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 α 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.
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.
Materials and Methods
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 α-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.
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.
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.
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.
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⇓).
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⇓).
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⇓).
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⇓).
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⇓).
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.
Selected Abbreviations and Acronyms
|BNP||=||brain natriuretic peptide|
|CGRP||=||calcitonin gene–related peptide|
|CSF||=||cerebral spinal fluid|
|FPI||=||fluid percussion injury|
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.
- Copyright © 1997 by American Heart Association
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