(Stroke. 1997;28:844-849.)
© 1997 American Heart Association, Inc.
Articles |
Isoprostanes: Free Radical–Generated Prostaglandins With Constrictor Effects on Cerebral Arterioles
From the Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University (Richmond).
Correspondence to Dr Stuart W. Hoffman, Department of Pharmacology and Toxicology, Medical College of Virginia, PO Box 980613, 410 N 12th St, Room 754, Richmond, VA 23298. E-mail swhoffman{at}gems.vcu.edu
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Abstract |
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Background and Purpose Isoprostanes are generated by cyclooxygenase-independent free radical attack of arachidonic acid and are potent constrictors of the peripheral vasculature. Traumatic brain injury stimulates oxygen radical production and is associated with cerebral blood flow reduction. However, no specific vasoconstrictor has been identified as the cause of posttraumatic blood flow reduction. The purpose of this study was to determine whether isoprostanes constrict cerebral arterioles.
Methods The effects of 10-9 to
10-5 mol/L 8-iso-prostaglandin
F2
(8-iso-PGF2),
8-iso-prostaglandin E2
(8-iso-PGE2), and prostaglandin
F2 (PGF2) on pial
arteriolar diameter were measured in anesthetized rats using a
closed cranial window and in vivo microscopy.
Results All prostanoids produced vasoconstriction. Of
these, 8-iso-PGF2 produced the greatest
vasoconstriction (34%±2), followed by 8-iso-PGE2
(25%±4) and PGF2 (20%±2). After six
cerebrospinal fluid washouts of the cranial window, both
8-iso-PGF2– and
8-iso-PGE2–treated vessels remained slightly constricted,
whereas the PGF2-treated vessels returned to
control diameter. Coapplication of the semiselective
thromboxane A2/prostaglandin
H2 receptor antagonist SQ29548 completely
blocked the vasoconstriction induced by
8-iso-PGF2 and 8-iso-PGE2.
Conclusions Isoprostanes are potent constrictors of cerebral arterioles and appear to act at a receptor that is similar to the thromboxane A2/prostaglandin H2 receptor. Isoprostanes may play a role in the reduction of cerebral blood flow that occurs after brain injury and subsequent oxygen radical production.
Key Words: brain injuries • cerebral circulation • cerebral ischemia • lipid peroxidation • oxygen radical • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Traumatic brain injury generates a cascade of secondary events that magnifies the area of damage in the injured brain (see Fig 1
).1
This secondary damage is caused by the uncontrolled release of
physiologically active substances into the
microenvironment of the brain, resulting in cellular
toxicity.2 Much of this toxicity is either directly or
indirectly related to the formation of free radicals.3 4
Free radicals, especially the hydroxyl and the peroxynitrite radicals,
are potent initiators of lipid peroxidation. After injury, free
radicals are generated by a variety of mechanisms.4 5 For
instance, free radicals can be initiated by dissociation of iron from
heme, by activation of the cyclooxygenase pathway
of arachidonic acid metabolism, and by
mitochondrial dysfunction.4 Cells have many
endogenous mechanisms for controlling the damage caused by
free radicals; however, at the time of injury many of these protective
strategies can be overwhelmed.4 6 This free radical
overload leads to the damage of many cellular components, including
proteins, DNA, and phospholip- ids, thus causing denaturation and cellular
dysfunction.4 In addition, free radical attack on membrane
lipids can produce substances that can be cytotoxic or have biological
activity.3 7 8 9 10 11
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One family of bioactive compounds generated by free radical attack on
membranes is the cyclooxygenase-independent
prostaglandins, isoprostanes.10 12 13
Isoprostanes are formed by free radical attack on
arachidonate, which resides in the SN-2 position of
phospholipids (Fig 1
).13 The esterified fatty acid is then
converted to an isoprostane through ß-cleavage of the resulting
peroxy acid, followed by rearrangement to isoprostane. The resulting
isoprostane is then cleaved by a phospholipase and released.
