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pH Dependence of Blood-Brain Barrier Permeability
to Lactate and Nicotine
WILLIAM OLDENDORF, M.D.,
L E O N BRAUN, B.A.,
577
A N D E A I N CORNFORD, P H . D .
SUMMARY Brain uptake of radiolabeled D and L-lactate, D-glucose and nicotine, as measured by the
intra-carotid bolus method, was examined over a range of pH of the injected solution. The uptake of L-lactate
was highest at pH 6.1, and lowered significantly at pH 7.2, 7.5 and 8.4. In contrast, the uptake of the
D-enantiomer was not as dramatically affected. Glucose uptake was not affected by alterations in pH. Nicotine
uptake decreased with pH reduction through a range of 8.3-4.2. These data suggest that it is the uncharged
molecule which penetrates the blood-brain barrier by both carrier and lipid mediation. A mechanism relating
to these observations is postulated and possible relevance to lactate washout from ischemic brain discussed.
Stroke Vol 10, No 5, 1979
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PREVIOUS STUDIES have established that bloodbrain barrier (BBB) permeability to lactate is, in large
part, carrier-mediated since it is saturable13 and
stereospecific.1' *•6 The brain normally exhibits a net
efflux of lactate, the jugular lactate concentration being greater than the arterial. Because of its very active
glycolytic mechanism, the brain also produces considerable amounts of lactate when ischemic. Brain pH
is reduced in ischemic foci and definition of any alteration in the rate of lactate efflux or influx in such
pathological states would be of clinical relevance. In
the present study, we have examined BBB transport of
L and D lactates through a range of pH values.
Nicotine was similarly studied. Since nicotine is a base
and penetrates the BBB freely at physiological pH,6 it
was thought to be of value to examine the effect of increased ionization at lower pH on its BBB penetration
in the same experimental arrangement as that used for
D and L-lactate. Additionally, D-glucose was
similarly studied as a representative neutral substance.
To establish whether the 3H-water reference changes
with injected pH, 2 groups of animals were studied at
high and low pH using 3H-water as the test substance
and uC-butanol as the reference. Radiolabeled
butanol has been shown to be completely cleared
through a wide range of brain blood flows.7
Methods
The intracarotid single bolus injection technique has
been employed in a variety of studies of the BBB.2-"""
Adult Wistar rats (200-350 g) of either sex were used
throughout this study. The right common carotid
artery was surgically isolated after intraperitoneal
sodium pentobarbital anesthesia. A small volume (0.2
ml) of the mixture of buffer and radiolabeled compounds (3H-water, 14C-test substance and 113mIndium-EDTA, in the proportions listed below) were
injected as an abrupt bolus into the carotid artery and
5 sec later the animal was decapitated. Because the
bolus volume is much greater than the volume of the
regional arterial lumen, thefluidinjected displaces the
regional arterial blood and the bolus passes through
From VA Brentwood Medical Center and the Department of
Neurology, Reed Neurological Research Center, UCLA School of
Medicine, Los Angeles, CA.
the brain microcirculation with approximately the
same composition as when injected. In the present
study the major variable is the pH of the injectate. The
pH of the injectate was adjusted to a desired value and
an attempt made to maintain it through microcirculatory passage by including a substantial concentration of an appropriate buffer having a pK at or near
the injected pH.
The ipsilateral hemisphere was dissected from the
cranium and extruded through a 20 gauge needle into
two liquid scintillation vials each containing 1.5 ml of
an organic base (Soluene, Packard Instrument Co.,
Downers Grove, IL). The tissue was dissolved and
routinely prepared for liquid scintillation counting of
the 3 isotopes and the brain uptake index (BUI) for
each experimental state determined as described
previously.10 Appropriate time corrections were made
to correct for the decay of 113m-Indium (physical
Tl/2 = 100 min) which occurred between the times
the individual sample vials were counted.
