Global Ischemia Impairs ATP-Sensitive K+ Channel Function in Cerebral Arterioles in Piglets
Background and Purpose Indirect evidence from studies in which calcitonin gene–related peptide was used indicates that anoxic stress suppresses functioning of cerebral vascular ATP-sensitive K+ channels. The purpose of this study was to directly examine effects of total global ischemia on cerebral arteriolar dilator responses to activators of ATP-sensitive K+ channels.
Methods We measured pial arteriolar diameters in anesthetized piglets using a closed cranial window and intravital microscopy. Baseline diameters were approximately 100 μm. Arteriolar responses to aprikalim (10−8 and 10−6 mol/L), a pharmacological activator of ATP-sensitive K+ channels, and iloprost (0.1 and 1 μg/mL), a physiological activator of these channels, were determined before and 1, 2, and 4 hours after a 10-minute period of total global ischemia. Ischemia was caused by increasing intracranial pressure.
Results Before ischemia, aprikalim dilated cerebral arterioles by 7±2% at 10−8 mol/L and by 25±4% at 10−6 mol/L (n=5). At 1 hour after ischemia, aprikalim did not cause significant dilation at either dose (3±2% at 10−8 mol/L and 7±4% at 10−6 mol/L; P<.05 compared with corresponding preischemic response). Arteriolar dilation returned toward normal values at 2 and 4 hours. Similar results were found with iloprost. Furthermore, prior treatment with indomethacin (5 mg/kg) preserved normal arteriolar dilation to aprikalim and iloprost after ischemia. In contrast, arteriolar dilator responses to prostaglandin E2 were intact after ischemia.
Conclusions Ischemia transiently eliminates cerebral arteriolar dilation to activation of ATP-sensitive K+ channels; arteriolar responses are suppressed at 1 hour and return toward normal over 2 to 4 hours. In addition, reduced responsiveness can be prevented by prior treatment with indomethacin.
In the cerebral circulation, ATP-sensitive K+ channels are present and play an important role in regulation of vascular resistance during a variety of situations. For example, ATP-sensitive K+ channel activation promotes cerebral vascular dilation to CGRP and prostacyclin as well as to other stimuli.1 2 3 4 5 6 7
In a previous study, cerebral ischemia followed by reperfusion was able to eliminate or reduce arteriolar dilation to CGRP in piglets for up to 4 hours.1 The mechanism for impaired cerebral vascular responsiveness to CGRP is unclear but might involve ischemia-induced changes in functioning of ATP-sensitive K+ channels.1 8 We are unaware of previous studies that have examined responsiveness of cerebral or peripheral vessels to direct activators of vascular ATP-sensitive K+ channels after ischemia.
In this study, we tested the hypothesis that global ischemia would reduce cerebral arteriolar dilation to pharmacological (aprikalim) and physiological (iloprost) activation of ATP-sensitive K+ channels. Aprikalim is adirect, specific activator of ATP-sensitive K+ channels.9 10 11 12 Iloprost is a stable prostacyclin analogue that activates ATP-sensitive K+ channels through mechanisms involving receptor-linked stimulation of adenylate cyclase.3 In addition, we assessed the effects of indomethacin on functioning of ATP-sensitive K+ channels after ischemia. It has been shown previously that indomethacin pretreatment preserves arteriolar dilator responses to CGRP after ischemia.1
Materials and Methods
Experiments were performed on newborn pigs (1 to 7 days) 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 amounts of α-chloralose were 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 polyethylene tubing (PE-90). Arterial blood pressure, gases, and pH were maintained within the normal physiological range. The head of each piglet 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 with a microscope (Wild M36) equipped with a television camera (Panasonic), and arteriolar diameter was measured with a video microscaler (IV-550, For-A Co).
Cerebral Ischemia/Reperfusion Injury
Cerebral ischemia/reperfusion injury was produced by implantation of a hollow brass bolt in 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 with 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.
At the beginning of each experiment, the cranial window was flushed with aCSF several times until a stable baseline was obtained. Then arteriolar responses to aprikalim (10−8, 10−6 mol/L) were determined. Each dose of aprikalim in aCSF was introduced into the window, the infusion was stopped, and arteriolar diameter was recorded for the next 5 to 10 minutes. Animals were subsequently divided into either the sham or ischemia groups. In the sham group, the bolt was implanted but intracranial pressure was not increased. In the ischemia group, intracranial pressure was increased for 10 minutes. In both groups, arteriolar responses to topical aprikalim were determined again at 1, 2, and 4 hours. We also determined whether indomethacin pretreatment could preserve responsiveness to aprikalim after ischemia. In these animals, indomethacin (5 mg/kg IV) was given 20 minutes before ischemia. Arteriolar responses to topical aprikalim were determined before ischemia and 1 hour after ischemia.
