(Stroke. 1997;28:2273-2280.)
© 1997 American Heart Association, Inc.
Articles |
Brain Injury Impairs ATP-Sensitive K+ Channel Function in Piglet Cerebral Arteries
From the Departments of Anesthesia and Pharmacology, University of Pennsylvania, and The Children's Hospital of Philadelphia, Philadelphia, Pa.
Correspondence to William M. Armstead, PhD, Department of Anesthesia, Children's Hospital of Philadelphia, 34th & Civic Center Blvd., Philadelphia, PA 19104.
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Abstract |
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Background and Purpose Traumatic injury is the leading cause of death for infants and children, and mortality is increased with head injury. Previous studies have shown that pial arteries constricted and that responses to several nitric oxide (NO)–dependent dilator stimuli were blunted after fluid percussion injury (FPI) in newborn pigs. Membrane potential of vascular muscle is a major determinant of vascular tone, and activity of K+ channels is a major regulator of membrane potential. Recent data show that the NO releasers sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) and 8-bromo-cGMP elicit dilation via ATP-sensitive K+ channel (KATP) activation. The present study was designed to investigate the effect of FPI on KATP channel function.
Methods Chloralose-anesthetized newborn pigs
equipped with a closed cranial window were connected to a percussion
device that consisted of a saline-filled cylindrical reservoir and a
metal pendulum. Brain injury of moderate severity (1.9 to 2.1 atm) was
produced by allowing the pendulum to strike a piston on the cylinder.
Pial artery diameter was measured with a video microscaler. Data were
analyzed by repeated measures ANOVA. An 
level of
P<.05 was considered significant.
Results FPI blunted dilation to cromakalim (10-8, 10-6 mol/L), a KATP agonist (10±1% and 27±2% versus 3±1% and 7±2% before and after FPI, respectively, n=8). Similarly, FPI blunted dilation to calcitonin gene–related peptide, an endogenous KATP activator. FPI also blunted dilator responses to SNP, S-nitroso-N-acetylpenicillamine, and 8-bromo-cGMP (10-6 to 10-8 mol/L) (10±1% and 20±1% versus 2±1% and 8±2% for SNP before and after FPI; 9±1% and 16±1% versus 2±1% and 4±1% for 8-bromo-cGMP before and after FPI, respectively, n=8). In contrast, responses to papaverine and brain natriuretic peptide were unchanged after FPI.
Conclusions These data show that KATP channel function is impaired after FPI. Furthermore, these data suggest that impaired function of mechanisms distal to NO synthase contribute to altered cerebral hemodynamics after FPI.
Key Words: newborn • cerebral circulation • pigs • nucleotides, nitric oxide
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Traumatic injury is the leading cause of death for infants and children, and the presence of head injury greatly increases mortality.1 Morbidity and mortality of head-injured infants are particularly severe because they either die from this injury or become neurologically crippled.2 FPI is an experimental model for blunt head trauma.3 Previous studies have shown that FPI resulted in pial arterial vasoconstriction and decreased cerebral blood flow within 10 minutes of injury in newborn pigs.4 Additionally, responses to several NO-dependent dilator stimuli were blunted after FPI in piglets.5 6 7 However, little is currently known about the mechanism of control of the cerebral circulation in the newborn after traumatic brain injury.
Relaxation of blood vessels can be mediated by several mechanisms, including cGMP, cAMP, and K+ channels.8 Membrane potential of vascular muscle is a major determinant of vascular tone, and activity of K+ channels is a major regulator of membrane potential.9 Activation or opening of these channels increases K+ efflux, thereby producing hyperpolarization of vascular muscle. Mem- brane hyperpolarization closes voltage-dependent calcium channels and thereby causes relaxation of vascular muscle.9 10 Direct measurements of membrane potential and K+ current in vitro indicate that several different types of K+ channels are present in cerebral blood vessels. In addition, a number of pharmacological studies using activators and inhibitors have provided functional evidence that K+ channels, especially KATP channels, regulate tone of cerebral blood vessels in vitro and in vivo.8 While several recent studies have characterized the role of K+ channels in cerebrovascular control under physiological conditions, less is known concerning their contributions under pathological conditions.
