(Stroke. 1998;29:2575-2579.)
© 1998 American Heart Association, Inc.
Original Contributions |
Functional Changes in Human Pial Arteries (300 to 900 µm ID) Within 48 Hours of Aneurysmal Subarachnoid Hemorrhage
From the Totman Laboratory for Cerebrovascular Research, Department of Pharmacology, University of Vermont, College of Medicine, Burlington, and Neurological Surgeons, PC, Phoenix, Ariz (C.L.W.).
Correspondence to John A. Bevan, MD, Totman Laboratory for Cerebrovascular Research, Department of Pharmacology, University of Vermont, College of Medicine, Burlington, VT 05405-0068.
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Abstract |
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Background and Purpose—Animal studies of cerebral arteries 2 to 3 days after experimental subarachnoid hemorrhage (SAH) provide evidence of arterial change such as hyperresponsiveness to contractile agonists. There is evidence that small arteries, as well as those large enough to be seen on angiography, may be involved. To directly test these possibilities, the contractile and dilator responses of pial artery segments taken from patients up to 48 hours after SAH were compared with those from patients having elective surgery for an aneurysm (Clip) and with those from normal brain vessels overlying tumors (controls).
Methods—Segments were mounted on a resistance artery myograph for measurements of wall force changes.
Results—There were no differences in maximum contractility (Emax) of the 3 groups of segments. The responses of the SAH segments to K+ (30 mmol/L) were 60.7±4.6% of Emax (n [number of vessels]=18), which was significantly greater than those of controls (29.9±5% Emax) (n=20). Clip responses were the same as control. Contractions of SAH segments to norepinephrine (1 µmol/L) were 54.3±7.9% Emax (n=12), and these were significantly greater than those of controls (15.1±6.2% Emax) (n=25). All SAH segments showed spontaneous contractile activity of varying patterns. Spontaneous activity did not occur in the Clip group and occurred in only 50% of control segments. Dilation to acetylcholine was numerically less in SAH and Clip segments than in controls, but differences were not statistically significant. The change in agonist responsiveness could result from exposure to agents that damage the blood vessel wall, resulting in partial depolarization of endothelial and smooth muscle cells.
Conclusions—Small human pial arteries are hyperresponsive to contractile agents and show spontaneous contractile activity within 48 hours of SAH. Such effects could result in narrowed resistance arteries and reduction in cerebral blood flow. These effects emphasize the wisdom of early therapeutic intervention.
Key Words: aneurysm • cerebral ischemia, transient • contractility • pial arteries
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Cerebral vasospasm is a serious complication of subarachnoid hemorrhage (SAH) after rupture of a cerebral aneurysm. It can be recognized on angiography as narrowing of the larger cerebral arteries and also clinically as a possible basis for increasing cerebral ischemia. These 2 features are commonly but not invariably associated.1 The presence of arterial narrowing, which is often extensive and diffuse, with distribution frequently consistent with the concurrent ischemia, has initiated many experimental investigations into its cause. Since the changes are only apparent in humans several days after SAH, reaching a peak at about the 7th day, most research effort has been focused on the alterations present at this time. Although there is considerable disagreement concerning the processes responsible for the arterial narrowing, there are many candidates.2 3 4 5 6
Studies in animal models have shown that changes can occur in the larger cerebral arteries before the time that vasospasm is recognized in humans. Early changes described include hypersensitivity to constrictors7 8 9 10 and diminution of endothelial-dependent dilation. The latter was recently documented in human basilar arteries obtained during autopsy 1 day after SAH.11 The recognition of changes in large cerebral arteries served to concentrate experimental studies on these arteries. However, one in vitro study of arteries from a monkey model showed alterations in resistance arteries.12 Such a possibility seems reasonable in view of the observed clinical ischemia and the observation that diameter changes in large arteries must be very sizable to have a serious impact on blood flow.13 Furthermore, significant early decreases in cerebral blood flow have been documented.14 15 This takes place despite the dysfunction or loss of autoregulatory capacity found after SAH that would probably result in vasodilation.16 17 18 Changes in penetrating arteries were not observed in a rabbit model of cerebral vasospasm even though alterations occurred in the basilar artery. This may be because blood did not penetrate into the Virchow-Robin space.19
The present study was performed to determine whether early changes
occur in small human pial arteries within 48 hours of SAH.
