1
J Physiol 0.0 (2021) pp 1–2
JOURNAL CLUB
The Journal of Physiology
Cerebrovascular control: What’s
so base-ic about it?
Audrey Drapeau1,2 ,
Garen K. Anderson3
and Justin D. Sprick4
1
Faculty of Medicine, Department of
Kinesiology, Université Laval, QC, Canada
2
Research center of the Institut universitaire
de cardiologie et de pneumologie de
Québec-Université Laval, QC, Canada
3
Department of Physiology & Anatomy,
University of North Texas Health Science
Center, Fort Worth, TX, USA
4
Division of Renal Medicine, Department
of Medicine, Emory University Department
of Medicine, Atlanta, GA, USA
Email: audrey.drapeau@criucpq.ulaval.ca
Edited by: Kim Barrett & Laura Bennet
Linked articles: This Journal Club article
highlights an article by Caldwell et al.
To read this article, visit https://doi.org/
10.1113/JP280682.
Amongst the myriad of mechanisms
that interact to regulate cerebral blood
flow (CBF), alterations in arterial gases,
specifically the partial pressure of arterial
carbon dioxide (PaCO2 ), are of great
importance. By nature, CO2 transportation
contributes to the acid–base equilibrium
within the intravascular space, as well as in
the perivascular space. Consequently, such
alterations in pH predicate cerebrovascular
reactivity to CO2 (CVR). It remains to be
determined whether the intrinsic control
of the cerebral vasomotor tone is a direct
result of intraluminal PaCO2 , bicarbonate
[HCO3 – ], arterial pH or a combination of
these.
One way of investigating the influence
of alterations in acid–base balance on
cerebrovascular control is through
examining CVR following high altitude
ascent. Indeed, Fan et al. (2010) observed
enhanced ventilatory and CO2 sensitivity
following an ascent to high altitude, which
was attributed to alterations in pH buffering
capacity during hypercapnia. Specifically,
high altitude exposure causes a reduction
in bicarbonate availability as a result of
renal compensation following respiratory
alkalosis. With a reduction in bicarbonate
bioavailability, there is a greater reduction
in perivascular pH for a given change in
PaCO2 , resulting in an augmented CVR
response (Fan et al. 2010). Although their
study highlights an important role of the
bicarbonate buffering system in modulating
CVR, limitations include the use of transcranial Doppler ultrasound that measures
blood velocity rather than CBF per se,
which may underestimate CVR during
hypercapnia as a result of middle cerebral
artery dilatation (Coverdale et al. 2014)
. Additionally, a modified rebreathing
protocol was used as the stimulus to
increase PaCO2 , which may have contributed
to intra-individual variability in the change
in PaCO2 that was observed (Borle et al.
2017) .
In a recent issue of The Journal of Physiology, Caldwell et al. (2021) report on the
integrative relationship between PaCO2 ,
pH and cerebrovascular tone that was
explored in the context of acute metabolic
alkalosis. In a highly unique and technically
challenging protocol, the previously
identified limitations were addressed
by obtaining CBF measurements (rather
than cerebral blood velocity alone) via
duplex Doppler ultrasonography of the
extracranial vessels and manipulating PaCO2
via end-tidal forcing, which allows for
PaCO2 to be controlled on an individual
basis. CVR was measured through stepwise
iso-oxic alterations in PaCO2 (−10, −5, +5,
and +10 mm Hg), before and following
an infusion of a hypertonic solution of
sodium bicarbonate (NaHCO3 – ; 8.4%,
50 mEq 50 mL−1 ) delivered through
venous catheterization. A radial arterial
catheterization was performed allowing
for direct measures of key variables such
as PaCO2 , HCO3 – , H+ and pH through
repeated arterial blood sampling. This
protocol successfully elevated arterial pH
(7.41 ± 0.02 vs. 7.46 ± 0.03, P < 0.001) and
[HCO3 – ] (26.1 ± 1.4 vs. 29.3 ± 0.9 mEq L−1 ;
P < 0.001) to assess the direct influence of
[HCO3 – ] on CVR. Interestingly, Caldwell
et al. (2021) observed no difference in
absolute CBF at each matched stage of PaCO2
following bicarbonate infusion despite
pH being elevated. This finding suggests
that in the setting of acute metabolic
alkalosis, CBF is regulated by PaCO2 , rather
than arterial pH. Additionally, Caldwell
et al. (2021) report a greater resting CBF
(∼7%) following bicarbonate infusion
in the presence of an unaltered PaCO2 .
