(Stroke. 1995;26:2103-2111.)
© 1995 American Heart Association, Inc.
Articles |
Prostacyclin Receptor Activation and Pial Arteriolar Dilation After Endothelial Injury in Piglets
From the Laboratory for Research in Neonatal Physiology, Department of Physiology and Biophysics, University of Tennessee, Memphis.
Correspondence to Charles W. Leffler, PhD, Department of Physiology and Biophysics, University of Tennessee at Memphis, 894 Union Ave, Memphis, TN 38163. E-mail cleffler@ physiol.utmem.edu.
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Abstract |
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Background and Purpose Both light/dye endothelial injury and indomethacin treatment inhibit hypercapnia-induced cerebral prostacyclin synthesis and pial arteriolar dilation in newborn pigs. Topical iloprost can allow hypercapnia-induced dilation of pial arterioles to occur in piglets treated with indomethacin. We addressed the hypothesis that prostacyclin receptor activation with iloprost can return the ability of pial arterioles with endothelial injury to respond to hypercapnia. We also examined whether the endothelial dependence and the permissive role of prostacyclin extended to histamine-induced dilation or are specific for hypercapnia.
Methods Experiments used chloralose-anesthetized
piglets equipped with closed cranial windows. Hypercapnia
(PaCO2 
80 mm Hg) and topically applied
histamine (10-6 and 10-5 mol/L) dilated pial
arterioles. Dilations in response to both stimuli were abolished by
light/dye treatment.
Results Simultaneous topical treatment with iloprost (10-12 mol/L, which caused no residual dilation, returned dilation of pial arterioles to both hypercapnia and histamine. On removal of iloprost, responses were again absent and returned with readdition of iloprost to the cortical cerebrospinal fluid. Neither isoproterenol nor sodium nitroprusside returned responses to hypercapnia after light/dye treatment.
Conclusions These data add further support to the hypothesis that prostacyclin represents an important endothelial-derived signal in the newborn pig cerebral circulation that can permit appropriate responses by adjacent smooth muscle in response to specific stimuli.
Key Words: cerebral circulation • histamine • hypercapnia • prostacyclins • pigs
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Introduction |
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Considerable data suggest that prostanoids, specifically prostacyclin, are involved in hypercapnia-induced cerebral vasodilation in newborn pigs.1 These prostanoids appear to be of endothelial origin since cerebral microvascular endothelial cells, but not vascular smooth muscle or glia, increase prostanoid synthesis in response to increased PCO22 and light/dye-induced endothelial injury in vivo blocks hypercapnia-induced cerebral vasodilation without markedly depressing pial arteriolar reactivity in general.3
Prostacyclin analogues and hypercapnia increase cerebral production of cAMP, and the dilation, as well as the cAMP elevation induced by hypercapnia, is blocked by indomethacin treatment.4 Thus, one might suggest that prostacyclin produced by endothelial cells activates adenylyl cyclase in adjacent vascular smooth muscle cells, causing cerebral vasodilation in response to hypercapnia. However, after indomethacin treatment prostacyclin receptor agonists, at concentrations so low that they produce no residual dilation, permit dilation in response to hypercapnia to occur in newborn pigs.5 This permissive role appears to be unique for prostacyclin receptor agonists since even dilator concentrations of isoproterenol and sodium nitroprusside are without effect. Indomethacin directly blocks prostaglandin H synthase in all the cells and also inhibits iloprost binding to cerebral microvascular smooth muscle cells as well as iloprost-induced increases in cAMP.6 Thus, the indomethacin treatment should directly and completely remove the prostacyclin influence. Whether the loss of pial arteriolar dilation to hypercapnia after endothelial injury is also due to a loss of the permissive role of prostacyclin has not been demonstrated.
Therefore, the present experiments were designed to test the hypothesis that prostacyclin receptor activation with iloprost can return the ability of pial arterioles with light/dye-induced endothelial injury to respond to hypercapnia. We also examined whether another dilator prostanoid-associated response, pial arteriolar dilation to histamine,7 was also affected by endothelial injury and involved a permissive role of prostacyclin to determine whether this mechanism is specific for hypercapnia or extends to certain other prostanoid-associated responses as well. Alternative vasodilators that activate either adenylyl cyclase (isoproterenol) or guanylyl cyclase (sodium nitroprusside)8 were evaluated additionally for ability to reestablish lost responses.