Isoprostanes have been described as having the same D-, E-, and
F-ringed structure as cyclooxygenase-generated
prostaglandins, except that their hydrocarbon chains are in
a cis position in relation to the pentane ring as opposed to
a trans position.14 Because isoprostanes have a
space-occupying conformation and are formed in situ on the
phospholipid, their presence in cellular membranes can lead to changes
in membrane fluidity and integrity.15 16
A previous study has shown that these compounds are formed after brain
injury, wherein levels of 8-iso-PGF2 can
increase 10-fold over baseline.17 This finding confirms
that there is a substantial amount of lipid peroxidation in
traumatically injured brain and also indicates that isoprostanes are
generated in amounts that could possibly influence the local
environment. Published evidence indicates that like
cyclooxygenase-dependent
prostaglandins, isoprostanes can also have potent
vasoconstrictive effects on the peripheral
vasculature.7 10 18 19 These studies have shown that
isoprostanes produce dramatic vasoconstriction in the
peripheral circulation, leading to severe
hypoperfusion.7 10 18 19
Traumatic brain injury often leads to severe reduction in blood flow, which is one of the most important causes of secondary brain damage associated with head trauma.20 Clinical reports have stated that ischemic damage occurs in 91% of the severe head-injury cases, and the presence of posttraumatic ischemia has been correlated with higher mortality and poorer neurological outcomes.20 Using laser-Doppler flowmetry to measure changes in CBF, we have previously reported that blood flow is reduced by as much as 35% to 40% during the first hour after experimental fluid percussion brain injury in rats.21 In a more recent study, we have demonstrated that this injury-related reduction in CBF in rats can be almost totally prevented by an intravenous infusion of superoxide dismutase.11 This and other experimental evidence indicate that free radicals or their byproducts could play a major role in the posttraumatic reduction of CBF.22 23 Although many factors could be responsible for the loss of cerebral perfusion after neurotrauma, the coexistence of both lipid peroxidation and reduced blood flow suggests a possible role for isoprostanes. If isoprostanes, byproducts of lipid peroxidation, are a link between these two distinctly different consequences of head trauma, then the development of more rational treatments for brain injury might follow. In this study, we explore the actions of topically applied isoprostanes on the diameter of pial arterioles using the acute closed cranial window technique in rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Surgical Preparation
Thirty-three young adult male Sprague-Dawley rats were used to examine the effect of isoprostanes on rat cerebral arteriolar diameter, using the acute cranial window technique and in vivo microscopy as previously described.24 Rats were anesthetized with thiopental (75 mg/kg) and supplemented with pentobarbital.
After completion of the tracheotomy, each rat was ventilated with room air. The end-expiratory CO2 of each rat was continuously monitored with a capnometer (Transverse Medical Monitors, model 2200) and was maintained at approximately 30 mm Hg by adjusting the respirator rate and volume. Arterial blood pressure was measured through a cannula inserted into the right femoral artery. Arterial samples were periodically analyzed with a Corning Blood Gas Analyzer to ensure normal Pao2, Paco2, and blood pH levels. A cannula was also inserted into the right femoral vein for systemic administration of supplemental anesthetic.
Pial arteries were visualized using a cranial window that was implanted by the following method. A midline incision was made in the scalp of an anesthetized rat. The skin and fascia were retracted, and a 3-mm-diameter craniotomy was made over the left parietal cortex using a trephine. With the aid of a surgical microscope, microscissors were used to remove the dura and expose the pial surface of the brain. A round metal cranial window with a diameter of 12 mm was implanted over the craniotomy. The round glass window and the area of superfusion within this metal frame are 6.5 mm in diameter. The cranial window is equipped with three openings. Two openings were used as an inlet and outlet for filling the space under the cranial window with test solutions. The inlet and outlet valves were positioned such that the test solutions flowed over the cortical surface as viewed through the cranial window. The third opening of the cranial window was connected to a Statham pressure transducer for continuous measurement of intracranial pressure. The outlet of the window was connected to plastic tubing; the open end of the tubing was placed at a fixed level to give a constant intracranial pressure of 5 mm Hg throughout the experiment. The space under the window and the plastic tubing were filled with artificial CSF. This fluid was equilibrated with gas containing 5.9% CO2, 6.6% O2, and 87.5% N2, which produces a pH and gas tensions in a normal range for CSF. The vehicle for all agents applied under the cranial window was artificial CSF. The diameter responses of three to five arterioles were studied in each rat using a Vickers image-splitting device as previously described.25 The responses of the arterioles in a given rat were averaged, and this single number was used to compute the average for a group of rats.