This observation provides the first human
© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society
evidence for a direct vasodilatory influence
of HCO3 – on cerebral vessels.
One proposed mechanism to explain the
direct vasodilatory influence of HCO3 –
is based on a previous study by Boedtkjer
et al. (2016). Using an in vitro isolated vessel
preparation of mouse basilar arteries, it was
suggested that reductions in bicarbonate
may directly cause vasoconstriction
through
an
endothelium-dependent
mechanism
activated
through
the
membrane bound receptor, receptor protein
tyrosine phosphatase gamma (RPTPy).
Activation of this receptor by bicarbonate
is reported to alter calcium sensitivity in
vascular smooth muscle cells; a notion
that is supported by the lack of a vasomotor response to bicarbonate in RPTPy
knockout mice. However, the vasomotor
effects of bicarbonate were only present
under reduced bicarbonate concentrations,
with the RPTPy pathway being maximally
activated at a bicarbonate concentration
of 22 mm. This finding suggests that
further increases in bicarbonate above
resting concentrations do not promote
vasodilatation, but rather that reductions
in bicarbonate below 22 mm cause vasoconstriction (Boedtkjer et al. 2016). Of note,
this notion is contrary to the direct vasodilatory role of bicarbonate observed by
Caldwell et al. (2021) where an increasing
[HCO3 – ] (post-infusion all >27.2 ±
1.3 mEq L−1 ) was reported to cause cerebral
vasodilatation. These differences between
studies could potentially be attributed to
differential roles of RPTPy between species
(mouse vs. human) or may even suggest the
possibility of a separate, yet to be identified
sensor of bicarbonate that explains the
direct vasodilatory actions observed by
Caldwell et al. (2021).
Considering how fluid and ion
transfer across the blood–brain and
blood–cerebrospinal fluid barriers, the
question arises as to what drives HCO3 –
transportation? As elegantly summarized
by Caldwell et al. (2021), the current
five proposed mechanisms are: (i) the
buffering capacity of interstitial fluid by
brain cells mostly by interconversion of
CO2 and HCO3 – intracellularly and across
their membranes; (ii) the production of
lactic acid within brain cells including the
buffering of the hydrogen ion (H+ ) in the
extracellular fluids by the CO2 /HCO3 –
system; (iii) the exchange between the
DOI: 10.1113/JP281398
2
removal of lactate– and H+ with the
addition of HCO3 – ; (iv) the removal
of excess ions from the brain due to
the interstitial and cerebrospinal fluid
circulation; and, lastly, (v) the exchange of
H+ and HCO3 – across the choroid plexus
or blood–brain barrier. The latter two
pathways are highlighted by Caldwell et al.
(2021) to justify the occurrence of HCO3 –
in their study design model.
Even if [HCO3 – ] directly affected the
vascular smooth muscle tone to increase
CBF in the study by Caldwell et al.
(2021), it should be noted that this
vasodilatory response was insufficient
to affect cerebrovascular responsiveness
to acute steady-state changes in PaCO2 .
Indeed, Caldwell et al. (2021) demonstrated
that total CBF was acutely regulated by
PaCO2 rather than intraluminal arterial
pH and also that the CVR responses
were a consequence of alterations in the
buffering capacity following the NaHCO3 –
infusion. Caldwell et al. (2021) illustrated
the compensatory buffering response
throughout respiratory acidosis and
alkalosis by comparing the absolute
change in arterial [HCO3 – ], [H+ ] and
pH for a given matched change in PaCO2
between pre- and post-cerebrovascular
CO2 reactivity stages. They interpretated
a smaller change in arterial pH in the
hypo- and hypercapnic ranges compared
to the pre-CVR to indicate an increase
in the buffering capacity. Interestingly,
when indexing arterial [H+ ] following
NaHCO3 – infusion, Caldwell et al. (2021)
reported that relative hypocapnic CVR
was higher, whereas relative hypercapnic
CVR was lower. These results suggest an
alteration in the buffering capacity between
PaCO2 and arterial H+ /pH consequent to
the infusion only during hypercapnia.
Although speculative, it is possible that a
shear stress mediated vasodilatory response
could have increased the bioavailability
in nitric oxide concurrent with the CO2
induced vasodilatory response. They also
speculated on differences in acid–base
buffering capacity during hypo- and hypercapnic CVR. They interpreted that the acute
regulation of CBF by PaCO2 is the result of
the changes in arterial [H+ ]/pH induced
by the alterations in PaCO2 that consistently
relate to changes in the relationship between
CBF and [H+ ]/pH.