Responsiveness of these vessels to norepinephrine and
raised K+ that caused contraction less than
tissue maximum was increased in comparison to that in vessels obtained
during elective surgery for clipping and those from normal brain tissue
discarded during surgery for tumors. The SAH segments invariably
exhibited spontaneous rhythmic and sometimes maintained periods of
tone. The significance of this last feature is problematic
because 
50% of pial arteries from healthy brain tissue exhibited
such activity. The changes observed after SAH are consistent
with cellular damage and constriction due to exposure to blood
clot–derived substances.
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Methods |
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This study was approved by the Ethics Committee of the University of Vermont. Human pial artery segments were obtained during neurosurgical procedures. Control arteries were taken from disease-free regions of the cerebral cortex removed for access to tumor. Pial segments were occasionally available during surgery for cerebral artery aneurysm clipping within 48 hours of SAH and during elective surgery on patients without hemorrhage (Clip). In the latter 2 groups, an artery that would otherwise be discarded for access to the aneurysm became available. Some were obtained during surgery for anterior communicating artery aneurysms, when the gyrus rectus is routinely removed. Others were obtained while a surgical pathway was pursued to a middle cerebral artery aneurysm when the sylvian fissure was split because sometimes arteries traverse this fissure. Arteries were brought to the laboratory in cold oxygenated physiological salt solution (PSS) containing deferoxamine (100 µmol/L), heparin (10 U/mL), penicillin (50 U/mL), and streptomycin (50 µg/mL). PSS has the following composition (mmol/L): NaCl 119, KCl 4.7, KH2PO4 1.18, MgSO4 1.17, NaHCO3 24.9, CaCl2 1.6, EDTA 0.023, and dextrose 5.5. All vessels were held at 4°C in PSS solution for 16 to 20 hours before they were mounted on a myograph. Preservation of animal arteries under these conditions does not change their reactivity.20
Segments were cut into 2.5- to 3-mm-long rings and mounted in resistance artery myographs.21 22 They were suspended in Krebs' physiological solution maintained at pH 7.4±0.1, 37°C, and gassed continuously with 95% O2/5% CO2. The rings were connected to force transducers (Grass FT03) to record isometrically changes in wall force. The myograph mounting wires were slowly separated until a just significant change in the force record was observed. Wire separation was taken to be half the unstretched circumference. A similar experimental protocol was followed for all 3 groups. Changes in the exact time course of manipulations, however, invariably occurred because of the concomitant spontaneous changes in tone that varied in time course and pattern.
After equilibration for 60 minutes in PSS solution, because the
segments varied in their internal diameter, wall thickness, and
elasticity, the active length-tension relationship was determined for
each segment before the experimental protocol. The rings were first
stretched to an internal diameter known from experience to be less than
optimum and then were exposed to 30 or 40 mmol/L KCl. A stepped
increase in passive wall tension of 20% was then achieved by
stretch, and tissues were exposed to KCl when equilibrium was reached.
The preload when the contractile response to KCl was within 20% of the
prior response was considered to provide optimum length. The rings were
then allowed to equilibrate for an additional 30 minutes. The
arterial segments were then exposed to
norepinephrine (10 µmol/L); at the contractile
plateau, we added acetylcholine (1 to 10 µmol/L) followed by
substance P (10-8 mol/L) (if there was no
response to acetylcholine) to assess the function of the
endothelium. Relaxation to acetylcholine was expressed
as percent preaddition tone. At the end of each experiment, the
arterial segments were maximally contracted with 127
mmol/L KCl/Krebs' solution and arginine vasopressin (1 µmol/L).
This is defined as Emax. Contractions to
norepinephrine and K+ are expressed
as percent Emax.
Drugs Used
The following drugs were used: acetylcholine hydrochloride,
norepinephrine bitartrate, substance P (Sigma), and
arginine vasopressin (Bachem California). Drugs were dissolved in
Krebs' solution, prepared freshly every day and kept on ice.
Statistical Analysis
Data are given as mean±SEM. Statistical significance of mean
differences was determined with the Student's t test. A
probability value of 0.05 was accepted as significant for differences
between groups.
