). Plasma catecholamines

increased during exercise and the two blocks

augmented these concentrations (adrenaline: 0.3 � 0.0

to 1.2 � 0.2 nmol L)1 vs. 0.3 � 0.1 to 0.5 � 0.1

nmol L)1 and noradrenaline: 2.4 � 0.6 to 9.8 �

1.7 nmol L)1 vs. 1.2 � 0.1 to 3.7 � 0.6 nmol L)1).

Pulmonary _V O2 (to 1.6 � 0.1 L min)1) and ventilation

(to 40 � 3 L min)1) increased without any signi®cant

effect of the two blocks.

DISCUSSION

This study con®rmed the ®nding that during exercise

the increase in CO and MCA Vmean were diminished by

cardio-selective b-1 adrenergic blockade (Ide et al.

1998). The important ®nding was that sympathetic

blockade at the level of the neck eliminated the

limitation to the increase in MCA Vmean following

cardio-selective b-1 adrenergic blockade.

Table 1 Blood gas variables at rest

and during exercise with and without

pharmacological interventions

Control Block

Rest Cycling Rest Cycling

pH(a) 7.41 � 0.00 7.39 � 0.00** 7.42 � 0.01 7.38 � 0.01*

pH(v) 7.38 � 0.00 7.36 � 0.01** 7.39 � 0.01 7.35 � 0.01*

PCO2(a) (kPa) 5.5 � 0.1 5.4 � 0.2 5.4 � 0.2 5.4 � 0.1

PCO2(v) (kPa) 6.5 � 0.2 6.6 � 0.2 6.1 � 0.3 6.6 � 0.2

PO2(a) (kPa) 13.8 � 0.6 13.0 � 0.4* 13.3 � 0.2 12.2 � 0.4**, PO2(v) (kPa) 5.2 � 0.2 5.2 � 0.2 5.4 � 0.1 4.8 � 0.2

Hb(a) (mmol L)1) 8.8 � 0.3 9.2 � 0.3** 8.9 � 0.3 9.3 � 0.3**

Hb(v) (mmol L)1) 8.8 � 0.2 9.1 � 0.2** 8.8 � 0.2 9.1 � 0.3**

SO2(a) (%) 97 � 0.00 97 � 0.00 97 � 0.00 96 � 0.00

SO2(v) (%) 72 � 2.00 70 � 2.00** 74 � 2.00 63 � 3.00*,  

NA(a) (nmol L)1) 1.2 � 0.1 3.7 � 0.6** 2.4 � 0.6  9.8 � 1.7**,  

A(a) (nmol L)1) 0.3 � 0.1 0.5 � 0.1* 0.3 � 0.00 1.2 � 0.2**, 

Pharmacological intervention; b-1 adrenergic blockade and stellate ganglion blockade. Values are

mean � SE.

a: arterial value; v: venous value; pH: pH of blood; PCO2: carbon dioxide tension; PO2: O2 tension;

Hb: haemoglobin; SO2: haemoglobin saturation; O2, NA: noradrenaline; A: adrenaline; Compared

with rest, * P < 0.05, ** P < 0.01; compared with control,   P < 0.05,    P < 0.01.

Table 2 MCA Vmean, cardiovascular

and pulmonary variables at rest and

during exercise before and after phar-

macological intervention

Control Block

Rest Cycling Rest Cycling

Right MCA Vmean (cm s)1) 55.5 � 3.1 66.9 � 3.1* 56.8 � 3.3 64.2 � 2.8*, Left MCA Vmean (cm s)1) 58.6 � 3.7 69.6 � 3.5* 60.7 � 3.7 68.8 � 3.5*

MAP (mmHg) 86 � 2 98 � 4* 100 � 5  103 � 5 HR (beats min)1) 65 � 5 133 � 4* 62.0 � 4.0  115 � 4*, CO (L min)1) 5.2 � 0.4 12 � 1* 4.6 � 0.2*,  10 � 1*, 

_V O2 (L min)1) 0.3 � 0.1 1.6 � 1.0* 0.3 � 0.02 1.6 � 1.1*

VE (L min)1) 8 � 0 40 � 3* 7 � 1 39 � 2*

Data were obtained from eight subjects. Values are mean � SE. MCA Vmean: middle cerebral artery

blood velocity; MAP: mean arterial pressure; HR: heart rate; CO: cardiac output (n � 5): _V O2: O2

uptake; VE: ventilation.