Although these latter results further
improve
the
understanding
of
Journal Club
cerebrovascular control, the influence
of acid–base balance on cerebrovascular
control turns out to be not so basic after
all. In this context, the potential limitations
of the study should be highlighted. As
acknowledged by Caldwell et al. (2021),
one important limitation is linked to the
sample characteristics. Only young men
(age 25 ± 6 years, height 181 ± 4 cm,
weight 78 ± 11 kg) were included, which
limits the ability to relate these findings to
women. Additionally, the order of trials was
not randomized, which may have further
influenced the observed results as a result
of an order effect, if present.
There are a number of clinical implications
that could emanate from these findings.
One such exemplar is the reduction in
CBF experienced by end-stage renal
disease patients undergoing haemodialysis.
Haemodialysis causes reductions in
CBF (∼7–12%) that are linked to
cognitive dysfunction and brain structural
abnormalities (Sprick et al. 2020). One of
the goals of haemodialysis is correction
of metabolic acidosis, a hallmark of
end-stage renal disease. This correction
is accomplished through the infusion
of supraphysiological concentrations of
bicarbonate in the dialysate (typically
32–39 mmol L–1 ). Based on the direct
cerebrovascular
dilatory
effects
of
bicarbonate reported (∼7 %), it would be of
interest to explore whether the bicarbonate
rich dialysate may be one mechanism
opposing intradialytic reductions in CBF.
In conclusion, Caldwell et al. (2021)
report the novel finding that PaCO2 ,
rather than arterial pH, mediates CVR
in the setting of acute metabolic alkalosis.
Additionally, a direct vasodilatory effect
of bicarbonate has been observed for the
first time in humans. These findings have
important implications for advancing our
understanding of acid–base balance in
cerebrovascular physiology, although the
mechanism responsible for mediating
this bicarbonate-induced cerebral vasodilatation remains to be clarified. Future
directions should include assessing the
role of the influence of bicarbonate on
cerebrovascular control in females, as well
as elucidating the sensor and transducer of
cerebrovascular dilatation in response to
bicarbonate.
J Physiol 0.0
References
Boedtkjer E, Hansen KB, Boedtkjer DMB,
Aalkjaer C & Boron WF (2016). Extracellular
HCO3 – is sensed by mouse cerebral arteries:
Regulation of tone by receptor protein
tyrosine phosphatase gamma. J Cereb Blood
Flow Metab 36, 965–980.
Borle KJ, Pfoh JR, Boulet LM, Abrosimova
M, Tymko MM, Skow RJ, Varner A & Day
TA (2017). Intra-individual variability in
cerebrovascular and respiratory chemosensitivity: Can we characterize a chemoreflex “reactivity profile”? Respir Physiol
Neurobiol 242, 30–39.
Caldwell HG, Howe CA, Chalifoux CJ, Hoiland
RL, Carr JMR, Brown CV, Patrician A,
Tremblay JC, Panerai RB, Robinson TG,
Minhas JS & Ainslie PN (2021). Arterial
carbon dioxide and bicarbonate rather than
pH regulate cerebral blood flow in the setting
of acute experimental metabolic alkalosis. J
Physiol 599, 1439–1457.
Coverdale NS, Gati JS, Opalevych O, Perrotta A
& Shoemaker JK (2014). Cerebral blood flow
velocity underestimates cerebral blood flow
during modest hypercapnia and hypocapnia.
J Appl Physiol 117, 1090–1096.
Fan JL, Burgess KR, Basnyat R, Thomas KN,
Peebles KC, Lucas SJ, Lucas RA, Donnelly J,
Cotter JD & Ainslie PN (2010). Influence
of high altitude on cerebrovascular and
ventilatory responsiveness to CO2 . J Physiol
588, 539–549.
Sprick JD, Nocera J, Hajjar I, O’Neill WC,
Bailey JL & Park J (2020). Cerebral blood
flow regulation in end-stage kidney disease.
Am J Physiol Renal Physiol, 319, F782–F791.
Additional information
Competing interests
No competing interests declared.
Author contributions
AD, GA and JS were responsible for the
conception and design of the work. AD, GA
and JS were responsible for the analysis and
interpretation of data for the work. AD, GA and
JS were responsible for drafting the work and
revising it critically for important intellectual
content. AD, GA and JS approved the final version
of the manuscript submitted for publication. All
of the authors agree to be accountable for all
aspects of the work.
Funding
No funding was received.
Keywords
acid-base balance, bicarbonate, cerebral blood
flow, cerebrovascular reactivity to carbon dioxide
© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society