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A review of hemoglobin and the pathogenesis of cerebral vasospasm

RL Macdonald and BK Weir

Stroke. 1991;22:971-982
doi: 10.1161/01.STR.22.8.971
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971

Progress Review

A Review of Hemoglobin and the


Pathogenesis of Cerebral Vasospasm
R. Loch Macdonald, MD, and Bryce K.A. Weir, MD

We believe that current experimental and clinical evidence can be most satisfactorily
interpreted by assuming that oxyhemoglobin is the cause of cerebral vasospasm that follows
subarachnoid hemorrhage. We review the pathogenetic mechanisms by which oxyhemoglobin
affects cerebral arteries. The relative importance of each of these mechanisms in the genesis of
vasospasm, the biochemical pathways of oxyhemoglobin-induced smooth muscle contraction,
and the intracellular actions of oxyhemoglobin on smooth muscle and on other cells in arteries
are still not definitely established. (Stroke 1991^2:971-982)

into the supernatant fluid starting after 2 days.917-23

C erebral vasospasm is an important cause of


cerebral ischemia and death1"3 following
aneurysmal subarachnoid hemorrhage
(SAH). Cerebral vasospasm is usually the most fre-
quent serious complication in survivors of SAH,1-3
With time OxyHb is oxidized to methemoglo-
bin,91718-20 but further breakdown of heme to biliru-
bin occurs only in vivo.617-24 The exact mechanisms by
which heme groups of hemoglobin (Hb) are broken
although recent reports show that with hypervolemic down into bilirubin are not known, but they probably
hypertensive therapy and calcium channel antago- require enzymes present only in living cells.25 After
nists, morbidity and mortality from vasospasm may SAH, RBCs remain fixed in the subarachnoid space
have become relatively less important.4 for days and they disappear by hemoryzing, similar to
Advances have also been made in identifying the the process in vitro.17-26
spasmogen responsible for vasospasm and in defining
how it causes arterial narrowing. Oxyhemoglobin In 1944, Zucker27 recognized that RBC cytosol was
(OxyHb) is probably the principal pathogenetic vasoactive although platelets and serum were much
agent.5"7 We review evidence supporting the theory more potent vasoconstrictors. Further experiments
that OxyHb causes vasospasm. This substance has have documented that RBCs contain a vasoactive
many mechanisms of action that may be important in substance that is released by hemolysis.18"22-28"37
vasospasm. These include the release of free radi- Humans with clinically significant vasospasm on
cals8-9; the initiation and propagation of lipid perox- average have higher temperatures and more often
idation9; metabolism to bilirubin, which is another have leukocytosis than patients with ruptured aneu-
potential spasmogen10-11; the release of vasoactive rysms without vasospasm.38 In experimental animals,
eicosanoids12 and endothelin13 from the vessel wall; hemogenic meningitis, which may produce these
perivascular nerve damage14-15; the inhibition of en- changes, is due to the heme component of RBCs.39'40
dothelium-dependent relaxation16; and the induction Many investigators have assayed the vasoactivity of
of structural damage in the arterial wall.15 incubated and aged mixtures of whole blood, blood
components, and cerebrospinal fluid (CSF) on dog
Attempts to Isolate the Spasmogen and cat basilar arteries in vitro. 18-20,2231-33,41 Results
Incubation of blood in vitro results in slow hemo- are remarkably concordant between experiments and
lysis of erythrocytes (RBCs) with release of OxyHb may be summarized as follows. Fresh serum, platelet-
rich plasma, and lysed RBCs have significant vasoac-
From the Division of Neurosurgery, University of Alberta, tivity whereas fresh, intact RBCs are inert. With
Edmonton, Canada. incubation, serum and platelet-rich plasma become
Dr. Macdonald is a fellow of the Alberta Heritage Foundation inactive whereas the contractile activity of intact or
for Medical Research. This work was supported in part by grants
to Dr. Weir from the National Institutes of Health (5 R01 h/sed RBCs persists. Similar experiments were per-
NS25946-03) and the Medical Research Council of Canada (MA formed in vivo by Mcllhany and colleagues,35 who
9158). injected vasoactive fractions of hemoryzed RBCs, as
Address for correspondence: B.K.A. Weir, Professor and Chair- collected on Sephadex G-75 gel filtration chromatog-
man, Department of Surgery, University of Alberta, 2D1.02 W.C.
Mackenzie Health Sciences Center, Edmonton, Alberta, T6G 2B7, raphy, into the cisterna magna of dogs. Vasoconstric-
Canada. tion of the basilar artery was observed for 2 days.
Received February 1, 1991; accepted April 3, 1991. Peterson et al42 found that RBC lysis was necessary