Second messengers such as NO and cGMP may also interact with the KATP channel. For example, data from an electrophysiological study indicate that cGMP activates KATP channels in vascular smooth muscle cells obtained from the rat aorta.11 In the newborn pig, the NO releaser SNP elicits dilation that was blocked by Rp 8-bromo-cGMPs and LY 83583, protein kinase G, and soluble guanylate cyclase inhibitors, respectively, indicating that NO primarily elicits its effects via production of cGMP.12 13 In other experiments, it was observed that SNP and the cGMP analogue 8-bromo-cGMP produced pial artery dilation that was blunted by the KATP channel antagonist glibenclamide.12 Since SNP and 8-bromo-cGMP pial dilation was also observed to be unchanged after the administration of the Kca2+ channel antagonist iberiotoxin,14 these data as a whole indicate that NO elicits pial dilation via the sequential release of cGMP and opening of the KATP channel. Although recent studies indicate that generation of oxygen free radicals contributes to altered cerebral hemodynamics and blunted dilation to NO-dependent dilator stimuli,6 15 the role of more distal signal transduction mechanisms, such as impaired K+ channel function, was not considered.
Therefore, the present study was designed to investigate the effect of FPI on KATP channel function.
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Materials and Methods |
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Forty-four newborn pigs (1 to 5 days old) of either sex were used in these experiments. All protocols were approved by the Institutional Animal Care and Use Committee. Animals were anesthetized intramuscularly with ketamine hydrochloride (33 mg/kg) and acepromazine (3.3 mg). Anesthesia was maintained with
-chloralose (30 to 50
mg/kg, supplemented with 5 mg/kg per hour IV). A catheter
was inserted into a femoral artery to monitor blood pressure and to
sample blood for determination of blood gas tension and pH. Drugs to
maintain anesthesia were administered through a second
catheter placed in a femoral vein. The trachea was cannulated, and the
animals were mechanically ventilated with room air. A heating pad was
used to maintain the animals at 37°C to 38°C. A cranial window was placed into the parietal skull of these anesthetized animals. The window consists of three parts, a stainless steel ring, a circular glass coverslip, and three ports consisting of 17-gauge hypodermic needles attached to three precut holes in the stainless steel ring. For placement, the dura was cut and retracted over the cut bone edge. The cranial window was placed in the opening and cemented in place with dental acrylic. The space under the window was filled with artificial CSF of the following composition (in mg/L): KCl 220, MgCl2 132, CaCl2 221, NaCl 7710, urea 402, dextrose 665, and NaHCO 2066. This artificial CSF had the following chemistry: pH 7.33, PCO2 46 mm Hg, and PO2 43 mm Hg, which was similar to endogenous CSF. Pial arterial vessels were observed with a dissecting microscope, a television camera mounted on the microscope, and a video monitor. Vascular diameter was measured with a video microscaler.
Methods for brain FPI have been described previously.16 A device designed by the Medical College of Virginia was used. A small opening was made in the parietal skull contralateral to the cranial window. A metal shaft was sealed into the opening on top of intact dura. This shaft was connected to transducer housing, which was in turn connected to the fluid percussion device. The device itself consisted of an acrylic plastic cylindrical reservoir 60 cm long, 4.5 cm in diameter, and 0.5 cm thick. One end of the device was connected to the transducer housing, while the other end had an acrylic plastic piston mounted on O-rings. The exposed end of the piston was covered with a rubber pad. The entire system was filled with 0.9% saline (37°C). The percussion device was supported by two brackets mounted on a metal platform. FPI was induced by striking the piston with a 4.8-kg pendulum. The intensity of the blow (usually 1.9 to 2.3 atm with a constant duration of 19 to 23 milliseconds) was controlled by varying the height from which the pendulum was allowed to fall. The pressure pulse of the blow was recorded on a storage oscilloscope triggered photoelectrically by the fall of the pendulum. The amplitude of the pressure pulse was used to determine the intensity of the injury.