Experimental Protocol
After surgical preparation and implantation of the cranial
window, the animals were treated with the following procedure.
Initially, to establish baseline diameter, the window was washed with 1
mL of artificial CSF at 5-minute intervals. Additionally, at the end of
each 5-minute interval, just before the next flushing with the CSF,
pial arteriolar diameter was measured.
To determine whether isoprostanes are
physiologically active, we infused three
different prostanoids after the establishment of baseline. Only one
compound was tested in each rat. The prostanoids
(8-iso-PGF2, 8-iso-PGE2, or
PGF2; Cayman Chemical) were infused in
increasing concentrations (10-9 to
10-5 mol/L) and were applied in 1-mL volumes
at 5-minute intervals. Pial arteriolar diameters were measured at 2 and
5 minutes after the infusion of each test solution. After
administration of the five concentrations of prostanoids, there was a
30-minute washout period wherein CSF was infused under the window every
5 minutes, with readings every 2 and 5 minutes after each washout.
In a second study using different rats, baseline diameter was
determined after two washouts with artificial CSF containing
10-5 mol/L SQ29548 (Biomol), a semiselective
TXA2/PGH2 receptor
antagonist.10 Baseline was the average of two
readings taken 5 minutes after each washout with SQ29548. After
establishment of baseline, isoprostane was administered at the same
concentration range as described in the first study, except every 1 mL
of CSF contained 10-5 mol/L SQ29548. The
isoprostane was then washed out three times, once every 5 minutes, with
CSF containing 10-5 mol/L SQ29548. Next, the
antagonist was washed out with three infusions of CSF
alone, once every 5 minutes. After the last CSF washout, 1 mL of either
10-5 mol/L 8-iso-PGE2 or
8-iso-PGF2 was infused under the window, and
pial arteriolar diameter was measured at 2 minutes after infusion to
determine whether arterioles were still responsive to the
isoprostanes.
Statistics
Both one-way and repeated measures ANOVA were performed and were
followed by Tukey-Kramer comparisons to determine differences between
the groups using SuperAnova statistical software for Macintosh. A value
of P<.05 was considered significant.
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Results |
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All groups of animals had similar blood pressure, end-expiratory CO2, arterial pH, arterial PaO2, PaCO2, and control arteriolar diameter (Table
). During the
experimental period, vasoreactivity measurements were taken every 2
minutes after application of test solution. As shown in Fig 2, all three prostanoids produced a
concentration-dependent constriction of pial arterioles. Repeated
measures ANOVA was used to determine differences in arteriolar response
among the six experimental groups. A repeated measures ANOVA for the
overall pial arteriole response indicated that there were group
differences (F3,15=15.6, P<.05) and
group-by-concentration differences (F27,131=13.1,
P<.05). Post hoc analyses indicated that all three
prostanoids produced significant vasoconstriction, with the
8-iso-PGF2 producing significantly more
constriction than PGF2. Post hoc
analyses of the interaction of group by concentration of
prostanoids indicated that 8-iso-PGF2
produced vasoconstriction that was significantly greater than that of
PGF2 at concentrations of
10-7 mol/L or greater. The
vasoconstrictive actions of
8-iso-PGF2 were greatest at
10-5 mol/L (34%±2) compared with
8-iso-PGE2 (23%±4) and PGF2
(20%±2) (Fig 2).