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Materials and Methods |
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All procedures that involved animals were reviewed and approved by the Animal Care and Use Committee of the University of Tennessee, Memphis. Newborn pigs (1 to 3 days old) were anesthetized with ketamine hydrochloride (33 mg/kg IM) and acepromazine (3.3 mg/kg IM) and maintained on
-chloralose (50
mg/kg IV initially plus 5 mg/kg each). The animals were intubated and
ventilated with air. Catheters were inserted in the femoral vein for
maintenance of anesthesia and blood withdrawal and
in the femoral artery to record blood pressure and draw samples for
blood gases and pH analysis. These values were maintained
within normal limits except during hypercapnic challenge. Body
temperature was maintained at 37°C to 38°C. The scalp was
retracted, and a hole 2 cm in diameter was made in the skull over the
parietal cortex. The dura was cut without touching the brain, and all
cut edges were retracted over the bone so that the periarachnoid space
was not exposed to bone or damaged membranes. A stainless steel and
glass cranial window was placed in the hole and cemented into place
with dental acrylic. The space under the window was filled with aCSF
(Na+ 150 mEq/L, K+ 3 mEq/L,
Ca2+ 2.5 mEq/L, Mg2+ 1.2 mEq/L,
Cl- 132 mEq/L, 3.7 mmol/L glucose, 6 mmol/L urea,
HCO3- 25 mEq/L; typically, pH 7.33;
PCO2 46 mm Hg; PO2 43
mm Hg) through needles incorporated into the sides of the window. The
volume of fluid directly beneath the window was 500 µL and was
contiguous with the periarachnoid space. Pial vessels were observed with a dissecting microscope. Diameters were measured with a video micrometer coupled to a television camera mounted on the microscope and a video monitor. One or two precapillary vessels were measured in each piglet. If two vessels were examined, the smaller vessel (typically 30 to 70 µm) was designated as small arteriole and the larger vessel (typically 70 to 160 µm) was designated as large arteriole for comparison of responses between smaller and larger precapillary vessels. For the purposes of the present experiments, selection of size ranges was totally arbitrary and was used solely for the purpose of comparing responses of vessels of different sizes in the same pigs.
Experimental Design
The primary experimental design consisted of initial
measurements and treatments (hypercapnia, isoproterenol, histamine,
sodium nitroprusside) and production of light/dye microvascular
injury in vivo (see below), followed by repeated hypercapnia or
histamine; application of iloprost (a gift from Schering AG
Pharmaceutical Research), isoproterenol, or sodium nitroprusside; and
repeated treatments in the presence of that agonist. When lost cerebral
vasodilation returned in the presence of iloprost, the iloprost was
removed, and the response to the cerebral dilator treatment was
examined again in the absence of the iloprost. Then iloprost was once
again applied and the cerebral dilator treatment examined again.
Treatments (hypercapnia, isoproterenol, histamine, sodium
nitroprusside) were administered for 10-minute periods with sufficient
irrigation of the space beneath the cranial window performed between
treatments to remove the previous stimulus and allow return to control
pial arteriolar diameters. Two of the four dilator treatments were used
in the same animals before and after light/dye
endothelial injury since we have repeatedly found that
effects of these treatments as administered are readily reversible and
highly reproducible over time. Hypercapnia was produced by ventilating
with a mixture of 10% CO2, 21%
O2, and 69% N2. Pial arteriolar
diameter and arterial pressure were measured. In newborn
piglets hypercapnia does not cause large or consistent changes
in arterial pressure. The most common arterial
pressure response is an initial increase of approximately 10 mm Hg
that returns to control or slightly lower by 5 minutes of hypercapnia.