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Results |
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Contractile and dilator responses of human pial artery segments taken from patients up to 48 hours after hemorrhage (SAH), from those having similar surgery but without prior hemorrhage (Clip), and from normal brain tissue during surgery for tumor (control) were compared. The age ranges of the groups were 37 to 78 years for SAH, 53 to 64 years for Clip, and 15 to 73 years for control. Diameters ranged from 320 to 950 µm (mean, 534 µm) for SAH; 480 to 800 µm (mean, 671 µm) for Clip; and 250 to 950 µm (mean, 569 µm) for control. These mean values were not significantly different from each other. The agents used were norepinephrine (1 µmol/L), a nearly maximum concentration in control segments; K+ (30 mmol/L), which causes
40% of the maximum
high-K+ response; and acetylcholine (1 to 10
µmol/L), which causes a maximum endothelial-dependent
dilation in control human pial arteries. Observations were also
made of the time-dependent changes in the resting tone level.
Contractile Responses to Norepinephrine and
Potassium
The maximum contractile responses of the 3 groups of artery
segments were not different from each other.
The mean equilibrium response of the SAH segments to
norepinephrine (1 µmol/L) was 359% of that in
control segments (Figure
). The
norepinephrine (1 µmol/L)–induced responses of the
SAH segments were 240% of the control norepinephrine
maximum (10 µmol/L) (Figure). In control arteries the maximum
response to this agonist is 23% of tissue maximum.23
There were insufficient norepinephrine responses in the
Clip group to make a comparison. The responses to raised
K+ (30 mmol/L) of the SAH segments
(60.7±4.6% Emax) (n [number of
vessels]=18) were 203% of control (29.9±5%
Emax) (n=20), a value that was not significantly
different from the maximum elicited by K+
(127 mmol/L) in control vessels (74.5±4.8%
Emax) (n=20). The responses of the Clip segments
(31.3±2% Emax) (n=6) were not significantly
different from those of control.
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Dilation to Acetylcholine
The maximum dilator responses of the SAH segments to acetylcholine
(1 to 10 µmol/L) were 45±7.7%
(n=18) of preaddition tone (Figure
). This
value was not significantly different from the dilations observed in
the Clip segments (48.2±12.7%) (n=6). That of control vessels was
66.2±8.7% (n=25). These 3 group responses were not statistically
significantly different from each other.
Spontaneous Rhythmic Activity
Spontaneous changes in resting tone are commonly seen in human
pial arteries examined under the conditions of these studies. Gokina et
al24 reported the incidence to be 50% in segments
taken from patients free of clinical vascular disease. The maximum
amplitude of the spontaneous changes in tone in a particular experiment
varied from 25% to 70% of tissue maximum
(Emax). All segments from SAH patients showed
some form of spontaneous rhythmic activity. The pattern was extremely
variable, but in segments from 2 patients the peak level was close
to tissue maximum. No spontaneous activity was observed in the Clip
segments.
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Discussion |
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The new observations of this study are that human pial arteries between 300 and 900 µm ID obtained during surgery <48 hours after SAH show increased contractile responsiveness to submaximal concentrations of norepinephrine and increased extracellular potassium compared with pial artery segments taken from patients having elective aneurysm clipping or tumor surgery. Their capacity to respond to the endothelial-dependent dilator acetylcholine is numerically but not statistically less than that of control. However, since a similar trend was encountered in the Clip group, the change cannot necessarily be attributed to the hemorrhage. All SAH segments showed periods of maintained and/or spontaneously changing levels of muscle tone. The incidence of this feature in control segments was
50%.24 These are
the first observations made on small human brain vessels after SAH at a
time before the appearance of angiographic and symptomatic
vasospasm. The reason why the maximum dilation to acetylcholine of the
Clip group is numerically less than that of control and similar to that
of the SAH group is not immediately apparent. It could be that control
artery segments obtained during tumor surgery, because of their
relatively increased availability in comparison to Clip segments, were
preferentially selected for ease of removal and handling by the
surgeon. Relaxation to 10 µm acetylcholine, a maximum
concentration, is expressed in relation to the preaddition tone in each
case. It is not known if and how maximum
endothelial-dependent relaxation varies with tone level
and the vascular smooth muscle membrane potential (see below) that has
been found to be less after SAH.25
In 1995, Onoue et al26 studied helical strips of basilar
and main trunk middle cerebral arteries from cadavers who died 8 to 19
days after the onset of SAH. They found diminished contractile
responses to KCl, prostaglandin
F2
a, norepinephrine, and
serotonin. Endothelial-dependent relaxation
to acetylcholine and bradykinin and
endothelial-independent relaxations to prostacyclin and
nitroglycerin were also attenuated. They concluded that
the primary change was smooth muscle damage, and therefore vasospasm at
this time was not due to excessive active vasoconstriction. This
reduction in active wall function was consistent with the
findings of many studies of large arteries from animals 
5 days after
SAH (for example, see References 2, 4, 27, and 282 4 27 28 ).