The 113m-Indium generator used was obtained
from New England Nuclear (NEN) (Radiopharmaceuticals Division, North Billerica, MA). To each
ml of 113m-Indium eluted, 10 fil of sterile disodium
edetate (150 mg/ml) solution (Endrate, Abbott
Laboratories, North Chicago, IL) was added and the
Indium-EDTA adjusted to a pH of approximately 7.4
with 7.5% sodium bicarbonate solution. Other
radiochemicals used were purchased from NEN
(Boston, MA 02118) and were of the highest specific
activity available. In a total volume of 0.2 ml a mixture was prepared containing approximately 0.6 /uCi
of the UC test substance (e.g. lactate, nicotine), 4-6
/iCi of tritiated water and 50 jiCi of Indium-EDTA,
typically in a 10 raM buffer. The buffers and their
respective pKs used in this study were piperazineN,N-bis(2 ethane sulfonic acid) (PIPES), pK = 6.8; 2
(N-morpholine) ethane sulfonic acid (MES), pK =
6.15; morpholinopropane sulfonic acid (MOPS), pK
= 7.20; N-2-hydroxyethyl piperazine N-2-sulfonic
acid (HEPES), pK = 7.55; N,N-bis(2 hydroxyethyl)
glycine (BICINE), pK = 8.35; and cyclohexylaminopropane sulfonic acid (CAPS), pK = 10.4. In each
case the solution's pH was adjusted to the pK of its
buffer before injection except in the most acidic injection of nicotine where the pH was adjusted to 4.7, considerably below the pK (6.15) of the MES buffer used.
578
STROKE
These buffers, in crystalline form, were obtained from
Calbiochem (San Diego, CA).
To establish whether the 3H-water clearance
changes with changing injected pH, 2 groups of 3
animals each were studied using 3H-water as the test
substance and 14C-butanol as the diffusible reference.
In one group the injected pH was 6.1 and in the other
8.4.
Unless otherwise indicated, all values for results are
in the form of a mean (=x), standard deviation ( = SD)
and sample number (=n). The Student's /-test was
used to test for statistical significance between differing experimental conditions. Counts per minute (cpm)
recorded on the liquid scintillation counter were converted to disintegrations per minute by cubic regression analysis and compared with similarly quenched
standard samples of known activity.
V O L 10, N o
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TABLE 1 Effect of Changing pH of the Intracarotid Injected
Solution Upon the Brain Uptake of Enantiomers of Lactate
(pKa = S.SS)
pH
6.15
7.20
7.55
8.40
L-lactate
BUI
20.5
15.9
12.2
8.9
±
*
*
±
2.2
1.5
0.8
0.4
1979
o 40.
D-GLUCOSE
> 30J
tr.
UJ
2
20
to
O
6.0
Results
As indicated in table 1, and figure 1, the brain uptakes of both D- and L-enantiomers of lactate increase
with a decrease in pH of the injected bolus. These
changes in L-lactate brain uptake index (BUI) were all
statistically significant. The uptake of D-lactate was
not altered as dramatically by pH changes as the
L-enantiomer. Brain uptake of the neutral hexose
D-glucose was not significantly altered by changes in
injected hydrogen ion concentration (table 2).
The clearance of 8H-water was not different when
injected at pH 6.1 or 8.4 (BUI at pH 6.1 = 84 ± 4, at
pH 8.4 BUI = 85 ± 5; butanol used as the reference
substance).
Since both lactate and glucose are transported
across the BBB by specific (monocarboxylic and hexose, respectively) carrier systems,2- "•16 subsequent
studies examined the effect of varying the injected
hydrogen ion concentration on brain uptake of
nicotine which penetrates the BBB by virtue of its lipid
solubility.6 As indicated in table 3 and figure 2, this
slightly charged base, which is not transported by a
carrier system, exhibits pH-dependent changes in BBB
penetration. Nicotine (pKl = 6.16; pK2 = 10.96) uptake is reduced by lowering the pH of the injected
solution.
5, SEPTEMBER-OCTOBER
7.0
8.0
pH OF INJECTED SOLUTION
FIGURE 1. The single-pass clearance by brain after carotid
arterial injection ofl4C-L and D-lactate as a function ofpH
of the injected solution.
Discussion
Several recent studies indicate that, in a variety of
biological membranes other than BBB, transport is
pH dependent. For. example, the movement of
phosphate,16 lactate,17 beta-hydroxybutyrate,18
propionate and octanoate,19 several anions,20 as well as
threonine,21 and pentazocine,22 is subject to pH
dependence. It has recently been suggested that within
the clinical range of blood pH the blood-brain and
blood-CSF distributions of morphine and its
derivatives might be sensitive to alterations in pH.23
The effects of pH on lactate uptake described here
suggest that, within the range likely to be found
regionally in pathological states, pH can be a substantial modulator of carrier-mediated BBB transport.
These data indicate that BBB transport of lactate
increases as hydrogen ion concentration is increased.
This is in contrast to nicotine in which increased
ionization (resulting from reduction of pH) reduces
BBB permeability. The uptake of D-glucose was not
measurably altered by changes in pH (of the injectate).