Hypercapnia produces sustained vasodilation that is typically maximal
and constant from 7 to 10 minutes of treatment. Maximal dilation was
recorded as the response. At 10 minutes of hypercapnia, an
arterial blood sample for blood gases and pH
analysis was drawn. Histamine was placed beneath the cranial
window at concentrations of 10-6 and 10-5
mol/L. Dilation usually began very quickly, reaching a maximum within
minutes. The maximal vasodilation, which usually occurred within 5
minutes of application, was recorded as the response to histamine.
Isoproterenol was placed beneath the cranial window at concentrations
of 10-7 and 10-6 mol/L. Dilation typically
begins immediately and reaches a maximum within 1 to 2 minutes. The
maximal vasodilation was recorded as the response to isoproterenol.
Sodium nitroprusside was placed beneath the cranial window at a
concentration of 10-5 mol/L. Dilation occurred rapidly
during the first minutes, and the maximal vasodilation, which usually
occurred within 5 minutes of application, was recorded as the
response to sodium nitroprusside. Isoproterenol and sodium
nitroprusside were used to detect any generalized change in vascular
reactivity, because responses to isoproterenol and sodium nitroprusside
are consistent over time and not associated with prostanoids or
endothelium dependent.1 3 Since previous
studies showed that light/dye treatment did not block dilation to
isoproterenol or sodium nitroprusside, these treatments were not
administered after light/dye and before iloprost. With the omission of
these treatments the time between light/dye and the further treatments
was not as prolonged and the total duration of the experiment was
reduced, preventing deterioration of the preparation.
After light/dye treatment and hypercapnic or histamine retreatment, iloprost (10-12 mol/L), isoproterenol (10-7 mol/L), or sodium nitroprusside (10-6 mol/L) was topically applied and maintained for the remainder of the experiment; ie, all aCSF contained the agonist (except for removal and return of iloprost as described above). These doses of agonists were subthreshold to produce sustained dilation but instead produced slight (10% to 20%) transient dilation, with arterioles returning within 10 minutes to diameters that existed before treatment in the continued presence of the agonist. In other piglets, iloprost was used at concentrations of 10-13 and 10-11 mol/L. In experiments in which iloprost at 10-13 mol/L was used after light/dye initially, 10-12 mol/L iloprost was used subsequently. To determine whether iloprost affected vascular responses to hypercapnia or histamine in the absence of endothelial injury, dilation to hypercapnia was examined in the absence and presence of topical iloprost (10-12 mol/L).
Production of Endothelial
Injury
Endothelial damage in vivo was produced as
described previously in newborn pigs,3 with the use of
modifications of techniques that produced selective
endothelial damage in adult cerebral
microcirculation.9 10 Briefly, microvascular injury was
produced by activating sodium fluorescein, injected
intravenously, with appropriately filtered light from a
mercury arc lamp. Measurements of pial arterioles were made with the
use of a halogen source at low intensity that was turned off between
measurements to prevent inadvertent damage to sensitized
vessels. The mercury arc lamp was focused to produce uniform
illumination of the surface under the window. Immediately after the
change to the mercury lamp, sodium fluorescein 160 mg/kg IV
was injected (in 8 mL/kg volume). Within approximately 5 minutes,
platelet aggregates were observed, initially in veins and then in
arterioles. Adherence to endothelium was apparent, but
aggregates soon broke free as larger clumps were formed. After 9
minutes of activating light, the mercury lamp was extinguished. After
the light/dye treatment, the cranial windows were repeatedly irrigated
during a 60-minute period in darkness, at which time experimentation
was resumed. We have found that depending on the angle of the light
path and the focal distance relative to the distance to the window,
similar effects can be produced by the same light source from 30
seconds to 9 minutes. The time must be optimized to produce
endothelial dysfunction without altering vascular
reactivity in general. As described above, responses to topical
isoproterenol and sodium nitroprusside were used to assess vascular
reactivity in general.
Previously, the light/dye treatment as used in the present experiments was shown to cause ultrastructural changes in pial vascular endothelial cells.3 After light/dye treatment, vascular endothelium displayed more numerous surface pits, vacuolar cytoplasmic inclusions, and some mitochondrial damage. Tight junctions remained intact, and no evidence of endothelial sloughing was observed. In addition, no detectable damage to vascular smooth muscle was observed.