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After the last infusion of prostanoid, the window was washed out with
CSF. Resulting observations showed that rats treated with isoprostanes
responded differently than rats that had received
PGF2 (Fig 3). In these two
groups, vasomotor tone did not completely return to normal even after
six washouts with CSF.
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To determine whether the TXA2/PGH2
receptor antagonist SQ29548 inhibits isoprostane-induced
vasoconstriction of pial arterioles, CSF containing the
antagonist was first infused under the window. A
t test of the initial response to SQ29548 revealed that
there was no difference between mean arteriolar diameter during the
control period and the mean arteriolar diameter during the period when
CSF containing SQ29548 was infused (data not shown,
t16=0.447). Next, the ability of
antagonist to inhibit the vasoconstriction induced by
isoprostanes was tested. A repeated measures ANOVA for overall pial
arteriole response after the coadministration of the
TXA2/PGH2 receptor antagonist
showed no differences between the isoprostane and the control groups
that received artificial CSF (P>.05, Fig 4).
After the final infusion of isoprostane, both isoprostane and the
antagonist were washed out from the cranial window to test
whether removal of the antagonist would allow
vasoconstriction to return when isoprostane was reapplied to the brain.
A one-way ANOVA comparing the vascular responses to isoprostanes before
and after the washout of SQ29548 with three 1-mL artificial CSF washes
indicated that there were significant differences
(F3,12=14.2, P<.05, Fig 5).
Further analyses indicated that both isoprostanes caused
significant vasoconstriction after the removal of the
antagonist.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our results indicate that isoprostanes are potent vasoconstrictors of the pial arterioles, producing as much as 34% constriction at a concentration of 10-5 mol/L. The vasoconstrictor effect of 8-iso-PGE2 was between that of PGF2
and
8-iso-PGF2. The action of
cyclooxygenase-dependent prostanoids on cerebral
vessels has been previously reviewed by White and Hagen.26
The currently reported vasoconstriction in response to
PGF2 is similar to that previously reported
for in vivo rat and mouse arterioles.27 28 The vascular
effects of both isoprostanes were still apparent after repeated
washouts, whereas normal vascular tone returned in rats that were
treated with PGF2. The more rapid return to
control diameter by PGF2 suggests intrinsic
differences in the way isoprostanes and PGF2
induce vasoconstriction. In addition, the vasoconstrictor action of
both isoprostanes can be completely blocked by the
TXA2/PGH2 receptor
antagonist SQ29548, suggesting that these nonenzymatically
formed prostaglandins mediate their effects through
activation of a TXA2/PGH2-like receptor.
Our results also indicate that the antagonizing effect of the SQ29548
is reversible, with vasoconstrictor responses to isoprostanes returning
after removal of the antagonist.
These results demonstrate that isoprostanes are potent vasoconstrictors
of pial arterioles and are in agreement with previous studies
investigating the peripheral vascular responses to
isoprostanes.7 8 10 15 These previous studies found that
isoprostanes were extremely potent in constricting arteriolar diameter
in rat kidney, lung, and liver. In the kidney, for instance,
10-5 mol/L
8-iso-PGF2 reduced both blood flow and
glomerular filtration rate by at least
40%.10 15
Our data indicate that the TXA2/PGH2 receptor antagonist SQ29548 blocks the contractile action of the isoprostanes in a manner that is similar to its effect in peripheral organs.7 18 19 We found the antagonist to be reversible. After three washouts of the cranial window chamber with CSF, followed by an infusion of isoprostane, the vasoconstrictor response returned. Such response indicates that there is a competition between the isoprostanes and the antagonist, with the SQ29548 having slightly higher affinity for the binding site than the isoprostanes.7
The specificity of SQ29548 deserves comment. Binding studies have shown
that SQ29548 displaces 8-iso-PGF2 from
TXA2/PGH2 receptors on vascular smooth
muscle cells, indicating that there is competition for that receptor
site.7 Other studies indicate that SQ29548 most
effectively blocks vasoconstriction and biochemical responses induced
by TXA2/PGH2 mimetics and isoprostanes
and less effectively blocks the cerebral vasoconstriction caused by
PGF2 in newborn piglets.29 30
In newborn piglets, the SQ29548 blocks the contractile response of
cerebral arterioles to high doses of acetylcholine but has no effect on
the vasoconstrictor response to
norepinephrine.30 Thus, SQ29548 appears to be
most specific for TXA2/PGH2 receptors
but may affect, to a lesser degree, the response to other agonists. The
effect of SQ29548 on the responses to other agonists is, however,
complicated by the uncertainty as to whether these agonists may also be
stimulating formation of TXA2/PGH2.