Protocol
Drug effects on the diameter of two types of pial
arterial vessels–small arteries (baseline diameter, 120 to
160 µm) and arterioles (baseline diameter, 50 to 70 µm)
were examined to determine whether segmental differences in the effect
of brain injury on drug-induced pial dilation could be identified. Pial
arterial vessel diameter was determined every minute for a
10-minute exposure period after infusion onto the exposed parietal
cortex of artificial CSF containing no drug and after infusion of
artificial CSF containing a drug. Typically, 1 to 2 mL of CSF was
flushed through the window over a 30-second period. Needles
incorporated into the side of the window allowed for the injection of
CSF under the window and the runoff of excess CSF. Cerebral cortical
periarachnoid CSF (300 µL) was collected by slowly infusing
artificial CSF into one side of the window and allowing the CSF under
the window to drip freely into a collection tube on the opposite
side.
Responses of arterial vessels to SNP (10-8, 10-6 mol/L; Sigma Chemical Co), SNAP (10-8, 10-6 mol/L; Research Biochemicals International), 8-bromo-cGMP (10-8, 10-6 mol/L; RBI), (-) cromakalim (10-8, 10-6 mol/L; Smith-Kline Beecham), CGRP, papaverine, and brain natriuretic peptide (all 10-8, 10-6 mol/L; Sigma) were obtained before and 1 hour after FPI. Each of the agonists was applied in an ascending concentration manner. There was a period of 20 minutes after the highest concentration of one agent was washed off before a different agent was infused. A maximum of three agonists was administered to each animal. The percent changes in artery diameter values were calculated on the basis of the diameter measured for each drug in the control period before injury for preinjury (control) values; the diameter present in the control period before drug administration after injury was used for brain injury values. To determine whether increased tone of pial vessels per se could affect responses to dilator stimuli, responses to cromakalim, CGRP, SNP, SNAP, and 8-bromo-cGMP were obtained in the absence and presence of coadministered U46619 (1 ng/mL, Upjohn). Time control experiments were conducted in a separate series of animals and were designed to obtain responses to drugs initially and then 1 hour later. Normal (0.9%) saline was used as a vehicle for all agonists, and it had been previously observed to have no effect on arterial vessel diameter.5 6 All working drugs were made fresh on the day of use.
To determine the selectivity of cromakalim and CGRP for activation of the KATP channel, responses to these agonists were obtained in the absence and presence of glibenclamide (10-6 mol/L, RBI) or iberiotoxin (10-7 mol/L, RBI), KATP, and KCa2+ channel antagonists, respectively. The stock glibenclamide solution (10-3 mol/L) was made by initially dissolving this agent in a small amount of DMSO (200 µL) and the balance (9.8 mL) in ethanol. This vehicle was then diluted 1:1000 in CSF to make the working solution. This CSF vehicle had no effect on pial artery diameter (157±3 versus 158±4 µm, n=5). The vehicle for iberiotoxin was 0.9% saline.
To determine the role of cAMP in the responses to CGRP, responses to this agonist were obtained in the absence and presence of Rp 8-bromo-cAMP (10-5 mol/L, Biolog Life Science Institute), a cAMP antagonist. Additionally, a CSF sample for cAMP analysis was collected after a 10-minute exposure to CGRP.
Cyclic Nucleotide Analysis
CSF samples collected after a 10-minute exposure to a drug were
analyzed for cAMP using scintillation proximity assay methods.
Commercially available kits for cAMP (Amersham) were used. Briefly,
this assay determines cyclic nucleotide concentration for
binding to an antiserum that has a high specificity for the cyclic
nucleotide. The antibody-bound cyclic
nucleotide is then reacted with an anti-rabbit second
antibody bound to fluoromicrospheres. Labeled cyclic
nucleotide bound to the primary rabbit antibody can then be
measured by determining the amount of light emitted by the
fluoromicrospheres. All unknowns were assayed at two dilutions.
The concentration of the unlabeled cyclic nucleotide is
calculated from the standard curve via linear regression
analysis.
Statistical Analysis
Pial artery diameter, systemic arterial pressure,
and cAMP values were analyzed with ANOVA for repeated measures.