Statistical Analysis
Values for each variable are presented as mean±SEM.
Comparisons among populations used ANOVA with repeated measures.
Fisher's protected least significant difference test was used to
determine differences between groups. Significant responses to stimuli
(ie, comparisons with zero change) used t tests.
P<.05 was considered significant.
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Results |
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Data showing diameters of the larger and smaller pial arterioles as well as arterial pressures, blood gases, and pH before and after light/dye treatment in the piglets in which iloprost (10-12 mol/L) was used as the post-light/dye agonist are shown in Table 1
. With the exception of the
hypercapnic periods when PaCO2 was 80 to 90
mm Hg in this group and arterial pH was 7.05 to 7.1, the
arterial pressures, blood gases, and pH were within normal
limits for newborn pigs and not affected by interventions. Before
light/dye treatment, both hypercapnia and treatment with isoproterenol
(10-6 mol/L, topically) dilated pial arterioles. The
percent dilation caused by these treatments is shown in Fig 1. After light/dye injury, hypercapnia did not cause
dilation of pial arterioles (Table 1, Fig 1). Topical application of
10-12 mol/L iloprost did not cause any sustained change in
pial arteriolar diameter (Table 1). However, after light/dye injury, in
the presence of iloprost pial arterioles once again dilated in response
to hypercapnia (Table 1, Fig 1). Effects of light/dye injury and
iloprost after treatment were similar in larger and smaller arterioles.
The vasodilation to hypercapnia in the presence of iloprost was reduced
compared with vasodilation before light/dye treatment. However, as has
been reported previously, light/dye treatment does cause a small
generalized decrease in dilation to all agonists, including
isoproterenol.3 Therefore, compared with the relative
responses to isoproterenol before and after light/dye, the dilator
response to hypercapnia after light/dye in the presence of iloprost was
largely restored. Removal of iloprost from the CSF under the cranial
window abolished the vasodilator responses to hypercapnia, and with
return of iloprost to the aCSF the hypercapnia-induced cerebral
vasodilation returned (Table 1, Fig 1). Increasing the amount of
iloprost to 10-11 mol/L caused no further increase in
responsiveness to hypercapnia over 10-12 mol/L (Table 2). A lower dose of iloprost (10-13 mol/L)
did not return the dilation to hypercapnia after light/dye treatment
(Table 3).
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Iloprost (10-12 mol/L) had no effect on responses to hypercapnia or histamine in control piglets (not treated with light/dye). Thus, the increase in pial arteriolar diameter in response to hypercapnia (PaCO2=72±5 mm Hg) was 66±5% in the absence and 67±5% in the presence of iloprost. The dilation to histamine (10-6 mol/L) was 30±5% in the absence and 29±5% in the presence of iloprost (10-12 mol/l) (13 arterioles in 5 piglets).
In contrast to iloprost, treatment with topical isoproterenol did not
return hypercapnia-induced cerebral vasodilation after light/dye
injury. Thus, as shown in Table 4 and Fig 2, before light/dye treatment both hypercapnia and
topical application of sodium nitroprusside produce similar
vasodilation of piglet pial arterioles. Light/dye microvascular
injury abolished hypercapnia-induced cerebral vasodilation.
Although significant vasodilation occurred in response to hypercapnia
in the presence of isoproterenol, the response was less than 25% of
that before light/dye injury. In contrast, the responses to topical
application of sodium nitroprusside were only slightly reduced compared
with the response before injury. Removal of isoproterenol and
replacement with iloprost returned cerebral vasodilation in response to
hypercapnia to light/dye-injured pial arterioles (Table 4, Fig 2).
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Similar to isoproterenol, topical application of sodium nitroprusside
did not return hypercapnia-induced cerebral vasodilation to
light/dye-injured pial arterioles (Table 5, Fig 3). Removal of sodium nitroprusside and
replacement with iloprost returned vasodilation to hypercapnia to
levels similar to those produced by topical application of
10-6 mol/L isoproterenol after light/dye injury.
