Effects of Ischemia on Cerebral Arteriolar Dilation to Arterial Hypoxia in Piglets
Background and Purpose—Arterial hypoxia mediates cerebral arteriolar dilation primarily via mechanisms involving activation of ATP-sensitive K+ channels (KATP), which we have shown to be sensitive to ischemic stress. In this study, we determined whether ischemia/reperfusion alters cerebral arteriolar responses to arterial hypoxia in anesthetized piglets. Since adenosine plays an important role in cerebrovascular responses to hypoxia, we also determined whether adenosine-induced arteriolar dilation is affected by ischemic stress. We tested the hypothesis that reductions in cerebral arteriolar dilator responses after ischemia would be proportional to the contribution of KATP to hypoxia and adenosine.
Methods—Pial arteriolar diameters were measured using a cranial window and intravital microscopy. We examined arteriolar responses to arterial hypoxia (inhalation of 8.5% and 7.5% O2), to topical adenosine (10–5 and 10–4 mol/L) and to arterial hypercapnia (inhalation of 5% and 10% CO2 in air) before and after 10 minutes of global ischemia. Ischemia was achieved by increasing intracranial pressure. Arterial hypercapnia was used as a positive control for the effectiveness of the ischemic insult. In addition, we evaluated cerebral arteriolar responses to 10–5 and 10–4 mol/L adenosine applied topically with or without glibenclamide, a selective inhibitor of KATP (10–5 and 10–6 mol/L). Finally, we administered theophylline (20 mg/kg, IV) to assess the contribution of adenosine to cerebral arteriolar dilation to arterial hypoxia.
Results—Before ischemia, cerebral arterioles dilated by 19±3% to moderate and 29±4% to severe hypoxia (n=7; P<.05); 13±2% to 10–5 and 20±1% to 10–4 mol/L adenosine (n=9; P<.05); and by 17±2% to moderate and 28±3% to severe hypercapnia (n=6; P<.05). After ischemia, cerebral arteriolar responses to hypoxia and adenosine were unchanged. In contrast, cerebral arteriolar dilation to hypercapnia was impaired by ischemia (1±1% and 2±1% at 1 hour; n=6). Glibenclamide reduced cerebral arteriolar dilation to adenosine by approximately one half (n=7). In addition, blockade of adenosine receptors by theophylline (20 mg/kg, IV) almost totally suppressed cerebral arteriolar dilation to arterial hypoxia (n=6).
Conclusions—Cerebrovascular responsiveness is selectively affected by anoxic stress. In addition, cerebral arteriolar dilation to hypoxia and adenosine is maintained after ischemia despite the expected impairment in KATP function.
Arterial hypoxia is a potent dilator stimulus in the cerebral circulation. Previous studies have provided evidence that adenosine, nitric oxide, prostanoids, opioids, and/or vasopressin promote cerebrovascular dilation to arterial hypoxia.1 2 3 4 5 6 7 8 9 10 11 12 The relative contribution of these substances to hypoxia-induced cerebrovascular dilation probably reflects differences in the species studied, the experimental approaches, and the variability of the severity and duration of hypoxic challenge.10 However, several lines of evidence indicate that an elevation of interstitial adenosine concentration is critical to eliciting hypoxic dilation of pial arterioles in newborn pigs.4 7 9 Furthermore, activation of KATP may mediate a substantial part of the cerebrovascular dilation to arterial hypoxia.4 12 13 This conclusion is based on the finding that application of selective KATP blockers attenuates cerebral arteriolar dilation to arterial hypoxia4 13 14 as well as to adenosine.4 In general, inhibition of KATP reduces cerebral arteriolar dilation to arterial hypoxia or adenosine by approximately 50%.