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972 Stroke Vol 22, No 8 August 1991

for development of vasospasm after the subarachnoid ring in the subarachnoid space is RBC hemolysis.50-52
injection of blood into dogs. In summary, during the Clearance of blood injected into the subarachnoid
time of vasospasm in man, the vasoactivity of blood space of animals is rapid, and most RBCs are removed
incubated in vitro, when tested on the basilar artery by methods other than hemolysis.40-53-55 This is prob-
in vitro, resides in RBCs. ably why single injections of liquid blood in experi-
The role of RBCs in generating vasospasm has mental animals fail to mimic human vasospasm.
been evaluated further by long-term in vivo studies. Hemolytic breakdown of RBCs observed micro-
The RBCs are the blood component necessary for scopically may also be observed by spectrophotomet-
development of vasospasm in cats43 and dogs.44 May- ric examination of pigments released into the CSF.
berg et al45 developed a piglet model whereby blood Barrows and colleagues17 used absorption spec-
components could be selectively applied to the mid- trophotometry to examine CSF after SAH; OxyHb
dle cerebral artery (MCA) for 10 days. Whole blood appeared 2 hours after SAH. By 4 days postictus
caused a significant reduction in lumen diameter. bilirubin was present, and over the following week
Selective application of washed RBCs, RBC cytosol, the amount of OxyHb decreased and that of bilirubin
and pure porcine Hb also caused significant vaso- increased. In the absence of further bleeding, both
spasm whereas leukocytes and platelet-rich plasma pigments disappeared after 2-3 weeks. Bilirubin is
did not. present in normal serum and could be observed in
The vasoactive substance released by RBCs has the CSF immediately after massive SAH. In cases of
been isolated by many groups.19-20-22^*1-33-36 The com- SAH methemoglobin was not detected, although it is
pound has consistently been found to be a peptide now believed to be present.56-57 Results of these and
with a molecular weight, spectrophotometric absorp- other studies58"60 show that OxyHb is present during
tion pattern, and movement on electrophoresis sim- vasospasm whereas small molecules and proteins
ilar or identical to those of OxyHb.19-20-22-31-33-36 Only such as albumin, noradrenaline, and serotonin are
Cheung et al32 found a molecular weight (40,000- cleared rapidly from the CSF.53-55
45,000 d) that is low for Hb, which has a molecular Buckell61 first investigated the contractile activity
weight of 64,500 d. of CSF from patients with ruptured aneurysms. Some
These investigations show that RBCs are essential CSF activity could be accounted for by serotonin, but
for the development of vasospasm. Results of studies in half the cases other substances were present that
isolating the spasmogen in RBCs and of long-term in caused contraction. The contractile activity of xan-
vivo studies43-45 point to OxyHb as the prime candi- thochromic CSF has been frequently studied.62-73
date to cause vasospasm. Allen et al62-63 suggested that the vasoactivity of
xanthochromic CSF was due to serotonin. Other
Studies of Cerebrospinal Fluid After investigators,64-67-70-74 however, report that drugs that
Subarachnoid Hemorrhage block serotonin, histamine, acetylcholine, norepi-
In man, vasospasm has its onset 3 days after SAH, nephrine, epinephrine, propranolol, and angiotensin
peaks after 6-7 days, and resolves by 14 days.46 This II do not prevent hemorrhagic CSF from contracting
unusual time course could be explained by the spas- cerebral arteries in vitro. Calcium channel antago-
mogen responsible for vasospasm exhibiting a similar nists have consistently at least partially blocked such
time course of appearance in the CSF near arteries in contractions.68-70 Evidence reviewed below indicates
spasm. An alternative hypothesis explains the delay that OxyHb-induced contractions show pharmaco-
in onset by suggesting that arterial narrowing is due logical properties similar to those of the agent in
to another mechanism such asfibrosisand inflamma- xanthochromic CSF. Sasaki et al74 further delineated
tory-cell infiltration of the arterial wall47 or to intimal the nature of the contractile activity by showing that
proliferation.48-49 In our opinion, this latter hypothe- disulfide bond-reducing agents blocked contractions
sis is untenable for a variety of reasons. There is no induced by xanthochromic CSF in dog basilar artery.
evidence that arterial wall area increases enough Disulfide bond reducers are known to block smooth
during vasospasm to narrow the lumen.4849 Intimal muscle contraction due to prostaglandins (PGs), Hb,
proliferation and arterial wall fibrosis typically de- and lipid peroxides. Yamamoto and colleagues75 iso-
velop after vasospasm resolves.49 lated a spasmogen from xanthochromic CSF that was
Pathology of the subarachnoid space following hu- believed to possibly be endothelin, although the sys-
man SAH shows that within 24 hours after SAH there tem used to assess vasoactivity was unconventional.
is intense porymorphonuclear cell infiltration of the If the vasoactivity in xanthochromic CSF is due to
meninges. Phagocytosis and breakdown of RBCs oc- OxyHb, then CSF OxyHb concentration should cor-
cur by 16-32 hours. Breakdown of RBCs peaks relate with severity of vasospasm. This relation has
around day 7 but continues for days, with clumps of been difficult to confirm, however, partly because
intact RBCs still enmeshed in the arachnoid for up to lumbar CSF OxyHb concentrations do not accurately
35 days after SAH. At 7 days, the inflammatory reflect concentrations adjacent to spastic arteries.76-77
reaction subsides and is composed equally of lympho- Ohta and coworkers76 found that vasospasm did
cytes and phagocytes. After 10 days, fibrosis of the correlate with the concentration of OxyHb in periar-
subarachnoid space begins. Therefore, during the terial hematomas after SAH. An additional problem
time of vasospasm, the most prominent process occur- with assays in vitro is that OxyHb may not be able to