One possible interpretation of these data is that
carrier-mediated lactate transport is of the un-ionized
species rather than of the ionized. Such a conclusion
contrasts with current understanding of ion transport
D-lactate
BUI
6.8
5.4
4.8
4.0
=* 1.1
± 0.5
± 0.74
± 0.6
n = 3 for each z ± SD. Alterations in L-lactate uptake were all statistically significant. Comparing pH 6.15 to 7.20, p < 0.0O5; pH 7.2 to 7.55,
p < 0.025; and pH 7.55 to 8.40, p < 0.005. Alterations in D-lactate uptake
were significant (p < 0.05) only when comparing changes of 1.2 pH units
or more.
Injected L-lactate concentration was 0.009 mM and for D-lactate, 0.156
mM.
TABLE 2 Effect of Changing pH of Intracarotid Injected
Solution Upon Brain Uptake of D-glucose
pH
Gluoose
BUI
6.15 (20 mM MES)*
7.55 (10 mM HEPES)*
8.40 (20 mM TAPS)*
34.4 ± 4.3
33.4 ± 3.3
35.6 =* 3.2
n — 6 for each x ± BD.
* » buffer abbreviations are defined in Methods.
Injected glucose concentration was 0.005 mM.
579
pH AND BBB LACTATE, NICOTINE UPTAKE/Oldehdorf et al.
TABLE 3 Effect oj Intracarotid Injected pH on Brain Uptake
of Nicotine
Buffer
lOmM
lOmM
lOmM
lOmM
lOmM
lOmM
MES
MES
MOPS
HEPES
TAPS
CAPS
pH
4.7
6.15
7.2
7.55
8.35
10.4
Nicotine
BUI
49
77
109
120
126
127
=•= 10
t4
=>
± 3
=t 3
=t 12
=t 5
Nicotine pKl = 6.16, pK2 = 10.96; n - 3.
Injected nicotine concentration was 0.009mM.
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in mitochondrial membranes in which the charged
species, rather than the un-ionized ones, are transported.20 Threonine, a neutral amino acid, is similarly
transported in a protozoan, trypanosome, in its
charged form.21 In rat erythrocytes and thymocytes
kinetic constants for beta hydroxybutyrate influx and
efflux were found to be altered with changes in pH.18
Qualitative similarities in transport characteristics of
the red cell membrane and the BBB have been noted
previously.9 It has also been demonstrated that in the
BBB, neutral and basically charged amino acids are
transported by separate carrier mechanisms,10
suggesting that the BBB may possess the ability to discriminate on the basis of ionic charge. [The possibility
exists that this charge discrimination may be secondary to discrimination based on steric factors.]
Other data obtained in the present study suggest
that, in the case of the substances reported here, it is
the un-ionized species which penetrates the BBB. A
finding related to this postulation is that in rat
leukocytes there is an increase in uptake velocity of
pentazocine with increases in hydrogen ion concentration.22 It was concluded that this analgesic drug was
transported when it bore no net charge.
A possible explanation of a mechanism of BBB uptake, based on the assumption that the un-ionized
molecular species are the transported, or membranepenetrating form, appears in figure 3. When pH =
pKa, any one molecule spends, on average, 50% of its
time in the un-ionized form, and 50% of its time in the
ionized state.
Lactate pKa is 3.83. At pH 7.4 only about one
molecule in 2800 is un-ionized at any one time. When
the pH is lowered one unit, the concentration of this
un-ionized species is increased by a factor of 10
whereas the fractional change of the ionized species
does not change appreciably; remaining in excess of
99% above a pH of 5.83 (pK 3.83 + 2 units). Thus, any
major effect of pH change on BBB permeability to lactate suggests it is the un-ionized species which is being
transported.
When ionized, the lactic acid molecule is much
more polar and thus more lipophobic than when
un-ionized. When in the un-ionized state the residual
polarity is due to hydrogen bonding (fig. 3). In this
more hydrophobic state the relative affinities of the
lactic acid molecule for the BBB carrier molecule,
BBB lipid moiety and the adjacent blood plasma water
favors its escape from plasma water and entry into the
capillary endothelial cell membrane (the BBB).
A
^IONIZED
STATE
POLARITY
DUE TO
ION CHARGE
SITE
CH3
H-C-OH
o'V>
._JL
CH3
^UN-IONIZED
H-C-OH
STATE
[POLARITY
1
DUE TO
,HYDROGEN
t BONDING
TIME
140.