Compared with rest, * P < 0.05; compared with control,   P < 0.05.

Ó 2000 Scandinavian Physiological Society 35

Acta Physiol Scand 2000, 170, 33±38 K Ide et al. � Exercise MCA Vmean and sympathetic blockade

An impaired ability to increase CO after b-1

blockade in normal man as in patients with cardiac

insuf®ciency limits blood ¯ow in working muscle

(Pawelczyk et al. 1992, Magnusson et al. 1997) and

blood velocity in the MCA (HellstroÈm et al. 1997, Ide

et al. 1998, 1999a, b). The level of reduction in the

exercise CO was ~15% with b-1 blockade in this study

and such a reduction in CO augments sympathetic

activity (Pawelczyk et al. 1992, Magnusson et al. 1997).

It remains controversial whether an elevated sympa-

thetic activity is of relevance for the brain. The

sympathetic nerve activity is thought to have little

in¯uence on cerebral vessels although they are richly

innervated. Yet, in the dog, the increase in cerebral

vascular resistance by haemorrhage at normotension is

eliminated by a adrenergic blockade (Pearce & D'alecy

1977). Also, the lowered MCA Vmean with a reduced

central blood volume developed during lower body

negative pressure (Levine et al. 1994) or head-up tilt

(Jùrgensen et al. 1993b) may be explained by sympa-

thetically mediated vasoconstriction of the cerebral

arteries. During central blood volume depletion, the

increase in sympathetic nerve activity shifts the cerebral

autoregulation curve to the right (Paulson et al. 1990)

and the vasoconstrictor sympathetic nerve activity over-

rides vasodilatation (Levine et al. 1994). Thus, the

results suggest that in the extreme condition where the

ability to increase CO is impaired during exercise with a

large muscle mass, the increase in sympathetic nerve

activity limits the cerebral circulation. In fact, the

arterial noradrenaline level increased by ~10 nM during

cycling with b-1 blockade compared with an increase by

~4 nM during control exercise.

Although blood pressure and CO increase manifold

during exercise, global cerebral blood ¯ow (gCBF)

determined by Kety±Schmidt technique is reported to

be unchanged (Scheinberg et al. 1953, 1954, Zobl et al.

1965), despite a 22% increase in MCA Vmean (Madsen

et al. 1993). Thus, an increase in blood ¯ow to one part

of the brain could result in a downregulated ¯ow in

another part of the brain2 . However, it is unknown

whether gCBF is maintained during exercise when the

exercise induced increase in MCA Vmean is attenuated

following the reduction in CO in humans. When gCBF

is determined by ¯uorescent microsphere technique

during treadmill exercise in the pig, there is an increase

in gCBF during exercise and it is attenuated in

congestive heart failure (Caparas et al. 2000). Further-

more, cerebral oxygenation determined by near infrared

spectroscopy is attenuated during cycling following b-1

blockade, supporting that the increase in cerebral blood

¯ow is reduced (Ide et al. 1999b3 ).