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Macdonald and Weir Hemoglobin and Vasospasm 973

exert all of its damaging effects in vitro. For example, Most of the above experiments confirm that OxyHb
OxyHb would not be converted to bilirubin in vi- causes vasoconstriction. Pure methemoglobin is proba-
tro,6'25 and its effects on the innervation of arteries bly inert, but the presence of small amounts of OxyHb
would probably be altered in vitro.78 will render a solution vasoactive. Wellum et al78-88 have
expressed concern that OxyHb is not a strong enough
Hemoglobin as a Vasoconstrictor vasoconstrictor to cause severe vasospasm. However, if
Vasospasm probably begins as smooth muscle con- OxyHb is responsible for vasospasm then short-term
traction, but due to the prolonged and severe nature of experiments in vitro would not replicate conditions in
the contraction, vasoconstriction becomes temporarily vivo, where arteries are exposed to high concentrations
irreversible.48-4979 There may be changes in vessel wall of OxyHb for many days. The concentration of OxyHb
collagen and in the contractile apparatus of smooth used in most in vitro and short-term in vivo studies
muscle that contribute to narrowing and cause stiffness ranges from 10"8 to 10"2 M, with maximal contraction
of the arterial wall.47'48-80-82 Morphological changes in developing at concentrations equal to and above 10~3
vasospasm and their relation to OxyHb are reviewed M, depending on the preparation.9-85-89-91-94'98-101 Mea-
below. Studies of the effects of Hb solutions on cerebral surements of Hb concentrations in subarachnoid he-
arteries both in vitro and in vivo are therefore relevant matomas76 suggest that adequate amounts of OxyHb
to theories implicating Hb as a cause of vasospasm. are present near vasospastic arteries for long enough to
produce maximum contraction.
Studies In Vitro
In vitro, Hb contracts isolated smooth muscle cells The issue of duration of exposure to the spas-
and cerebral arteries of several different animal mogen has been addressed in experimental models of
species.9'12-21-34'76'79'83-104 Fujii and Fujitsu83 reported vasospasm where changes in arterial diameter can be
that OxyHb contracted smooth muscle cells cultured assessed over many days. Single intracisternal injec-
from rat aorta. Ultrastructural changes including tions of low doses of OxyHb have been given to small
vacuolation, cell degeneration, and loss of internal numbers of dogs19-114-116 and baboons117 with vari-
cell structure were noted after 24 hours of exposure. able results but, unfortunately, single injections do
We have used electrophysiology to study smooth not produce a model that is similar to the human
muscle cells isolated from rat cerebral arteries.84 A condition, where large amounts of OxyHb are pres-
solution containing OxyHb and small amounts of ent adjacent to cerebral arteries for days.76
methemoglobin contracted cells and increased calci- Mayberg and colleagues45 developed a piglet
um-dependent potassium currents. Cells died rapidly model of SAH that kept high concentrations of Hb or
after exposure. Pure methemoglobin solution did not various blood components adjacent to the right MCA
cause any of these effects. for 10 days. Pure porcine Hb (roughly 15% as
Cook et al85 demonstrated that Hb causes slowly OxyHb) resulted in a significant decrease in lumen
developing and long-lasting contraction of dog cere- area that was equal to that caused by RBC cytosol
bral arteries, rabbit ear arteries, and rat stomach containing a similar amount of Hb. Although whole
fundus in vitro. These workers used a solution of Hb blood caused a greater decrease in lumen area than
containing 20% OxyHb. Asano and associates9-21 did Hb, these authors suggested that this was because
performed similar experiments on dog basilar artery the former was associated with more residual clot-
in vitro and found that both OxyHb and methemo- containing Hb at day 10. Therefore, all vasoactivity of
globin caused dose-dependent contractions, although the whole blood was accounted for by Hb.
OxyHb was much more potent. These results are In our laboratory, cynomolgus moiikeys had cath-
consistent with many others.86-8791-103 eters placed along the right MCA and connected to
Systemic and cerebral arteries have differing phar- subcutaneous CSF reservoirs.6 In a randomized and
macological properties79; these arteries also vary in controlled study of 40 monkeys, multiple intrathecal
their sensitivity to OxyHb, providing one reason for the injections of OxyHb, methemoglobin, bilirubin, mock
predilection of vasospasm for cerebral arteries.86-87'102 CSF, or supernatant fluid from an incubated mixture
of autologous blood and mock CSF were given for 6
Studies In Vivo days. Significant vasospasm of the right MCA, as
Many studies have investigated the short-term judged by comparison of angiograms taken at base-
effects of Hb applied to cerebral arteries exposed in line and on day 7, developed in animals injected with
105 OxyHb and supernatant fluid. Pure methemoglobin
situ.2o^6,76,io5-ii3 Tn i975 ; Chokyu exposed rat basi-
lar artery in situ and demonstrated a 30% constric- produced no significant arterial narrowing.
tion due to the topical application of hemoh/sate of
RBCs and a 19% constriction due to pure OxyHb. Mechanisms of
Similar to results in vitro, others have shown a similar Oxyhemoglobin-Induced Vasoconstriction
activity of OxyHb and have generally shown that Studies of How Oxyhemogbbin
methemoglobin is much less vasoactive.20-107'112 Only Causes Vasoconstriction
Fox106 reported that Hb did not contract canine Contraction caused by receptor-operated systems
basilar artery exposed in situ, but it is unclear if the usually decreases with time due to tachyphylaxis,
Hb solution used contained OxyHb. desensitization, and/or autoregulation.78-79 The time

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974 Stroke Vol 22, No 8 August 1991