3. A lactate molecule is continually losing and
gaining a proton. A single molecule alternates between these
I
NICOTINE
2 states and the polarity of the molecule moves up and down
OI20.
IO
through a considerable range. This graph diagrammatically
follows a single lactate molecule through time as it alter°IOO.
UJ
nates between its 2 states (shown here as it would appear at a
pH of approximately 5). The fraction of the time it is
>
protonated (and thus uncharged) is a function of the ambient
3 80.
proton (hydrogen ion) concentration. Thus, at lower pH
values the molecule is un-ionized a greater fraction of the
<
time.
In this un-ionized state the small, remaining molecular
2
polarity is due to hydrogen bonding capacity. At pH 7.4 any
d
one lactate molecule is un-ionized only about 1 /2800th of
the time. At one pH unit lower, this changes to 1 /280th of
20.
the time whereas the fractional change in the ionized species
is virtually nil. If the un-ionized species is transported, lower
I o4.0
.
pH should increase transport since the molecule is in the
5.0
10.0
6.0
7.0
8.0
9.0
pH OF INJECTED SOLUTION
relatively non-polar state more of the time. In this latter
state it is more hydrophobic and can more readily detach
FIGURE 2. A study similar to fig. 1 except that 14Cnicotine (a base withapKl of 6.16 and apK2 of 10.96) was itselffrom plasma water and attach itself to a BBB carrier
injected in a vehicle carried through the indicated pH range. site or enter the lipid moiety of the BBB.
FIGURE
580
STROKE
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The failure to see changes in BUI proportionate to
the concentration of the un-ionized species when the
pH is altered (see table 1) might be attributed to the
possibility that pH changes in the present studies are
limited to the region of the capillary lumenal membrane and probably not throughout the entire brain
capillary endothelial cell. Alternatively, Voorheis21
has indicated that pH-induced modifications of
transport also involve changes in ionizable groups on
the transport carrier. Such an explanation could not,
however, be invoked in the case of membrane penetration of compounds such as nicotine which gain access
to the brain by virtue of their lipid solubility.
In the early post-ischemic brain there often is a
hyperperfusion commonly attributed to regional tissue
acidosis due largely to accumulation of lactate and
carbon dioxide. The local pH in ischemic brain has
been calculated to be as low as 6.0 — 6.5.24'26 The
present data suggest that the increased permeability to
lactate at this pH, particularly when amplified by increased regional blood perfusion, could substantially
increase the efflux of lactate from the ischemic region.
From common observation that clinical nuclear brain
scans in the early post-ischemic period are normal, it
can be concluded that the BBB is not non-specifically
permeable in most such lesions and that transcapillary flux must largely be dependent upon carrier
systems.
From previous work with L and D lactate it is
assumed that transport of the D form probably occurs
almost entirely by virtue of its lipid solubility and that
the difference between the L and D forms represents
carrier-mediated transport of the former.1 In the present study both L and D forms exhibit increased
transport at lower pH. The effect on the D form is to
be expected since an increased lipid/water partition
coefficient is present at lower pH values.
If there were an immediate change in brain blood
flow during the bolus passage through the brain
microcirculation in response to the transiently abnormal pH, there could be an artifact introduced due to a
change in the relative clearance by brain of the labeled
lactate and the diffusible reference, 3H-water. The
3
H-water is, under the conditions of barbiturate
anesthesia used here, 85% cleared during one brain
passage. This could be increased in regions of lowered
flow and decreased in high-flow regions.
The independence of glucose uptake to pH changes
suggests that the D-glucose carrier is not measurably
altered by the transient pH shift produced during these
experiments. This does not necessarily disprove that
some of the changes of L-lactate uptake with pH
changes are due to pH-induced alterations in the
short-chain monocarboxylic acid carrier.
The present study indicates that in the BBB, as in
other membrane systems, changes in pH result in
permeability changes. Our data do not positively indicate that either the charged, or the uncharged
molecule is the form which penetrates the membrane;
nor does it preclude the possibility that certain classes
of molecules might be transported in the ionized state
VOL 10, N o
5, SEPTEMBER-OCTOBER
1979
while other types of charged molecules penetrate
membranes in the un-ionized state. The present study
indicates that L-lactate is transported more effectively
by the BBB at increased hydrogen ion concentrations.
This could have clinical relevance by affecting the rate
of washout of lactate from ischemic brain.