If the value was significant, Fisher's exact test was performed. A
value of P<.05 was considered significant. The n values
reflect data for one vessel in each animal. Values are
represented as mean±SEM of absolute values or as
percentages of change from control values. Data presented as
percent change were compared by nonparametric means with
the Wilcoxon signed rank test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Influence of Glibenclamide and Iberiotoxin on Cromakalim- and CGRP-Induced Pial Artery Dilation in Uninjured Animals
Cromakalim and CGRP (10-8, 10-6 mol/L), synthetic and endogenous KATP channel agonists, respectively, elicited reproducible pial small artery (120 to 160 µm) and arteriole (50 to 70 µm) dilation (Table 1
). Cromakalim- and CGRP-induced pial
artery dilation was blocked by glibenclamide
(10-6 mol/L) (Fig 1). In contrast, responses to these
agents were unchanged after iberiotoxin (10-7
mol/L) (Fig 1). Glibenclamide and iberiotoxin, themselves, had
no effect on pial artery diameter.
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Role of cAMP in CGRP-Induced Pial Artery Dilation in Uninjured
Animals
CGRP elicited dilation that was not associated with a change in
cortical periarachnoid CSF cAMP concentration (Fig 2). Additionally, CGRP-induced pial
artery dilation was unchanged in the presence of Rp 8-bromo cAMP
(10-5 mol/L), a cAMP
antagonist (Fig 2).
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Blood Chemistry
Mean level of brain injury was 2.0±0.1 atm. Mean
arterial blood pressure decreased from 64±3 to 53±1
mm Hg within 60 minutes of brain injury, n=24. Blood chemistry values
were obtained at the beginning and end of all experiments. Values were
unchanged after FPI. These values were 7.43±0.01, 33±1, and 93±4
versus 7.43±0.01, 34±1, and 94±5 versus 7.42±0.01, 34±2, and
94±6 mm Hg for pH, PCO2, and
PO2 before injury, after brain injury, and at
the end of the experiment, respectively, n=24.
Influence of FPI on KATP Channel Agonist–Induced Pial
Artery Dilation
Cromakalim and CGRP elicited reproducible pial artery dilation as
described above. FPI blunted pial dilation produced by these agents
(Fig 3).
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Influence of FPI on NO and cGMP-Induced pial artery
dilation
The NO releasers SNP and SNAP (10-8,
10-6 mol/L) also elicited reproducible
pial small artery and arteriole dilation (Table 2). FPI blunted pial dilation produced by
these agents (Fig 4). The cGMP analogue
8-bromo cGMP similarly elicited reproducible pial dilation (Table 2)
that was also blunted by FPI (Fig 5).
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Influence of FPI on Papaverine and BNP-Induced Pial Artery
Dilation
Papaverine and BNP (10-8,
10-6 mol/L) elicited reproducible pial
dilation similar to that described for agents above. In contrast,
responses to papaverine and BNP were unchanged after FPI (Fig 6).
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Influence of FPI and U46619 on Pial Artery Diameter
FPI decreased pial small artery diameter from 158±3 to
131±3 µm within 60 minutes, n=5. Similarly, pial arteriole
diameter was decreased from 68±3 to 56±2 µm by FPI, n=5.
U46619 (1 ng/mL) decreased pial vessel diameter similar to FPI.
For example, pial small artery diameter was reduced from 144±5 to
120±7 µm, while pial arteriole diameter was decreased from
68±3 to 55±2 µm, n=5.