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Vasodilation in response to topical application of histamine was also
inhibited by light/dye microvascular injury and once again occurred on
coadministration of iloprost (Table 6, Fig 4). Thus, before light/dye microvascular
damage, histamine produced dose-dependent dilation of newborn pig
arterioles. Isoproterenol also produced dose-dependent dilation.
After light/dye microvascular injury, histamine did not produce
significant vasodilation. Responses to isoproterenol are not greatly
affected by light/dye treatment.3 Topical application of
iloprost (10-12 mol/L) largely restored pial arteriolar
dilation in response to histamine to a dilation similar to that
produced by isoproterenol. Removal of the iloprost again prevented
vasodilation in response to histamine after light/dye microvascular
injury, and readministration of iloprost once again allowed pial
arteriolar dilation in response to histamine. As in the case of
hypercapnia, the lower dose of iloprost (10-13 mol/L) did
not return dilation to histamine after light/dye treatment (Table 3
).
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Discussion |
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Hypercapnia-induced pial arteriolar dilation lost after light/dye microvascular injury is returned by treatment with the prostacyclin receptor agonist iloprost at concentrations below those that produce sustained dilation. Light/dye injury also inhibits histamine-induced dilation, suggesting endothelial dependence of this response. As in the case of hypercapnia, after light/dye microvascular injury, dilation to histamine occurs in the simultaneous presence of iloprost. Neither isoproterenol nor sodium nitroprusside are effective in returning these lost responses. These data add further support to the hypothesis that prostacyclin represents an important endothelial-derived signal in the newborn pig cerebral circulation that can permit appropriate responses by adjacent smooth muscle to specific stimuli. We speculate that the physiological significance of such a signal may be communication to the vascular smooth muscle of the existence of a properly functioning endothelium. The short half-life of prostacyclin may explain why active prostanoid synthesis is necessary for cerebral vasodilation to occur in response to some stimuli associated with prostanoids.
Specific responses of the newborn pig pial arterioles are associated with increases in cerebral synthesis of dilator prostanoids and can be blocked by prior treatment with the prostaglandin H synthase inhibitor and prostacyclin receptor antagonist6 indomethacin.1 In newborn pigs, hypercapnia-induced pial arteriolar dilation is endothelium dependent,3 and the prostanoids produced in response to hypercapnia appear to be endothelial in origin.2 Histamine is another vasodilator stimulus that produces an increase in cerebral prostanoid synthesis and pial arteriolar dilation, both of which are blocked by indomethacin pretreatment in the newborn pig.7 The present study indicates that this response as well appears to be endothelial dependent. Hypercapnia and iloprost both produce vasodilation that is accompanied by an increase in cortical periarachnoid CSF cAMP.4 It had been assumed that augmented dilator prostanoid synthesis produced by prostanoid-associated stimuli caused receptor-mediated activation of adenylyl cyclase in smooth muscle leading to vasodilation. However, the recent finding that iloprost at a constant concentration that did not produce sustained dilation and was not associated with detectable increases in cAMP could return hypercapnia-induced pial arteriolar dilation to piglets pretreated with indomethacin5 clearly indicates that this assumption was not correct. The present study ties the endothelial-dependent concept to that of a permissive role of prostacyclin and also indicates that this permissive function is not unique to vasodilation in response to hypercapnia.