Acknowledgment
This study was supported by the Veterans Administration. We
thank the following for their assistance and valuable discussions:
Stella Z. Oldendorf, M.S., Drs. Paul D. Crane, William M. Pardridge, Arthur Cho, Arthur Yuwiler, and Shigeyo Hyman.
References
1. Oldendorf WH: Blood brain barrier permeability to lactate.
Eur Neurol 6: 49-55, 1971-1972
2. Oldendorf WH: Carrier mediated blood brain barrier transport
of short chain monocarboxylic acids. Am J Physiol 224:
1450-1453, 1973
3. Nemoto EM, Hoff JT, Severinghaus JW: Lactate uptake and
metabolism
by brain during hyperlactatemia
and
hypoglycemia. Stroke 5: 48-53, 1974
4. Nemoto EM, Severinghaus JW: The stereospecific influx
permeability of rat blood brain barrie'r (BBB) to lactic acid
(LA). Clin Res 19: 146-150, 1971
5. Nemoto EM, Severinghaus JW: Stereospecific permeability of
rat blood-brain barrier to lactic acid. Stroke 5: 81-84, 1974
6. Oldendorf WH: Lipid solubility and drug penetration of the
blood brain barrier. Proc Soc Exp Biol Med 147:813-816, 1974
7. Raichle ME, Eichling JO, Straatmann MG, Welch MJ, Larson
KB, Ter-Pogossian MM: Blood-brain barrier permeability of
[ll-C]-labeled alcohols and [15-0]-labeled water. Am J Physiol
230: 543-552, 1976
8. Oldendorf WH: Measurement of brain uptake of radiolabeled
substances using a tritiated water internal standard. Brain Res
24: 372-376
9. Oldendorf WH: Brain uptake of radiolabeled amino acids,
amines, and hexoses after arterial injection. Am J Physiol 221:
1629-1639, 1971
10. Oldendorf WH, Szabo J: Amino acid assignment to one of
three blood-barrier barrier amino acid carriers. Am J Physiol
230: 94-98, 1976
11. Pardridge WM, Oldendorf WH: Kinetics of blood-brain
transport of hexoses. Biochim BiophysActa382: 377-392, 1975
12. Cornford EM, Oldendorf WH: Independent blood brain barrier
transport systems for nucleic acid precursors. Biochim Biophys
Acta 394: 211-219, 1975
13. Oldendorf WH, Braun LD: [3-H] Tryptamine and [3-H] water
as diffusible internal standards for measuring brain extraction
of radiolabeled substances following intracarotid injection.
Brain Res 113: 219-224, 1976
14. Cornford EM, Braun LD, Oldendorf WH: Carrier mediated
blood brain barrier transport of choline and certain choline
analogs. J Neurochem 30: 299-308, 1978
15. Pardridge WM, Oldendorf WH: Transport of metabolic substrates through the blood brain barrier. J Neurochem 28: 5-12,
1977
16. Lowendorf HS, Slayman CL, Slayman CW: Phosphate transport in Neurospora. Kinetic characterization of a constitutive,
low affinity transport system. Biochim Biophys Acta 373:
369-382, 1974
17. Spencer TL, Lehninger AL: L-lactate transport in Ehrlich
ascites-tumor cells. Biochem J 154: 405-414, 1976
18. Regen DM, Tarpley HL: Effects pH on beta-hydroxybutyrate
transport in rat erythrocytes and thymocytes. Biochim Biophys
Acta 508: 539-550, 1978
19. Lamers JMJ, Hulsmann WC: Inhibition of pyruvate transport
by fatty acids in isolated cells from rat small intestine. Biochim
Biophys Acta 394: 31-45, 1975
20. Williamson JR: Role of anion transport in the regulation of
pH AND BBB LACTATE, NICOTINE UPTAKE/Oldendorf et al.
metabolism. In Hanson RW, Mehlman MA (eds)
Gluconeogenesis: Its Regulation in Mammalian Species. New
York, Wiley, 1976, pp 165-220
21. Voorheis HP: Changes in the kinetic behaviour of threonine
transport into Trypanosoma brucei elicited by variation in
hydrogen ion concentration. Biochem J 164: 15-25, 1977
22. Marks MJ, Medzihradsky F: Characterization of the transport
system for benzomorphans in leukocytes. Mol Pharmacol 10:
837-848, 1974
581
23. Kaufman JJ, Koski WS, Benson DW: Temperature and pH
sensitivity of the partition coefficient as related to the blood
brain barrier to drugs. Exp Eye Res 25 (suppl) 201-203, 1977
24. Ljunggren B, Norberg K, Siesjo BK: Influence of tissue acidosis
on restitution of brain energy metabolism following total
ischemia. Brain Res 77: 173-186, 1974
25. MacMillan V, Siesjo BK: Cerebral energy metabolism, In
Critchley M, O'Leary JL, Jennett B: Scientific Foundations of
Neurology. Phil, FA Davis Co, 1972, pp 21-32
Arterial Air Embolism in the Cat Brain
H. FRITZ, M.D.
AND K.-A.