Influence of U46619 on KATP Channel Agonist–, NO-, and
cGMP-Induced Pial Artery Dilation
To determine whether increased tone of pial vessels per se could
effect responses to dilator stimuli, responses to cromakalim, CGRP,
SNP, SNAP, and 8-bromo-cGMP (10-8,
10-6 mol/L) were obtained in the
absence and presence of U46619 (1 ng/mL). U46619 had no effect
on dilator responses when coadministered with each of the above
agonists (Table 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Results of the present study show that FPI blunted pial artery dilation elicited by CGRP and cromakalim. Additionally, although CGRP has been linked to cAMP-dependent dilator mechanisms by others,8 results of the present study do not support this idea since pial responses were not associated with changes in cortical periarachnoid CSF cAMP and were also not altered by Rp 8-bromo-cAMP, a cAMP antagonist. Since glibenclamide blocked dilation to CGRP and cromakalim while responses were unchanged in the presence of iberiotoxin, these data indicate that these agents are selective endogenous and synthetic activators of the KATP channel, respectively, consistent with previous studies.12 14 17 Similarly, dilator responses to SNP, SNAP, and 8-bromo-cGMP were also blunted after FPI. However, responses to BNP, an activator of particulate guanylate cyclase, and the nonselective dilator papaverine were unchanged. These changes in responsiveness of pial arteries after FPI were observed in the presence of moderate vasoconstriction (
17% reduction in vessel diameter). Similar
reductions in pial artery diameter in the presence of coadministered
U46619 did not alter responses to cromakalim, CGRP, SNP, SNAP, and
8-bromo-cGMP. Thus, there were marked alterations in dilator mechanisms
that were not the result of indirect effects of increased vascular
tone. Therefore, these data indicate that KATP channel
function was selectively impaired after brain injury. Previous studies in the newborn pig have observed that SNP and 8-bromo-cGMP elicit dilation via activation of KATP channels.12 However, others do not ascribe such a role for KATP channels in NO dilation, since pial responses to SNP were unchanged by glibenclamide.18 19 While the reasons for such differences between the present and previous studies are uncertain, such observations could result from differences in species, age, or experimental conditions. Additionally, in vivo approaches to the study of ion channels are limited in that pharmacological probes can only serve as an indirect index of ion channel contribution to vascular responsiveness. It has also been observed that responses to several NO-dependent dilator stimuli, including opioids and vasopressin, were blunted after FPI and partially restored by the preadministration of oxygen free radical scavengers,6 15 indicating that impaired NO function contributes to altered cerebral hemodynamics after FPI. Since responses to SNP and 8-bromo-cGMP were also blunted after FPI, these new data suggest that impaired function of mechanisms distal to NO synthase also contribute to altered hemodynamics after FPI. Because many different substances, including opioids,20 are thought to activate K+ channels to elicit dilation, such observations, are the first to suggest that impaired K+ channel function could serve as a common mechanism for altered cerebral hemodynamics after FPI. However, impaired functionality after brain injury is not nonspecific, since responses to BNP and the nonselective dilator papaverine were unchanged.
KATP channel activation has previously been observed to be involved in the control of the cerebral circulation. For example, an outward K+ current has been reported to produce dilation of dispersed cerebral artery smooth muscle cells,21 whereas KATP channel openers have been observed to cause dilation of isolated basilar and middle cerebral arteries.22 Moreover, in vivo studies support the idea that KATP channels are present in cerebral arterioles.23 On the other hand, it has also been reported that KATP channel openers such as cromakalim do not dilate cerebral arteries.24
Several substances have been suggested to be endogenous activators of KATP channels. In the cerebral circulation, pial arteries have been shown to be innervated by CGRP-containing nerve fibers.25 CGRP produces hyperpolarization of cerebral vascular muscle in vitro,26 while dilator responses of cerebral arteries are inhibited by glibenclamide, a KATP channel antagonist, indicating that dilation is mediated by the opening of this K+ channel.17
While characterizing the selectivity of cromakalim and CGRP for activation of the KATP channel in the present study, it was observed that iberiotoxin had no effect on pial artery diameter. The present data are similar to those of Taguchi et al who showed that iberiotoxin and charybdotoxin had little effect on cerebral arterioles in the adult rabbit.27 However, these data are in contrast to those obtained in vitro where inhibitors of the KCa2+ channel produce depolarization and vasoconstriction.28 29 The difference in magnitude of influence of these channels on basal tone in the present and previous studies may relate to segmental differences (large versus small cerebral vessels) or to experimental conditions (in vitro versus in vivo).