Hatake et al11 documented changes in reactivity of human basilar arteries obtained postmortem only 24 hours after the hemorrhage. No significant alteration was found in the contractile response to norepinephrine, serotonin, and raised K+, but relaxation was diminished in response to thrombin, bradykinin, and the calcium ionophore A23187. They concluded that the initial primary change was loss of endothelial dilator function.
The different observations early and late after SAH in the human are consistent with several studies of the long-term time course of cerebral arterial changes after SAH in animals. Nakagomi et al8 examined responses to serotonin of rabbit basilar arteries after the injection of autologous blood into the cisterna magna. On day 2, contractile responses were doubled compared with controls but were diminished on day 4 and lost on day 6. At all time periods studied, dilation to acetylcholine but not ATP was diminished. Vorkapic et al7 examined the function of the rabbit basilar artery 1 to 9 days after a similar technique of experimental SAH. Basilar artery sensitivity to contractile agonists was greater than in controls during the first few days. The maximum response to acetylcholine progressively decreased after day 1. According to Sutter et al,29 dilation to calcitonin gene–related peptide, which acts partially by activating K+ channels in the smooth muscle cells, was found not to be diminished on day 2. Macdonald et al30 described changes in arterial characteristics with time. At day 4, contractile ability was diminished and further decreased with time. Relaxation to papaverine at day 4 was also diminished but did not progress further.
The first study of brain resistance artery function was made in the monkey after SAH caused by the sudden withdrawal percutaneously of a needle previously placed through the intracranial portion of the internal carotid artery.12 Widespread vasospasm invariably occurred, associated with neurological deficit. Five days later, pial artery segments (100 to 150 µm OD) from the middle cerebral artery, mounted in a resistance artery myograph, showed reduced responses to norepinephrine and large irregular spontaneous excursions of tone. The mean maximum spontaneous force increase of the ipsilateral segments was10 times that of the contralateral. The spontaneous force changes were very variable in pattern and time course. The maximum contraction to norepinephrine (10 nmol/L to 10 µmol/L) on the hemorrhage side was only 20% to 30% of control. Acetylcholine-induced dilation was not tested.
Vollmer et al19 studied the rabbit basilar artery and also
its penetrating branches into the brain stem 3 days after SAH. The
basilar arteries showed increases in responsiveness to
serotonin and prostaglandin
F2a and decreased dilation to acetylcholine.
However, the same level of myogenic tone occurred in the small arteries
on both sides, and there were minimal differences in the effect of pH
and K+ change on tone. Serotonin and
acetylcholine reactivities were unaltered. It was speculated that the
presence of changes in the basilar but not the penetrating vessels
reflected the failure of the blood to surround the smaller
vessels.1 31
In the present experiments, human cerebral resistance arteries were examined within 48 hours of SAH. Our results are comparable to those in rabbit basilar studies several days after experimental hemorrhage. Rabbit basilar artery maximum contraction to serotonin, for example, was increased by 173% of control.7 In human pial arteries the response to norepinephrine (10-6 mol/L) was 359% of control. Such an increase was not apparent in the human basilar autopsy segments 1 day after SAH.11 Endothelium-mediated dilator response to acetylcholine of the rabbit basilar artery was only 55% of control at day 2. Hatake et al,32 studying human basilar artery segments 1 day after SAH, found that endothelial-dependent but not -independent dilation was reduced 50% to 80% depending on the agonist studied. The acetylcholine dilator response of human pial arteries showed a trend toward reduction that was not significant. These data are consistent with the occurrence of early hyperreactivity of vascular smooth muscle to constrictor agonists.