HOSSMANN,
M.D.
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SUMMARY In cats air embolism of the brain was produced by injecting 0.6 ml blood foam into the innominate artery proximal to the origin of both common carotid arteries. Air embolism caused transient
ischemia of the brain, reaching a maximum within 1 min after injection. Resolution of the air embolism began
a few minutes later and was completed within 15 min in the center and within 30 min in the border zone of the
main supplying arteries. During this phase tissue perfusion was inhomogenous with reduced flow rates in some
areas and reactive hyperemia up to 300% in others. This resulted in venous hyperoxia and a decrease of
arteriovenous oxygen difference to as low as 2 ml/100 ml blood. Reactive hyperemia was accompanied by
brain swelling and an increase in intracranial pressure from 3.6 ± 1.2 to 12.3 ± 2.0 mm Hg. The reason for
hyperemia was a decrease of cortical pH which fell from 7.33 ± 0.03 to 7.03 ± 0.05, and which caused a dilation of pial arteries up to 260%.
Immediately after embolism, the EEG flattened and oxygen consumption decreased. After normalization of
flow, oxygen consumption returned to normal, but EEG only partially recovered. Air embolism had little effect
on the water and electrolyte content of the brain, and produced very little damage to the blood-brain barrier.
Stroke Vol 10, No 5, 1979
THE EFFECT of ischemia on cerebral function,
metabolism and structure is a highly controversial
issue which, despite extensive research during the past
years, has not been satisfactorily solved. Many investigators feel that duration and intensity of ischemia
are the main denominators of tissue damage, whereas
others, including ourselves, are of the opinion that
post-ischemic events are of equal if not greater importance. Unexpected findings, such as the observation
that severe incomplete ischemia is more harmful than
total cerebrovascular arrest, have added to the confusion.1' 2
It is of little help when the different results are explained by differences in the experimental models as
long as the pathophysiology of these models is not
precisely known. We have, therefore, studied in
previous investigations different forms of ischemia,
and we found that, in fact, the pathomechanism of
ischemia varies considerably. Besides the duration and
completeness of ischemia, the site of occlusion seems
to be of particular importance. For instance, following
embolism of the capillary bed with microspheres, the
net flow rate of the brain may remain constant
because there is a redistribution of flow with
From the Max-Planck-Institut fur Hirnforschung, Forschungsstelle fur Himkreislaufforschung, Ostmerheimer Strasse
200, D 5000, Koln 91, West Germany.
Supported by the Deutsche Forschungsgemeinschaft.
hyperemia in the non-occluded vessels. The main injurious factor is the breakdown of the blood-brain
barrier (BBB), leading within a few minutes to severe
vasogenic brain edema and intracranial hypertension.3' * On the other hand, ischemia produced by extracerebral interruption of blood supply (inflow
occlusion), causes primarily a breakdown of the
energy producing metabolism, and an inhibition of all
endergetic processes. But there is no change in the
permeability of the blood-brain barrier to serum
proteins.6 Edema, if present, is of the cytotoxic type,
and it is rapidly reversible upon restoration of blood
flow.8 Finally, occlusion of the middle cerebral artery
causes initially metabolic disturbances and a cytotoxic
type of brain edema, but after a few hours vasogenic
edema supervenes.7-8
In the present series of experiments we have studied
the pathophysiology of air embolism, which is a model
of intracerebral small vessel occlusion. Air bubbles are
trapped in small intracerebral arteries, leading to
acute interruption of blood flow in the supplying
territories of the affected vessels.914 The site of occlusion, consequently, is proximal to the capillary bed but
distal from the large supplying arteries. We were,
therefore, interested to know whether the pathophysiology of air embolism resembles the inflow
occlusion or the microembolism type of ischemia. Our
results indicate that it combines elements of both
types, and that, for this reason, it is a useful model for
pH dependence of blood-brain barrier permeability to lactate and nicotine.
W Oldendorf, L Braun and E Cornford
Stroke. 1979;10:577-581
doi: 10.1161/01.STR.10.5.577
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