K+ channels appear to contribute to the physiological regulation of the cerebral circulation. For example, hypoxia produces relaxation of cerebral arteries in vitro and in vivo that may involve activators of K+ channels. In vitro, relaxation of carotid arteries and large cerebral arteries during hypoxia is inhibited by glibenclamide, which indicates a role of KATP channels.30 In vivo, KATP channel activation contributes to hypoxic cerebral vasodilation in the adult rabbit and newborn pig.20 Additionally, dilation of cerebral arterioles in response to hypercapnia31 or hypotension32 was observed to be inhibited by glibenclamide. Although such in vivo studies could be simplistically interpreted as evidence for the primary role of vascular smooth muscle cells in K+ channel function, the more probable scenario should reflect the dynamic interaction/modulation by endothelium, perivascular nerves, glial cells, and vascular smooth muscle in determining the overall vascular response. However, the present whole animal experimental design does not allow one to draw any conclusions with respect to the cell type affected by topically applied agents.
While several recent studies have characterized the role of K+ channels in cerebrovascular control under physiological conditions, less is known concerning their contributions under pathological conditions. Dilation of pial arteries in response to RP52891, a KATP channel activator, was observed to be impaired in diabetic rats,23 while basilar artery dilation to aprikalim, another KATP agonist, was blunted in stroke-prone spontaneously hypertensive rats.33 In the latter study, responses to forskolin and SNP were unchanged, indicating that adenylate cyclase–and guanylate cyclase–linked mechanisms were not altered in this rat model of hypertension. More recently, global ischemia has been observed to impair pial artery responses to CGRP and aprikalim in piglets, indicating that impairment of KATP channel function can be achieved by an acute stimulus.34 35 Again, in the latter study, responses to SNP were also unchanged after global ischemia. In contrast, responses to aprikalim and CGRP were augmented in a rat model of subarachnoid hemorrhage, while responses to SNP were decreased and those to 8-bromo-cGMP unchanged, indicating that KATP channel function was preserved but production of cGMP, and not its action, blunted responses in this injury model.36 The above studies exemplify the importance of the KATP channel in pathological conditions but also emphasize the lack of understanding concerning the relationship between altered K+ channel function and altered responses to other second messengers, such as NO and cGMP. Results of the present study, therefore, are the first to document the effect of brain injury on KATP channel function and the relationship of this observation to impaired NO function after this insult. Although mechanisms for impaired KATP channel function after brain injury are uncertain, such impairment could relate to brain injury–associated release of endothelin,37 a purported inhibitor of the KATP channel in vitro.38 Alternatively, brain injury could alter the number or binding of K+ channels available for activation, the degree of hyperpolarization that subsequently occurs, or the ultimate response to hyperpolarization itself.
Although many studies have characterized the hemodynamic effects of brain injury in adult animal models, few have done so in the newborn-to-infant time period. Results of recent studies show that developmental changes result in markedly different effects of brain injury on cerebral hemodynamics in newborn and juvenile pigs.4 For example, the following were observed: (1) pial vessels constricted more and cerebral blood flow falls and remains depressed longer in newborn than juvenile pigs. (2) There are marked increases in intracranial pressure in the newborn, but modest increases in intracranial pressure in the juvenile pig; and (3) differences in cerebral oxygenation, an index of metabolism; increased saturation followed by prolonged desaturation of hemoglobin for oxygen in the newborn and modest increases in saturation followed by mild desaturation in the juvenile.4 Furthermore, systemic arterial pressure has been observed to increase in studies in the adult pig16 and in juvenile pigs,4 whereas systemic arterial pressure decreases after brain injury in the newborn pig.4 These data suggest that cerebral and systemic hemodynamic responses after brain injury are age dependent. In fact, it has been suggested previously that the newborn is exquisitely sensitive to brain injury.4 Because both newborn pigs and children less than 1 year of age have skulls with unfused sutures, the age period of pigs chosen in these studies may approximate the newborn-to-infant time period in humans.
In conclusion, results of the present study are the first to show that KATP channel function is impaired after brain injury. Furthermore, these data suggest that impaired function of mechanisms distal to NO synthase contributes to altered cerebral hemodynamics after brain injury.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by grants from the National Institutes of Health and the American Heart Association. W.M. Armstead is an Established Investigator of the AHA. The authors thank Joseph Quinn for technical assistance in the performance of the experiments.
Received January 27, 1997; revision received June 11, 1997; accepted July 18, 1997.