In recent studies, we showed that KATP function in cerebral arterioles is impaired after ischemia. Thus, pial arteriolar dilations in piglets to aprikalim, CGRP, and iloprost, pharmacological and physiological activators of KATP, are largely absent 1 to 2 hours after 10 minutes of total global ischemia.15 16 In contrast, ischemia fails to alter cerebrovascular dilation to several stimuli that are not dependent on activation of KATP.15 17
The purpose of this study was to examine the effects of ischemia on cerebral arteriolar dilation to arterial hypoxia in piglets. This is an important issue because derangements of arterial blood gases and local ischemia often occur after successful resuscitation of babies that follows anoxic stress. In addition, we examined the effects of ischemia on cerebral arteriolar dilation to adenosine. Topical adenosine allows assessment of effects of ischemia on a major component of the arteriolar dilator response to arterial hypoxia4 7 9 without the presence of other, possibly complicating features, of hypoxia. We tested the hypothesis that ischemia-induced reductions in cerebral arteriolar dilation to arterial hypoxia and adenosine would be in proportion to dependence of these dilator responses to KATP. In addition, we also examined the effects of ischemia on arteriolar dilation to arterial hypercapnia to validate the potency of the ischemic stress.18
Materials and Methods
Experiments were carried out on newborn pigs (1 to 7 days old) of either sex weighing 1 to 2 kg. The procedures used in this study were approved by the Institutional Animal Care and Use Committee. The piglets were anesthetized with sodium thiopental (30 mg/kg, IP) and then α-chloralose (75 mg/kg, IV). Additional α-chloralose was given as needed to maintain a stable level of anesthesia. The piglets were intubated and artificially ventilated. A femoral artery and vein were cannulated with PE-90 tubing. Arterial blood pressure, blood gas values, and pH were maintained within the normal physiological range. Each piglet’s head was fixed in a stereotaxic apparatus, the scalp was cut, and the connective tissue over the parietal bone was removed. A craniectomy (19 mm in diameter) was made in the parietal bone. The dura was cut and reflected over the skull. A stainless steel and glass cranial window with three ports was put into the opening, sealed with bone wax, and cemented with cyanoacrylate ester followed by one or two layers of dental acrylic. The closed window was filled with aCSF that was warmed to 37°C and equilibrated with 6% O2, 6.5% CO2, balance N2. Arterioles were observed using a microscope (Wild M36) equipped with a television camera (Panasonic), and arteriolar diameters were measured with a video microscaler (IV-550, For-A Co).
Cerebral Ischemia-Reperfusion Injury
Cerebral ischemia-reperfusion injury was produced as described previously.15 17 In brief, a hollow brass bolt was implanted into the right parietal cranium 20 mm rostral to the cranial window. Immediately after placement of the cranial window, a 3-mm hole was drilled in the skull using an electric drill with a toothless bit, and the dura was exposed. A hollow bolt was inserted and secured in place with cyanoacrylate ester and dental acrylic. After implantation of the window and the bolt, aCSF was allowed to equilibrate with the periarachnoid CSF under the window for 20 minutes. To induce ischemia, aCSF was infused to maintain intracranial pressure above mean arterial pressure so that blood flow through pial vessels was stopped. Venous blood was withdrawn as necessary to maintain mean arterial blood pressure near normal values. At the end of the 10-minute period of ischemia, the infusion tube was clamped, and the intracranial pressure was allowed to return to preischemia values.
Interaction Between Global Ischemia and Arterial Hypoxia
At the beginning of each experiment, the cranial window was flushed with aCSF several times. Then, cerebral arteriolar responses were determined to two levels of arterial hypoxia (administration of 7.5% and 8.5% O2 in nitrogen). The exposure to each level of gas was limited to 3 to 4 minutes for two reasons. First, a 3- to 4-minute period of arterial hypoxia is sufficient to achieve maximal arteriolar dilation in piglets, as described by Leffler et al.19 And, second, repeated exposure to longer periods of arterial hypoxia might compromise the cerebral circulation when combined with ischemia. Animals were subsequently divided into either sham (n=6) or ischemia (n=7) groups. Animals in the sham group were exposed to two levels of hypoxia 1 hour after the first exposure. In the ischemia group, after recovery, animals were exposed to cerebral ischemia for 10 minutes. At 1, 2, and 4 hours after ischemia, cerebral arteriolar responses were again examined at both levels of arterial hypoxia.