Extensive discussion regarding light/dye microvascular injury and the selective elimination of hypercapnia-induced pial arteriolar dilation3 as well as potential mechanisms involved in the permissive role of prostacyclin in cerebral vasodilation to hypercapnia5 can be found in previous reports. Briefly, available data are consistent with the hypothesis that cerebral vascular responses associated with dilator prostanoids represent endothelial-dependent responses in the newborn pig cerebral circulation.2 3 Of course, demonstration that injury caused by light/dye treatment is limited to the endothelium alone is not possible. However, reductions in responses to two stimuli not associated with prostanoids, isoproterenol and sodium nitroprusside, were minor in comparison to the total abolition of responses to hypercapnia and histamine. Therefore, the loss of vasodilation to these later two stimuli could not be explained by a simple loss of responsiveness. In adults of several species, including humans, EDRF-NO appears to be an important endothelial-dependent vasodilator signal in the regulation of cerebral circulation.9 11 12 13 14 In contrast, in the newborn pig cerebral circulation the role of EDRF-NO is less clear, and dilator prostanoids appear to be much more dominant than in older animals. Such a role for prostanoids appears to extend to premature newborn human infants.15 16 17 There are additional examples of apparent permissive roles between signaling mechanisms in control of the cerebral circulation,18 19 including such a role for EDRF-NO in cerebral vasodilation to hypercapnia in adult rats.20 EDRF-NO has even been shown to play a permissive role under certain circumstances in coronary artery contraction.21 The mechanisms by which prostacyclin receptor agonists alter responses of vascular smooth muscle to specific stimuli are yet to be established and will certainly require investigation at the cellular level. These mechanisms could involve potentiation, synergism, or activation of a detection or response system. However, failure of increasing concentrations of iloprost to accentuate further the dilation to hypercapnia would seem to argue against a synergistic mechanism. Also, the inability of isoproterenol and sodium nitroprusside to restore lost responses indicates that simply elevating vascular smooth muscle cyclic nucleotides will not reestablish responsiveness to either hypercapnia or histamine. For further discussion of these points, please see References 3 and 5.
Recently, it has been reported that NO contributes to cerebral
vasodilation in response to topical prostaglandin
I2 and prostaglandin E2 in newborn
pigs.22 Cerebral cGMP, but not cAMP, production
and vasodilation in response to the prostanoids were considerably
attenuated by cotreatment with
N
-nitro-L-arginine. These data, coupled with
the present data that sodium nitroprusside will not substitute for
the permissive role of prostacyclin and previous data that NO synthase
inhibitors have no effect on cerebral vasodilation to
hypercapnia4 in piglets, further illustrate the dichotomy
of mechanisms involved in direct vasodilation and the permissive
actions of prostacyclin.
Whether endothelially derived prostacyclin directly produces vasodilation of adjacent vascular smooth muscle by large increases in vascular smooth muscle cAMP or by NO-cGMP under any physiological or pathological conditions is not known. However, in the cases of both hypercapnia-induced and histamine-induced cerebral vasodilation in piglets, current evidence suggests that the role of prostacyclin receptor activation is purely a permissive one that alters cerebral microvascular vasoreactivity in response to the other stimuli. The expanding evidence that prostanoids can affect responses by acting permissively rather than as direct mediators should alter our conception of the potential functional roles of prostanoids in the cardiovascular system. We wonder whether other endothelial-derived vasoactive factors can play similar permissive roles (as mentioned above for EDRF-NO in the adult cerebral and coronary circulation), possibly providing intercellular communication of endothelial function, in specific vascular beds as well.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the National Institutes of Health (HL-34059 and HL-42851). We thank Stanley Lopez and Mildred Jackson for their help in the laboratory, Maria Swayze for her help with the manuscript, and Laura Malinick and Danny Morse for their help with the figures.
Received May 31, 1995; revision received July 25, 1995; accepted July 28, 1995.
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P. A. Parkinson, H. Parfenova, and C. W. Leffler Phospholipase C Activation by Prostacyclin Receptor Agonist in Cerebral Microvascular Smooth Muscle Cells Experimental Biology and Medicine, January 1, 2000; 223(1): 53 - 58. [Abstract] [Full Text]
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C. W. Leffler, L. Balabanova, and K. K. Williams cAMP production by piglet cerebral vascular smooth muscle cells: pHo, pHi, and permissive action of PGI2 Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1878 - H1883. [Abstract] [Full Text] [PDF]
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A. P. Willis and C. W. Leffler NO and prostanoids: age dependence of hypercapniaand histamine-induced dilations of pig pial arterioles Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H299 - H307. [Abstract] [Full Text] [PDF]
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 S.-S. Bolz and U. Pohl Indomethacin enhances endothelial NO release -- evidence for a role of PGI2 in the autocrine control of calcium-dependent autacoid production Cardiovasc Res, December 1, 1997; 36(3): 437 - 444. [Abstract] [Full Text] [PDF]
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