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References |
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1. Colombani PM, Buck JR, Dudgeon DL, Miller D, Hiller JA. One year experience in a regional pediatric trauma center. J Pediatr Surg. 1985;20:8-13.[Medline] [Order article via Infotrieve]
2. Duhaime AC, Gennarelli TA, Thibault LE, Bruce DE, Margulies SS, Wiser R. The shaken baby syndrome: a clinical pathological and biochemical study. J Neurosurg. 1987;66:409-415.[Medline] [Order article via Infotrieve]
3. Gennarelli TA. Animate models of human head injury. J Neurotrauma. 1994;11:357-368.[Medline] [Order article via Infotrieve]
4. Armstead WM, Kurth CD. Different cerebral hemodynamic responses following fluid percussion brain injury in the newborn and juvenile pig. J Neurotrauma. 1994;11:487-497.[Medline] [Order article via Infotrieve]
5.
Thorogood MC, Armstead WM. Influence of brain
injury on opioid-induced pial artery vasodilation.
Am J Physiol. 1995;269:H1776–H1783.
6.
Armstead WM. Influence of brain injury on
vasopressin induced pial artery vasodilation: role of superoxide
anion. Am J Physiol. 1996;270:H1272–H1278.
7. Devine JO, Armstead WM. The role of nitric oxide in opioid-induced pial artery vasodilation. Brain Res. 1995;675:257-263.[Medline] [Order article via Infotrieve]
8.
Kitazono T, Faraci FM, Taguchi H, Heistad DD.
Role of potassium channels in cerebral blood vessels.
Stroke. 1995;26:1713-1723.
9.
Nelson MT, Quayle JM.
Physiological roles and properties of potassium
channels in arterial smooth muscle. Am J
Physiol. 1995;268:C799–C822.
10.
Nelson MT, Potlak JB, Worley JF, Standen NB.
Calcium channels, potassium channels and voltage dependence of
arterial smooth muscle tone. Am J
Physiol. 1990;259:C3–C18.
11.
Kubo M, Nakaya Y, Matsuoka S, Saito K, Kuroda Y.
Atrial natriuretic factor and isosorbide dinitrate modulate
the gating of ATP-sensitive K+ channels in cultured
vascular smooth muscle cells. Circ Res. 1994;74:471-476.
12.
Armstead WM. Role of ATP-sensitive
K+ channels in cGMP-mediated pial artery
vasodilation. Am J Physiol. 1996;270:H423–H426.
13.
Wilderman MJ, Armstead WM. Relationship between
nitric oxide and opioids in hypoxia-induced pial
vasodilation. Am J Physiol. 1996;270:H869–H874.
14.
Armstead WM. Role of activation of calcium
sensitive K+ channels in nitric oxide and hypoxia
induced pial artery vasodilation. Am J Physiol. 1997;272:H1785-H1790.
15. Thorogood MC, Armstead WM. Influence of polyethylene glycol superoxide dismutase/catalase on altered opioid-induced pial artery dilation after brain injury. Anesthesiology. 1996;84:614-625.[Medline] [Order article via Infotrieve]
16.
Wei EP, Dietrich WD, Povlishock JT, Navari RM, Kontos
HA. Functional, morphological, and metabolic
abnormalities of the cerebral microcirculation after concussive brain
injury in cats. Circ Res. 1980;46:37-47.
17.
Kitazono T, Heistad DD, Faraci FM. Role of ATP
sensitive K+ channels in CGRP-induced dilation of basilar
artery in vivo. Am J Physiol. 1993;265:H581–H585.
18. Bari F, Errico RA, Louis TM, Busija DW. Interaction between ATP-sensitive K+ channels and nitric oxide on pial arterioles in piglets. J Cereb Blood Flow Metab. 1996;16:1158-1164.[Medline] [Order article via Infotrieve]
19.
Kontos HA, Wei EP. Arginine analogues inhibit
responses mediated by ATP-sensitive K+ channels.
Am J Physiol. 1996;271:H1498–H1506.
20.
Shankar V, Armstead WM. Opioids contribute to
hypoxia-induced pial artery dilation through activation of
ATP-sensitive K+ channels. Am J
Physiol. 1995;269:H997–H1002.