Interaction of Ischemia with the Vasodilation to Adenosine
We examined pial arteriolar diameter changes after topical application of adenosine (at 10–5 and 10–4 mol/L). In one group of animals, we determined whether arteriolar responses to adenosine are reproducible over time (n=6). Each dose of adenosine in aCSF was introduced into the window, the infusion was stopped, and pial arteriolar diameters were recorded over the next 5 to 10 minutes. In a separate group, cerebral arteriolar responses to topical adenosine (n=9) were determined before and 1 hour after ischemia.
Contribution of KATP to Adenosine-Evoked Arteriolar Dilation
In two separate groups of animals we monitored the effect of glibenclamide on adenosine-evoked cerebral arteriolar responses. We performed these experiments because the contribution of KATP in mediating adenosine-induced dilation is controversial.4 13 In one group (n=6), we applied glibenclamide topically in a concentration of 10–6 mol/L. The concentration of glibenclamide was 10–5 mol/L in the other group. These doses selectively inhibit KATP function.13 14 15 16 Glibenclamide was dissolved in dimethyl sulfoxide. The concentration of dimethyl sulfoxide was less than 0.1%, which is below the vasoactive range. Glibenclamide was applied topically 5 minutes before the adenosine administration. Then, the two drugs were applied together. We13 14 15 16 and others21 22 have shown previously that these doses of glibenclamide given in this way are effective and specific in blocking cerebral arteriolar dilation to aprikalim, a selective activator of KATP.
Blockade of Adenosine Receptors During Hypoxia
We determined cerebral arteriolar dilator responses during arterial hypoxia before and 15 minutes after intravenous administration of theophylline (20 mg/kg) (n=6). We did these experiments because the contribution of adenosine to cerebral arteriolar dilation in piglets is controversial.19 To document effectiveness of blockade, we also determined dilator responses to topical adenosine (10–5 and 10–4 mol/L) before and after administration of theophylline (n=4).
Interaction between Ischemia and Arterial Hypercapnia
As a positive control, effects of ischemia on arteriolar responses to arterial hypercapnia were examined. In the ischemia group (n=6), pial arteriolar responses to arterial hypercapnia (5% and 10% CO2 in air) were examined before and 1, 2, and 4 hours after ischemia. Piglets were exposed to each level of gas for at least 10 minutes. In the sham group (n=4), the hypercapnic challenge was repeated at 1, 2, and 4 hours after the first hypercapnic episodes.
All values are expressed as mean± SEM. When appropriate, data were analyzed using the paired t test or repeated measures ANOVA, or one way ANOVA. When the F value was significant, pair-wise comparisons were made using the Student-Newman-Keuls test. A value of P<.05 was considered statistically significant.
Arterial hypoxia dilated pial arterioles in a dose-dependent fashion (Table 1⇓; Fig 1⇓). Repeated hypoxia resulted in reproducible cerebral arteriolar dilation over time without altering baseline diameters (Table 1⇓).
Baseline arteriolar diameters were not different at 1, 2, or 4 hours after ischemia (Table 1⇑). Cerebral arteriolar dilation to hypoxia was not significantly reduced at 1, 2, or 4 hours after ischemia (Table 1⇑; Fig 1⇑).
Adenosine caused dose-dependent pial arteriolar dilation (Table 2⇓; Fig 2⇓). Repeated application of adenosine resulted in reproducible cerebral arteriolar dilation over time without altering baseline diameters (Table 2⇓). As shown in Fig 2⇓, pial arteriolar dilation to adenosine was unaffected by ischemia.
Topical application of glibenclamide in concentrations of 10–6 or 10–5 mol/L did not change baseline pial arteriolar diameters (Table 2⇑). In the two groups, before application of the KATP antagonist, baseline diameters were 104±2 and 101±3 μm, and diameters were 106±2 and 100±4 μm 5 minutes later, respectively, for the two concentrations. Cerebral arteriolar dilation to adenosine was reduced by approximately one half at either dose of glibenclamide (Table 2⇑).