Mayhan has previously examined the effect of SQ29548 on the response of cerebral arterioles in SHR to ADP and acetylcholine, which are endothelium-dependent dilators.31 SHR have a reduced dilator response to ADP and display vasoconstriction, instead of the normal dilator response to acetylcholine. After administration of SQ29548, Mayhan found that SHR vessels dilated more to ADP and dilated in response to acetylcholine. He suggested that impaired responses in cerebral arterioles of SHR may be related to chronic activation of the TXA2/PGH2 receptor. Because we have found that SQ29548 also blocks the response to isoprostanes, it may be additionally hypothesized that hypertensive injury of cerebral vessels increases isoprostane production, which alters reactivity to ADP and acetylcholine. Arguing against this possibility is our finding and that of Mayhan that SQ29548 alone did not alter arteriolar diameter, as might be predicted by blockade of a tonic vasoconstrictor.
With respect to traumatic brain injury, the literature suggests that
ischemic conditions often exist after various forms of brain
injury.32 33 34 35 Injuries such as head trauma, spinal cord
injury, subarachnoid hemorrhage, hemorrhagic stroke,
and reperfusion injury all produce a secondary reduction in blood
flow.32 33 34 35 As in experimental studies, some clinical
studies have shown that immediate treatment with free radical
scavengers can improve outcome.36 However, in the clinical
situation the course of antioxidant treatment is often delayed because
of numerous reasons, eg, patient transport time. This delay in
treatment could partially explain the unexpected lack of confirmation
of experimental animal results in more recent clinical studies using
antioxidants in head-injured humans.37 Previous research
has shown that in experimental models, peak hydroxyl radical formation
occurs within the first 30 minutes after injury, a time before which
neuroprotective substances can normally be administered. If the brunt
of lipid peroxidation takes place during the first 30 minutes after
injury, the formation of isoprostanes would also be expected to be
maximal during this time. Recently, Gopaul et al38 have
reported that isoprostanes can stay esterified in phospholipids for 24
hours after formation. This creates a situation where isoprostanes
residing in membranes may affect membrane fluidity. In addition, the
eventual release of these vasoactive compounds could have an effect on
the cerebral vasculature (see Fig 1). In a recent in vivo study, the
presence of free nonesterified isoprostanes after experimental brain
injury was shown to peak at 24 hours.17 The possibility
exists that these freed isoprostanes could then act on the cerebral
vasculature, causing CBF reductions. This would be in agreement with
the clinical literature that reports a delayed reduction in blood flow,
which can occur between several hours to days after an
injury.39
Considering that 8-iso-PGF2 has been found
to be significantly elevated after experimental traumatic brain injury
and that this compound has now been demonstrated to produce significant
constriction of pial arterioles, a potentially important link may be
made between trauma and posttraumatic decreases in CBF. Therefore, the
investigation of the precise role of isoprostanes in injury or
ischemia could be crucial to the understanding of secondary
injury mechanisms.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants NS-27214 and NS-07288 from the National Institute for Neurological Disorders and Stroke, National Institutes of Health. The authors would like to thank Dr Enoch P. Wei for technical assistance with the rat cranial window.
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Footnotes |
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Review of this article was directed by guest editor Richard J. Traystman, PhD.
Received October 16, 1996; revision received January 14, 1997; accepted January 16, 1997.
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