21. Bonnet P, Rusch NJ, Harder DR. Characterization of outward K+ current in freshly dispersed cerebral arterial muscle cells. Pfleugers Arch. 1991;418:292-296.[Medline] [Order article via Infotrieve]
22.
Nagao T, Sadosima S, Kamouchi M, Fujishima M.
Cromakalim dilates rat cerebral arteries in vitro.
Stroke. 1991;22:221-224.
23.
Mayhan WG, Faraci FM. Responses of cerebral
arterioles in diabetic rats to activation of ATP sensitive potassium
channels. Am J Physiol. 1993;265:H152–H157.
24.
McCarron JG, Quayle JM, Halpern W, Nelson MT.
Cromakalim and pinacidil dilate small mesenteric arteries, but not
small cerebral arteries. Am J Physiol. 1991;261:H287–H291.
25. Edvinsson L, Ekman R, Jansen I, McCulloch J, Uddman R. Calcitonin gene related peptide and cerebral blood vessels: distribution and vasomotor effects. J Cereb Blood Flow Metab. 1987;7:720-728.[Medline] [Order article via Infotrieve]
26.
Saito A, Makaki T, Uchiyama Y, Lee TJF, Goto K.
Calcitonin gene related peptide and vasodilator nerves in large
cerebral arteries of cats. J Pharmacol Exp
Ther. 1989;248:455-462.
27.
Taguchi H, Heistad DD, Kitazono T, Faraci FM.
Dilation of cerebral arterioles in response to activation of
adenylate cyclase is dependent on activation of
Ca2+-dependent K+ channels. Circ
Res. 1995;76:1057-1062.
28.
Asane M, Masuzawa-Ito K, Matsuda T, Suzuki Y, Oyama K,
Shibuya M, Sugita K. Functional role of charybdotoxin-sensitive
K+ channels in the resting state of cerebral
coronary and mesenteric arteries of the dog.
J Pharmacol Exp Ther. 1993;267:1277-1285.
29.
Brayden JE, Nelson MT. Regulation of
arterial tone by activation of calcium dependent potassium
channels. Science. 1992;256:532-535.
30.
Fredricks KT, Liu Y, Rusch NJ, Lombard JH. Role
of endothelium and arterial K+
channels in mediating hypoxic dilation of middle cerebral
arteries. Am J Physiol. 1994;267:H580–H585.
31. Faraci FM, Breese KR, Heistad DD. Cerebral vasodilation during hypercapnia: role of glibenclamide-sensitive K+ channels and nitric oxide. Stroke. 1994;25:1679-1683.[Abstract]
32. Lee WS, Kwon YJ, Yu SS, Rhim BY, Hong KW. Disturbances in autoregulatory responses of rat pial arteries by sulfonylureas. Life Sci. 1993;52:1527-1534.[Medline] [Order article via Infotrieve]
33.
Kitazono T, Heistad DD, Faraci FM. ATP-sensitive
potassium channels in the basilar artery during chronic
hypertension. Hypertension. 1993;22:677-681.
34.
Bari F, Louis TM, Meng W, Busija DW. Global
ischemia impairs ATP-sensitive K+ channel function
in cerebral arterioles in piglets. Stroke. 1996;27:1874-1881.
35.
Louis TM, Meng W, Bari F, Errica RA, Busija DW.
Ischemia reduces CGRP-induced cerebral vascular dilation in
piglets. Stroke. 1996;27:134-139.
36.
Sobey CG, Heistad DD, Faraci FM. Effect of
subarachnoid hemorrhage on dilation of rat basilar
artery in vivo. Am J Physiol. 1996;271:H126–H132.
37.
Kasemsri T, Armstead WM. Endothelin
production links superoxide generation to altered opioid
induced pial artery vasodilation following brain injury.
Stroke. 1997;28:190-197.
38.
Miyoshi Y, Nakaya Y, Wakatsuki T, Nakaya S, Fujino K,
Saito K, Inoue I. Endothelin blocks ATP-sensitive K+
channels and depolarizes smooth muscle cells of porcine
coronary artery. Circ Res. 1992;70:612-616.
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