course of vasospasm suggests that smooth muscle was dependent on a mechanism related to the endo-
contraction by a conventional receptor-operated sys- thelium but not involving endothelium-derived relax-
tem is not the sole mechanism responsible for arterial ing factor (EDRF). He suggested that PGs released
narrowing. Most agents suggested to be mediators of from endothelium by OxyHb were important in these
vasospasm, such as serotonin, biogenic amines, pep- contractions.
tides, and eicosanoids, however, probably act on cell The effects of inhibitors of PG and thromboxane
surface receptors.45-79118 Further, antagonists of re- synthesis on experimental and human vasospasm
ceptor-operated vasoconstrictors, including atropine, have been equivocal.92-135-139 Studies of OxyHb-in-
methysergide, cinanserin, ketanserin, phenoxybenz- duced dog basilar artery contraction in vitro show
amine, phentolamine, mepyramine, chlorphe- that indomethacin and aspirin, inhibitors of cyclooxy-
niramine, propranolol, saJbutamol, angiotensin, sar- genase, have no effect on86-90-103 or only partially
cosine, alanine, theophylline, and quinine, have prevent12-85-87-94-119 such contractions. Thromboxane
consistently failed to reverse OxyHb-induced con- synthetase inhibitors were also ineffective in prevent-
tractions of cerebral arteries in vitro and in ing OxyHb from contracting dog102 and guinea pig140
VJVO 3136,7635-87,94,93,98,103,107-109,112,119-121 basilar artery.
Drugs reported to relax smooth muscle contracted Thus, although OxyHb affects vessel wall ei-
with OxyHb include papaverine, calcium channel cosanoid production and could account for the alter-
antagonists, and some inhibitors of eicosanoid syn- ation in CSF levels of these substances after SAH,
thesis.85-86-95-108-109-119"121 The latter are discussed in inhibitors of synthesis of PGs and thromboxanes do
the next section. Although calcium channel antago- not prevent vasospasm. If OxyHb acts at multiple
nists partly reverse OxyHb-induced contraction of sites in the vessel wall (e.g., direct action on smooth
cerebral vessels in vitro, these drugs do not dilate muscle cells by the release of free radicals and the
monkey122 or human123124 cerebral arteries that are production of lipid peroxides, combined with the
vasospastic. Kajikawa et al108-109 found that after release of eicosanoids, EDRF, and endothelin from
exposing rat basilar arteries in situ to barium chloride the endothelium), then antagonizing only one of
for 3 hours, papaverine did not dilate them, providing these systems might not completely reverse the con-
evidence that the duration of contraction bears upon traction. Furthermore, other factors, such as leuko-
the ability of pharmacological antagonists to relax trienes, which are also potent vasoactive agents and
smooth muscle. the concentrations of which increase after SAH, have
OxyHb acutely increases the intracellular concen- not been thoroughly investigated.141-143