To confirm the ability of aprikalim to activate ATP-sensitive K+ channels, we determined arteriolar responses to topical aprikalim alone and topical aprikalim coadministered with topical glibenclamide (10−5 mol/L). Glibenclamide is an inhibitor of ATP-sensitive K+ channels.5 11 13 14 15
To examine whether ATP-sensitive K+ channels are activated in the postischemic period, we applied glibenclamide (10−5 mol/L) topically at 1 hour after ischemia.
We also determined the role of continued production of superoxide anion to altered arteriolar responses to aprikalim. At 40 to 50 minutes after ischemia, we applied superoxide dismutase (100 U/mL) alone in aCSF to the brain surface. At 60 minutes after ischemia, we coapplied superoxide dismutase with aprikalim. We16 and others17 have shown this dose of superoxide dismutase to be an effective scavenger of superoxide anions.
To assess effects of anoxic stress to a physiological activator of K+ channels, we examined arteriolar dilator effects of 0.1 and 1 μg/mL iloprost before and 1, 2, and 4 hours after 10 minutes of ischemia. In time control animals, we examined arteriolar effects of repeated applications of iloprost.
In another group of animals, we examined whether indomethacin would preserve dilator effects of iloprost after ischemia. Since indomethacin has been reported to block prostacyclin receptors, we also determined whether this effect was present in our animals. In these animals, we examined arteriolar dilator responses to iloprost before and 20 minutes after intravenous administration of 5 mg/kg indomethacin. After an additional administration of 5 mg/kg indomethacin, we induced 10 minutes of cerebral ischemia and examined arteriolar dilation after 1, 2, and 4 hours of reperfusion. We gave the additional dose of indomethacin to counteract the time delay between the initial administration of indomethacin and the period of ischemia. In an earlier study, we showed that the effectiveness of indomethacin is time dependent.
To confirm the role of ATP-sensitive K+ channels in mediating arteriolar dilation to iloprost,3 we coadministered glibenclamide with iloprost (0.1, 1, and 10 μg/mL).
To examine the effects of ischemia on arteriolar dilation to another prostaglandin, we measured arteriolar diameter changes to 0.1 and 1 μg/mL PGE2 before and 1, 2, and 4 hours after 10 minutes of ischemia. To assess the role of ATP-sensitive K+ channels in arteriolar responses to PGE2, we determined effects on arteriolar diameter of 0.1 and 1 μg/mL before and with coadministration of glibenclamide (10−5 mol/L).
All values are expressed as mean±SEM. When appropriate, data were analyzed with the paired t test, repeated measures ANOVA, or one-way ANOVA. When the F value was significant, pairwise comparisons were made with the Student-Newman-Keuls test. A value of P<.05 was considered statistically significant.
Arterial Blood Pressures
Arterial blood pressures were within normal limits for piglets and were unaffected by topical application of the drugs used in these experiments. In addition, arterial blood pressures were within normal limits during baseline and at 1, 2, and 4 hours after ischemia for all of the groups examined. For example, in the aprikalim/ischemia group (n=6) during baseline conditions before ischemia, arterial blood pressures were 59±4, 60±4, and 60±4 mm Hg during control, 10−8 mol/L aprikalim, and 10−6 mol/L aprikalim, respectively. At 1 hour after ischemia, arterial blood pressures were 60±6, 60±6, and 62±6 mm Hg during control, 10−8 mol/L aprikalim, and 10−6 mol/L aprikalim, respectively. At 2 hours after ischemia, arterial blood pressures were 60±4 mm Hg during control, 60±4 mm Hg during 10−8 mol/L aprikalim, and 61±4 mm Hg during 10−6 mol/L aprikalim. Finally, at 4 hours after ischemia, arterial blood pressures were 63±5, 62±5, and 64±5 mm Hg during control, 10−8 mol/L aprikalim, and 10−6 mol/L aprikalim, respectively.
Arteriolar Responses to Aprikalim
In both sham and ischemia groups, aprikalim initially dilated arterioles in a dose-dependent fashion. In sham animals, arteriolar dilation to aprikalim did not change over time (Table 1⇓, Fig 1⇓). In contrast, exposure to ischemia eliminated arteriolar dilation to aprikalim at 1 hour (Table 1⇓, Fig 2⇓). Arteriolar dilator responses to aprikalim were still modestly reduced at 2 hours, but responses returned to baseline values by 4 hours after ischemia.