Short, sometimes repetitive, and also prolonged periods of spontaneous raised muscle tone were seen only on the side of the hemorrhage in monkey pial artery on day 5,12 in rabbit basilar artery on day 2,7 and in the arteries of this study. Yamada et al33 noted an increase in myogenic tone in the 2-hemorrhage dog model at day 7. The absence of such phenomena in human autopsy basilar arteries26 may reflect delay in study and also the experimental use of the helical strip preparation, a somewhat damaging technique. No spontaneous activity was reported by Macdonald and Weir4 at day 4 in dogs using ring segments or in the perfused isolated penetrating arteries of the rabbit.19 These variable findings suggest that the significance of such activity is debatable.
Waters and Harder25 found at 30 minutes after SAH that the membrane potential of cat basilar artery smooth muscle was depolarized to a mean level of –50 mV compared with control levels of 62±5.2 mV, a value that was maintained essentially unchanged for the next 7 days. A reduction in the membrane potential of vascular smooth muscle cells is associated with an increase in agonist response. Dunn et al34 studied rabbit mesenteric artery membrane potential. When K+ in the bath solution was increased by 15 to 20 mmol/L, the membrane potential was reduced from –54 to –47 mV, revealing responses to lower concentrations of norepinephrine not previously seen and potentiating responses to higher concentrations and also to angiotensin II. Lombard et al35 associated decreases in membrane potential with increasing sensitivity of response to norepinephrine. It is possible that the blood in the cerebrospinal fluid released substances that, by increasing tone or as a result of cell membrane damage, shifted the membrane potential into a range at which a further small depolarization by agonists produces an exponential increase in internal cellular calcium concentration through voltage-dependent calcium channels.36 Depolarization of the endothelium where such channels are not present would be expected to reduce endothelial-dependent vasodilation. Calcium enters through nonspecific cation channels along the electrochemical gradient to activate the production of nitric oxide.37 A reduction of membrane potential in human pial arteries has been shown to be associated with both the genesis and augmentation of spontaneous rhythmic tone increases.24
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Acknowledgments |
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We wish to thank Heather Burbank, Allison Croke, and John Dodge for their skilled technical assistance during this study.
Received March 10, 1998; revision received August 25, 1998; accepted September 2, 1998.
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Editorial Comment
Department of Neurosurgery, University of California, Davis, Sacramento, California
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The authors have shown that segments of 300- to 900-µm vessels taken within 48 hours from patients with aneurysmal SAH are hypersensitive to vasoconstrictors and somewhat less responsive to endothelium-dependent vasodilation with acetylcholine. There was also a decreased dilator response in vessels taken during surgery for elective aneurysm clipping. I would agree with the authors' possible explanation for this: It is much easier to obtain fairly large segments without damaging the endothelium from superficial cortex overlying a tumor than it is from the depths during gyrus rectus removal or from the sylvian fissure, which always demands a certain amount of manipulation. In my opinion this also proves that the authors worked cautiously so as not to unnecessarily remove blood vessels from Clip or SAH patients just for the sake of their study, and I am certain that all ethical considerations were taken into account fully in this investigation. Whether 300- to 900-µm vessels represent conductance or resistance vessels in humans is open to debate. The distinction between conductance and resistance vessels is not inconsequential, partly because it has been suggested that there is dilation of resistance vessels during vasospasm of the angiographically visible conductance vessels.1 Despite this, the role of the resistance vessels in vasospasm is still unclear, but it is certain that no clinical vasospasm occurs without spasm in the conductance part. With this caveat in the interpretation of the data, the authors have done the "vasospasm community" a service by showing that what occurs in experimental animals is also the case in human aneurys- mal SAH.
Received March 10, 1998; revision received August 25, 1998; accepted September 2, 1998.
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- Grubb RL, Raichle ME, Eichling JO, Gado MH. Effects of SAH on cerebral blood volume, blood flow, and oxygen utilization in humans. J Neurosurg. 1997:46:446–453.
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