Pial arteriolar dilator responses to hypoxia were reduced after intravenous administration of theophylline. At 15 minutes after administration of theophylline, cerebral arteriolar diameters were not different from baseline values (103±3 versus 101±2 μm). Before theophylline, inhalation of 8.5% O2 resulted in pial arteriolar dilation of 25±4%. Theophylline administration resulted in an attenuated cerebral arteriolar dilation to hypoxia (7±2% above baseline level; P<.05).
Arterial hypercapnia caused repeatable, dose-dependent pial arteriolar dilation (Table 3⇓). However, ischemia reduced cerebral arteriolar responses to hypercapnia for up to 4 hours.
The major new finding is that ischemia does not alter cerebral arteriolar dilation to arterial hypoxia and to adenosine in piglets. Thus, despite a substantial contribution of KATP to arteriolar dilation to hypoxia and adenosine, normal responsiveness is intact. In contrast to arterial hypoxia and adenosine, cerebral arteriolar dilation to arterial hypercapnia is reduced by ischemia. Thus, cerebrovascular responses to arterial hypoxia and arterial hypercapnia, two stimuli commonly used to elicit cerebral arteriolar dilation as well as individual components of asphyxia, are differentially sensitive to anoxic stress.
As shown in numerous studies, arterial hypoxia activates multiple mechanisms that influence cerebrovascular tone. The relative contribution of various mechanisms of hypoxic vasorelaxation vary over time and depend on the severity of hypoxia. There is now a consensus that the release and effects of adenosine determine the majority of the cerebral vasodilator response to hypoxia in piglets.4 7 9 For example, adenosine concentrations in brain interstitial and cerebrospinal fluids increase to the vasodilator range within the first minutes of hypoxia.7 9 In addition, adenosine receptor antagonists4 7 18 23 and adenosine deaminase4 attenuate the hypoxic, hyperemic response in the cerebral circulation. Our present results also support the view that adenosine plays a significant role in hypoxia-induced cerebral vasodilation in newborn pigs. The relative contribution of adenosine to hypoxia-induced vascular changes may vary during the postnatal period24 25 and species-dependent variables may also exist.10
The mechanism by which endogenous adenosine causes cerebral vasodilation has been intensively studied.11 Several studies on isolated arteries have shown that adenosine activates KATP and that this effect was inhibited by glibenclamide.4 26 27 28 In addition, our data confirm recent results by Armstead4 and indicate that KATP contribute to adenosine-induced arteriolar dilation in the in vivo cerebral circulation of piglets. The precise mechanism of KATP activation remains unknown, but probably involves elevation of intracellular cAMP and stimulation of protein kinase A.27 29
In a previous study, we showed that arteriolar dilator responses to aprikalim, iloprost, and CGRP, selective activators of KATP, are greatly reduced after ischemia.15 16 Aprikalim is a widely used pharmacological activator of KATP.22 30 Iloprost, a stable analogue of prostacyclin, and CGRP may be entirely dependent on activation of KATP in promoting dilation of cerebral arterioles. Thus, coadministration of glibenclamide, a selective inhibitor of KATP, blocked arteriolar dilator responses to all three substances. In contrast to these three activators of KATP, adenosine and arterial hypoxia do not dilate cerebral arterioles exclusively via the opening of KATP. Thus, approximately one half of the arteriolar dilation to adenosine4 and arterial hypoxia4 13 is intact with coapplication of glibenclamide, which implies that other mechanisms independent from activation of KATP are also involved. Nonetheless, based on the relative importance of KATP in promoting dilation to these stimuli,4 13 it was an unexpected finding that normal arteriolar responsiveness remained after ischemia. Our results with adenosine confirm an earlier report by Mayhan et al.31