tration of inositol phosphates, which are second
messengers involved in smooth muscle contraction.125 Free Radicals
There are few other reports investigating the intra- OxyHb spontaneously autoxidizes to methemoglo-
cellular mechanism of action of OxyHb, which is bin, releasing superoxide anion radical (O2").8-144
obviously an important question. Spectrophotometric studies show that after SAH,
hemolyzing subarachnoid RBCs release OxyHb,
Eicosanoids which autoxidizes to methemoglobin, potentially re-
Eicosanoids are products of enzymatic metabolism leasing O2" into the subarachnoid space.55-59 In
of arachidonic acid and include PGs, thromboxanes, conjunction with the iron in Hb, O2" has been
and leukotrienes.126 postulated to initiate and propagate lipid peroxida-
After SAH in monkeys and dogs, vasospastic ves- tion by the Haber-Weiss reaction and Fenton chem-
sels synthesize less PGI2 and more vasoconstricting istry.9-21 Lipid peroxides are known to cause vasocon-
PGE2.126-130 Decreased vasodilator influence from striction and structural damage to cerebral arteries
PGI2, combined with endothelial damage with adher- both in vitro145-146 and in vivo.147'148
ence of platelets and release of vasoconstricting PGs There is additional evidence for a role of lipid
and thromboxane A2, could contribute to vaso- peroxidation, and therefore OxyHb, in the genesis of
spasm.3-12-130 The effects of OxyHb on vessel wall vasospasm. Vasoactivity of blood incubated in vitro
eicosanoid synthesis in vivo have been investigated by correlates with its concentration of OxyHb and with
Tokoro.129 He reported that injection of OxyHb into its content of lipid peroxides, represented by thiobar-
dog cisterna magna decreased PGI2 levels in the bituric acid-reactive substances.9-21-147 Concentra-
basilar artery 4 and 7 days later. There was no change tions of lipid peroxides in the CSF of patients with
in the thromboxane A2 level in the arterial wall. SAH correlate with vasospasm.9-21-147-149-150 An inhib-
Studies show that following SAH in humans, the itor of iron-dependent lipid peroxidation, U74006F
CSF contains elevated levels of PGF^ and possibly significantly diminished vasospasm in a primate
other PGs.126'131-133 Dog basilar artery removed 6 days model of SAH.151 Despite questions about the exact
after SAH synthesizes more PGE^ than normal.127128 mechanism of initiation of lipid peroxidation,152 de-
Experiments in vitro using bioassay systems to mea- tection of 5-hydroxyeicosatetraenoic acid in CSF
sure eicosanoids show that OxyHb releases vasoactive after SAH shows that lipid peroxidation occurs.153
PGs from several types of blood vessels,12-134-135 poten- Although OxyHb probably does propagate lipid
tially accounting for the changes seen after SAH. peroxidation after SAH, it has not been shown in vivo
Toda135 concluded that OxyHb-induced contraction that the process is essential for the development of