A critical issue for the transcranial Doppler deter-

mined MCA Vmean is to what extent Vmean re¯ects

volume ¯ow. In situations where the head remains

motionless as is the case during the release of an

occluding cuff around a leg, the changes in two

expressions of ¯ow velocity such as the maximal

frequency of the Doppler shift used in this study as

Vmean and the intensity weighted mean ¯ow velocity

(VIWmean) are comparable (Aaslid et al. 1989). On the

other hand, Poulin et al. (1999) also determined an

MCA blood ¯ow index during cycling, which is derived

by the VIWmean multiplied with total signal Doppler

power. Their ®ndings were that there was no signi®cant

change in MCA blood ¯ow index, although there were

increases in the former two expressions of ¯ow

velocities during exercise. Furthermore, the change in

Vmean is larger than in the VIWmean. According to these

authors, these discrepancies might be because of the

alteration in the arterial ¯ow pro®le as both the

amplitude and the frequency of the arterial pressure

waveform change. A concern using the VIWmean and

MCA ¯ow indices is their dependency on a high quality

of the Doppler signal and they would expect to be

affected more than Vmean by movement-related arte-

facts (Newell et al. 1994). During handgrip the increase

in Vmean is attenuated by axillary blockade, despite

similar increases in HR and MAP as during control

handgrip (Jùrgensen et al. 1993a). Furthermore, during

cycling the changes in Vmean are well followed by

cortical blood ¯ow as determined by the 133Xe clear-

ance technique (Jùrgensen et al. 1992) and internal

carotid artery blood ¯ow determined by duplex ultra-

sound Doppler (HellstroÈm et al. 1996).

One may suspect that the changes in MCA Vmean

are caused by the changes in MCA diameter in response

to cerebral autoregulation. During static exercise MCA

Vmean does not increase and also cortical blood ¯ow

determined 133Xe clearance remains stable, even though

blood pressure increases as much as during dynamic

exercise (Rogers et al. 1990, Jùrgensen et al. 1992).

Figure 1 Middle cerebral artery blood velocity (DMCA Vmean) from

rest to exercise following pharmacological intervention. Sympathetic

blockade was administered by b-1 adrenergic and left stellate ganglion

blockade. L: left MCA; R: right MCA. Values are mean � SE.

* Different from control P < 0.05.

36 Ó 2000 Scandinavian Physiological Society

Exercise MCA Vmean and sympathetic blockade � K Ide et al. Acta Physiol Scand 2000, 170, 33±38

Accordingly it is unlikely that cerebral autoregulation

involves a relatively large artery as the MCA. Actually,

the changes in MCA Vmean was not affected by the

sympathetic blockade at the level of the neck during

moderate intensity cycling, during hand-grip exercise

and during a cold pressor test (F. Pott, unpublished

observation). If the sympathetic activity constricts

MCA, the attenuated increase in MCA Vmean on the

unblocked side following pharmacological intervention

could underestimate the attenuation in ¯ow. However,

the increase in MCA Vmean could not be a result of

MCA vasoconstriction during exercise as sympathetic

blockade at the level of the neck during exercise with

b-l blockade restored the exercise ± MCA Vmean to the

control exercise level.

For the differences in Vmean before and after b-1

blockade, seven subjects showed a larger reduction in

the right MCA than in the left MCA during exercise.

Thus, there was a statistically signi®cant effect of stel-

late ganglion blockade on the MCA Vmean with a

relatively large scatter, which may indicate that we were

unable to block all sympathetic ®bres to the cerebral

vessels in all subjects.

In summary, during exercise with b-1 blockade the

reduction in MCA Vmean was revealed to be sympa-

thetic nerve mediated vasoconstriction in the small

arteries. The pharmacological interventions did not

affect PaCO2 that might in¯uence cerebral blood ¯ow

and MAP became elevated. Thus, an impaired ability to

increase CO during exercise with a large muscle mass

appears to limit blood ¯ow distribution not only to

active muscle but also to such a vital organ as the brain

and that this ¯ow restriction is by way of the sympa-

thetic nervous system.

We acknowledge Mss Heidi Hansen, Birgitte Jessen, Karin Juel

Hansen for the expert technical assistance and Drs Elizabeth

Pemberton and Marc J. Poulin for revising the manuscript. This

study was supported by The Danish Medical Foundation (504-14).

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