We considered several possible explanations to account for the retained cerebral arteriolar responses to arterial hypoxia and adenosine. First, alternative dilator mechanisms, including actions of arachidonic acid19 and other as yet undefined factors may have compensated for decreased function of KATP. Although activation of calcium-activated potassium channels has been shown to participate in dilator responses of rat isolated cerebral arterioles,32 recent evidence indicates that their contribution to cerebral arteriolar dilation in piglets is doubtful.21 Second, the limited KATP function remaining after ischemia may be sufficient to allow normal arteriolar responsiveness. In our previous study, modest arteriolar dilation to aprikalim was present after ischemia, while glibenclamide coapplication completely abolished aprikalim-induced dilation.15 Thus, low levels of KATP function may allow normal arteriolar responsiveness to be present for arterial hypoxia and adenosine, perhaps via a “permissive” role as has been suggested for nitric oxide1 and prostaglandins.33 34 Third, the effects of ischemia on arteriolar responses to aprikalim, iloprost, and CGRP may involve inactivation of sites distinct from the KATP or of sites that are not essential for channel functioning.27 For example, ischemia may impair the function of prostacyclin and CGRP receptors or coupling between receptors and KATP. In addition, ischemia-induced alterations in binding sites for aprikalim may not interfere with adenosine- or hypoxia-stimulated increases in KATP function. Also, changes in KATP channel function could be different depending on whether activation is from extra- or intracellular directions. And fourth, preadministration of exogenous adenosine or release of endogenous adenosine by hypoxia could attenuate ischemic damage11 and thus preserve normal vascular responsiveness.
In contrast to arterial hypoxia, arteriolar dilation to arterial hypercapnia was abolished at 1 hour after ischemia, and normal dilator responses returned to normal 4 hours after ischemia. In piglets, cerebral arteriolar dilation to arterial hypercapnia is not due to activation of KATP.19 Recovery of arteriolar responsiveness to arterial hypercapnia over 2 to 4 hours after ischemia is similar to those observed previously in response to aprikalim and iloprost,15 and may represent general recovery of cerebral blood vessels. It is interesting that cerebral arteriolar responses to arterial hypoxia are extremely stable during this period when dilator responses to other stimuli are attenuated.
Babies are frequently exposed to hypoxic/anoxic stress during the perinatal period, and cerebrovascular dysfunction may contribute to or potentiate development of neurological sequelae. Results from the present study and other studies show that cerebrovascular responsiveness is affected selectively by anoxic stress. Thus, cerebral arteriolar dilation to CGRP,16 prostacyclin,15N-methyl-d-aspartate,17 and arterial hypercapnia is largely abolished by 1 hour after ischemia, while responsiveness to arterial hypoxia, adenosine, sodium nitroprusside,17 and prostaglandin E215 is intact. Proper management of babies after hypoxic/ischemic stress should take into consideration these relatively selective changes in responsiveness of the cerebral circulation.
Selected Abbreviations and Acronyms
|aCSF||=||artificial cerebrospinal fluid|
|CGRP||=||calcitonin gene–related peptide|
|KATP||=||ATP-sensitive K+ channels|
This study was supported by grants HL-30260, HL-46558, and HL-50587 from the National Institutes of Health and a grant from the Hungarian Ministry of Education (FKFP 0713/1997).
- Received June 30, 1997.
- Revision received September 17, 1997.
- Accepted October 7, 1997.
- Copyright © 1998 by American Heart Association
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Taguchi H, Heistad DD, Kitazono T, Faraci FM. ATP-sensitive K+ channels mediate dilatation of cerebral arterioles during hypoxia. Circ Res. 1994;74:1005–1008.
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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.
Louis TM, Meng W, Bari F, Errico RA, Busija DW. Ischemia reduces CGRP-induced cerebral vascular dilation in piglets. Stroke. 1996;27:134–139.