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Macdonald and Weir Hemoglobin and Vasospasm 975

vasospasm. This would require evidence that inhibi- After SAH in dogs, vasospastic basilar arteries
tors of lipid peroxidation prevent vasospasm151 and contracted with PGF^ and uridine 5'-triphosphate
evidence that lipid peroxidation precedes the devel- exhibit impaired relaxation to arginine vasopressin
opment of vasospasm since the arterial wall damage and thrombin.161-162 Endothelium-dependent relax-
that accompanies vasospasm would produce lipid per- ation is also inhibited after SAH in rabbits163164 and
oxides.152 Furthermore, since vasospasm correlates monkeys.165
best with large volumes of subarachnoid blood,5-154 the OxyHb and other ferrous hemoproteins but
concentrations of lipid peroxides in CSF would be not methemoglobin or ferric hemoproteins are
elevated in association with vasospasm whether or not well-known inhibitors of endothelium-dependent
their production is related to vasospasm. relaxation in a number of vascular preparations in
Effects of free radical-scavenging enzymes on the vitro.16.95-104.121.140.160.166-173 Whether or not endo-
vasoactrvity of OxyHb on cerebral arteries in vitro have thelium-dependent relaxation occurs correlates
been reported.36-84'90-91.9'*.109 Kamiyama and cowork- with levels of cyclic guanosine monophosphate in
ers110 found that superoxide dismutase, catalase, and the arterial wall.166
l,4-diazabicyclo[2.2.2]octane were effective inhibitors A study in vivo of endothelium-dependent relax-
of OxyHb-induced contraction of cat basilar artery ation and Hb was reported by Byrne et al.113 In pigs,
exposed in situ. Fujita et al90 found superoxide dismu- intracistenial injection of OxyHb caused acute vaso-
tase to be ineffective at antagonizing OxyHb-induced constriction of intrathecal arteries. Intracarotid infu-
contraction of dog basilar artery in vitro. The effects of sion of acetylcholine caused vasodilation before the
catalase alone have also been inconsistent.36-91-94 intracisternal injection of OxyHb and vasoconstric-
Electrophysiological studies of isolated rat cere- tion afterwards.
bral artery smooth muscle cells have shown OxyHb to Kanamaru et al120 found that xanthochromic CSF
activate calcium-dependent potassium currents and from SAH patients could inhibit A23187-induced
cause cell death.84 Catalase protected cells from endothelium-dependent relaxation in dog basilar ar-
OxyHb, whereas superoxide dismutase did not. Xan- tery in vitro. The levels of OxyHb in CSF correlated
thine and xanthine oxidase did not cause electrophys- with the degree of inhibition of endothelium-depen-
iological changes in cells, whereas the generation of dent relaxation.
hydroxyl radical in the bathing solution was damag- The ability of OxyHb to inhibit endothelium-de-
ing. The findings implicate the hydroxyl free radical pendent relaxation suggests that OxyHb is responsi-
rather than other oxygen free radicals although it ble for this event after SAH. How OxyHb prevents
may be difficult to define the actual free radicals endothelium-dependent relaxation has been investi-
involved based on such scavenger experiments.152 gated. Both SAH and OxyHb damage arterial endo-
In summary, superoxide dismutase and catalase thelium, possibly decreasing EDRF synthesis by en-
alone are poor antagonists of OxyHb-induced cere- dothelial cells.1548-174 Kim et al,161 however, used a
bral artery contraction. There are several possible bioassay system for EDRF to show that EDRF
reasons for this. Free radical mechanisms may not be secretion by vasospastic dog basilar artery was not
important or they may not be the sole pathway in the impaired. EDRF may be nitric oxide,160 and Hb binds
genesis of contraction by OxyHb. Superoxide dismu- nitric oxide with an affinity 1,500 times higher than its
tase and catalase may not be able to penetrate affinity for oxygen.175 Thus Hb, which presumably
arterial walls to get to the locations where damaging does not enter cells, could prevent EDRF, if it is
free radical reactions occur.152 Activity of both super- nitric oxide, from entering smooth muscle cells and
oxide dismutase and a hydrogen peroxide scavenger producing its effects.
may be necessary to prevent the genesis of oxygen- The effects of OxyHb on EDRF have been assessed
derived free radicals since superoxide dismutase pro- in vitro using more physiological systems that isolate
duces hydrogen peroxide, which can form hydroxyl the intraluminal and extraluminal aspects of the artery.
radical in the presence of iron or ferrous pro- Although OxyHb applied extraluminally to dog and
teins.155-156 Catalase or glutathione peroxidase, if rabbit cerebral arteries has been found to have little
present, would catabolize hydrogen peroxide, pre- effect on endothelium-dependent relaxation,170171
venting this reaction. Hydrogen peroxide157 and iron other researchers reported the inhibition of endotheli-
ions158 can also inhibit superoxide dismutase. um-derived responses after exposing extraluminal sur-
faces of cerebral arteries to OxyHb.104-172
Endothelium-Dependent Relaxation The effects of Hb on endothelium are further
Furchgott and Zawadzki159 showed that the va- complicated by observations that acetylcholine
sodilatory action of acetylcholine on rabbit aorta causes transient hyperpolarization and relaxation of
was mediated by release of an intermediate sub- rat aorta and guinea pig basilar artery precontracted
stance from endothelial cells. This substance has by noradrenaline.170 Hb prevents relaxation but
been termed EDRF. Other vasodilators relax vas- doesn't alter hyperpolarization. It has been hypoth-
cular smooth muscle through this endothelium- esized that acetylcholine releases EDRF and endo-
dependent mechanism, which has been subject to thelium-derived hyperpolarizing factor from endo-
recent review.160 thelial cells.