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Cerebral ischemia can activate any of a multitude of complex mechanisms, depending on the duration, location, and intensity of the insult.R1 Some of these mechanisms, such as the release of nitric oxideR2 R3 and excitatory amino acids,R4 contribute directly to the immediate neuronal death characteristic of cerebral ischemic damage. Other mechanisms target the cerebral vasculature and alter its reactivity, resulting in both immediate and long-term consequences for postischemic recovery. Among the cerebrovascular responses long known to be particularly vulnerable to ischemia is the ability of the cerebral circulation to autoregulate its blood flow.R5 In addition, cerebral ischemia can attenuate hypercapnic reactivity, although this effect appears more variablyR6 R7 than loss of autoregulation. Reactivity to hypoxia can also be attenuated by ischemia, but this response is probably the least vulnerable of all cerebrovascular responses,R8 due perhaps in large part to the redundancy of mechanisms that mediate hypoxic cerebral vasodilatation.R9 Thus overall, ischemia produces a graded and selective loss of essential cerebrovascular responses in proportion to the severity and nature of the insult.
To explore a possible mechanistic basis for the selective effects of cerebral ischemia on different cerebrovascular responses, Bari et al tested the hypothesis that ischemic attenuation of hypoxic reactivity reflects the ability of ischemia to inhibit ATP-sensitive potassium channel function. These channels are clearly implicated in hypoxic cerebral vasodilatationR10 R11 R12 and have also been previously shown by the authors to be vulnerable to ischemia.R13 Using ischemic conditions known to attenuate ATP-sensitive potassium channel function in the neonatal piglet, the authors found that ischemia also attenuated hypercapnic reactivity as previously reported,R6 R8 R14 but had no effect on cerebral vasodilatation to either hypoxia or adenosine. Together, these findings reinforce the view that ischemia selectively alters essential cerebrovascular responses and further suggest that mechanisms independent of ATP-sensitive potassium channels can fully mediate postischemic hypoxic cerebral vasodilatation in the neonate.
Certainly, careful judgment must be exercised when extrapolating these results to other preparations and situations. The pattern and distribution of ischemia produced in these studies by artificially elevating intracranial pressure is quite different from that produced by vessel occlusion or cardiac arrest. In addition, the duration of hypoxia tested was relatively brief (3 to 4 minutes) and of moderate intensity (Pao2≈25 mm Hg) and therefore may not accurately predict responses to hypoxia of greater duration or intensity. Typically, more severe hypoxia produces greater decreases in the cellular ATP-to-ADP ratio and therefore may more vigorously activate ATP-sensitive potassium channels and heighten any apparent effects of channel dysfunction. Finally, the effects of ischemia are dramatically different in mature and immature brains,R15 R16 R17 as is the functional capacity of cerebrovascular ATP-sensitive potassium channels,R18 and thus the results may not exactly predict the effects of ischemia on hypoxic cerebral vasodilatation in the adult. Nonetheless, the study by Bari et al advances the important concept that in neonates, as previously shown in adults,R8 cerebrovascular responses to hypoxia are more robust than are responses to changes in arterial carbon dioxide tension. This strongly implies that cerebrovascular reactivity to hypoxia may be expected to survive a moderate ischemic insult but loss of this reactivity is a reliable indicator of poor outcome after a major cerebrovascular ischemic insult, regardless of age.
Selected Abbreviations and Acronyms
|aCSF||=||artificial cerebrospinal fluid|
|CGRP||=||calcitonin gene–related peptide|
|KATP||=||ATP-sensitive K+ channels|
- Received June 30, 1997.
- Revision received September 17, 1997.
- Accepted October 7, 1997.
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Taguchi H, Heistad DD, Kitazono T, Faraci FM. ATP-sensitive K+ channels mediate dilatation of cerebral arterioles during hypoxia. Circ Res.. 1994;74:1005-1008.
Reid JM, Paterson DJ. Role of K+ in regulating hypoxic cerebral blood flow in the rat: effect of glibenclamide and ouabain. Am J Physiol.. 1996;270:H45–H52.
Reid JM, Davies AG, Ashcroft FM, Paterson DJ. Effect of L-NMMA, cromakalim, and glibenclamide on cerebral blood flow in hypercapnia and hypoxia. Am J Physiol.. 1995;269:H916–H922.
Bari F, Louis TM, Meng W, Busija DW. Global ischemia impairs ATP-sensitive K+ channel function in cerebral arterioles in piglets. Stroke.. 1996;27:1874-1880. Editorial Comment, 1880-1881.
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