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976 Stroke Vol 22, No 8 August 1991

In addition to EDRF, endothelium-derived hyper- centrations that are too low to induce significant
polarizing factor, and eicosanoids, endothelial cells arterial narrowing after SAH.187 Findings that in-
synthesize a potent vasoconstrictor peptide, endothe- trathecal injections of OxyHb cause vasospasm
lin.176 Vasospasm is associated with increased CSF whereas injections of methemoglobin do not also cast
levels of endothelin.177-179 Findings that OxyHb aug- doubt on the bilirubin theory since both types of Hb
ments the release of endothelin from cultured bovine produce bilirubin in the subarachnoid space.6-25
cerebral artery endothelial cells suggest that OxyHb
may be responsible for elevating CSF endothelin Neuwgenic Effects
levels after SAH.13 Cerebral arteries receive adrenergic, cholinergic,
The importance of the endothelium in vasospasm and peptidergic innervation and possess receptors for
remains unclear, although OxyHb contracts cerebral neurotransmitters such as serotonin, a- and £-adren-
arteries denuded of endothelium, suggesting that ergic drugs, dopamine, and histamine although the
endothelin release is not requisite for vaso-
spasm.96.99.100.103.119.180 Further, if the endothelium is precise role of these nerves and receptors in the
removed after arteries are contracted with OxyHb, regulation of cerebrovascular tone is unknown.188-190
relaxation does not occur.104 Adventitial nerve endings in cerebral arteries degen-
erate after experimental SAH,14-15-48-190-191 and this is
Bilirubin accompanied by a transient loss of catecholamine histo-
In 1949, Jackson39 injected bilirubin into the cis- fluorescence around cerebral arteries.192-193 Disappear-
terna magna of dogs, producing severe inflammatory ance of perivascular nerves after SAH, however, did
reactions with fever, malaise, and increased CSF not correlate with vasospasm in rats194 and primates.195
protein and leukocyte concentrations. The reaction Sympathectomy can have no effect on196 or it can
was comparable to that induced by OxyHb, and he alleviate197 vasospasm in experimental animals and
believed that one of these two agents caused he- humans. Drugs that block a-adrenergic, ^-adrenergic,
mogenic meningitis. Angiography was not done. and muscarinic receptors have little effect on cerebral
Several early experiments found that bilirubin had vasospasm induced by whole blood198 and on vasocon-
no effect on cerebral artery diameters in vitro.105107 striction due to OxyHb.30-85-86-103.112-119.121
In these studies, bilirubin was applied to arteries for Despite contradictory evidence regarding the sig-
minutes only. Duff and colleagues10 reported that nificance of changes in cerebrovascular innervation
bilirubin solutions caused progressive vasoconstric- in relation to vasospasm, SAH clearly does damage
tion of cat and baboon basilar arteries. Electron these nerves and OxyHb may be responsible for this
microscopy of the arteries showed swelling of endo- degeneration.15-173-199 Inhibition of vasodilator nerves
thelial cells, degeneration of axons and varicosities in
the adventitia, and extensive vacuolation of smooth and potentiation of vasoconstricting nerves by OxyHb
muscle and endothelial cells. These results were may create a favorable setting for the development of
supported by investigations by Miao and Lee11 that arterial narrowing after SAH.173 Few studies in vivo
demonstrated the vasocontractile effects of bilirubin have been reported and obviously, results might be
on cerebral arteries. different when arteries are in situ with anatomically
Intrathecal injection of bilirubin for 6 days was intact innervation. The effects of OxyHb on peptider-
performed in our laboratory as part of a randomized gic innervation of cerebral arteries have not been
trial to study the role of various blood components in investigated in detail.189
the etiology of vasospasm in monkeys.6 Bilirubin
caused a nonsignificant 13% decrease in right MCA Synergistic and Other Effects
diameter. Ultrastructural examination of these arter- OxyHb accentuates the contractile effects of hypox-
ies did show some pathological changes. ia,1999 serotonin,97-102 potassium,140 and fibrin degra-
Although the time course of appearance of biliru- dation products39 on cerebral arteries in vitro. Recent
bin in the CSF after SAH is similar to that of investigations, however, have suggested that Hb, and
vasospasm,17-56 there are several reasons to doubt presumably OxyHb, is a sufficient cause of vaso-
that bilirubin is an important spasmogen. Bilirubin spasm.6'45 White118 believed that PGs were probably
contaminates CSF in other diseases such as neonatal important in vasospasm and that serotonin, plasmin,
and obstructive jaundice.58-181-183 Focal neurological and antithrombin III were possibly involved. Other
deficits, which might be related to vasospasm, have major contenders for the cause of vasospasm include
rarely been noted in these conditions.184 Wahlgren bilirubin,10'11 endothelin,13177-179 and lipid perox-
and Bergstrom58 found concentrations of bilirubin in ides.9-21 Since OxyHb is metabolized to bilirubin,25 is a
the CSF of patients with obstructive jaundice that potent propagator of lipid peroxidation,9-21 and aug-
caused vasospasm in the study of Duff et al.10 Bili- ments the release of eicosanoids and endothelin from
rubin, especially when bound to albumin, possesses arteries,12-13'94 consideration of any one of these sub-
antioxidant activity and inhibits lipid peroxida- stances as the sole cause of vasospasm may be a moot
tion.183-185186 Furthermore, in the subarachnoid point. Clearly, OxyHb, while potentially the only agent
space bilirubin is produced by an enzyme system with necessary to precipitate vasospasm, acts by diverse
limited capacity, which may result in bilirubin con- mechanisms to cause arterial narrowing.

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Macdonald and Weir Hemoglobin and Vasospasm 977

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978 Stroke Vol 22, No 8 August 1991

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595-602 hemoglobin • subarachnoid hemorrhage

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