Indomethacin pretreatment preserved arteriolar responses to aprikalim at 1 hour after ischemia. Before indomethacin, control arteriolar diameter was 93±8 μm, and diameters were 103±9 μm at 10−8 mol/L and 121±5 μm at 10−6 mol/L (P<.05 compared with control for both doses; n=6) (Fig 3⇓). After indomethacin administration and ischemia, control arteriolar diameter was 98±5 μm, and diameters were 108±6 μm at 10−8 mol/L and 129±4 μm at 10−6 mol/L of aprikalim (P<.05 compared with control; P>.05 for comparisons of percent change from control for each dose of aprikalim) (Fig 3⇓).
Administration of glibenclamide did not change arteriolar diameter after ischemia. At 1 hour after ischemia, arteriolar diameter was 117±8 μm before glibenclamide and 126±10 μm with application of glibenclamide (n=6; P>.05).
Coadministration of glibenclamide completely abolished arteriolar dilation to aprikalim (Fig 4⇓). Before administration of glibenclamide (n=9), arteriolar diameter was 100±5 μm during control, 107±6 μm at 10−8 mol/L (P<.05), and 128±6 μm at 10−6 mol/L (P<.05) (Fig 4⇓). Administration of glibenclamide did not alter resting arteriolar diameter. In the presence of glibenclamide, arteriolar diameter was 103±5 μm during control, 104±5 μm at 10−8 mol/L (P>.05), and 104±5 μm at 10−6 mol/L (P>.05).
Administration of superoxide dismutase at 1 hour after ischemia failed to preserve arteriolar responses to aprikalim. Before ischemia, arterioles dilated by 9±1% at 10−8 mol/L and by 24±3% at 10−6 mol/L (n=4). However, after ischemia and in the presence of superoxide dismutase, arteriolar dilation was reduced to 4±1% at 10−8 mol/L (P<.05) and to 13±2% at 10−6 mol/L (P<.05). In the presence of superoxide dismutase, arteriolar responses to the lower dose of aprikalim after ischemia were similar to responses at 1 hour in the absence of superoxide dismutase (Fig 2⇑). However, arteriolar responses to the higher dose of aprikalim were intermediate between untreated (Fig 2⇑) and indomethacin-treated (Fig 3⇑) animals.
Arteriolar Responses to Iloprost
Arteriolar responses to iloprost were reduced after ischemia (Table 2⇓, Fig 5⇓). Attenuation of arteriolar dilation was most pronounced at 1 hour after ischemia, and arteriolar dilation tended to return to baseline values from 2 to 4 hours. In contrast, pretreatment with indomethacin prevented reductions in iloprost-induced arteriolar dilation after ischemia (Table 2⇓, Fig 6⇓).
In time control animals, arteriolar responses were similar during both applications of iloprost. After recovery from a first application of iloprost, baseline was 101±3 μm, and arteriolar diameter increased to 114±2 μm (13±4%) at 0.1 μg/mL and to 122±5 μm (21±4%) at 1 μg/mL (P<.05 compared with baseline; n=4). Arteriolar dilator responses in time control animals were not different from initial responses to iloprost (Table 2⇑, Fig 5⇑).
Coadministration of glibenclamide completely abolished arteriolar dilation to iloprost (Fig 4⇑). In the absence of glibenclamide, baseline arteriolar diameter was 101±3 μm, and iloprost increased diameter to 115±5 μm at 0.1 μg/mL, to 126±7 μm at 1 μg/mL, and to 135±7 μm at 10 μg/mL (P<.05 for all comparisons with baseline; n=6). With coapplication of glibenclamide, diameters were 106±6 μm during baseline, 109±6 μm at 0.1 μg/mL, 111±6 μm at 1 μg/mL, and 112±7 μm at 10 μg/mL (P>.05 for all comparisons with baseline).
Indomethacin administration did not alter arteriolar dilation to iloprost (n=5) (Fig 7⇓). Before indomethacin, baseline arteriolar dilation was 106±4 μm and increased to 116±5 μm at 0.1 μg/mL iloprost and 133±6 μm at 1.0 μg/mL (P<.05 for both comparisons to baseline). After indomethacin administration, baseline diameter was 102±4 μm and increased to 110±5 μm at 0.1 μg/mL and to 128±8 μm at 1.0 μg/mL (P<.05 for both comparisons to baseline). There was not a significant difference between arteriolar dilator responses before and after indomethacin.
Arteriolar Responses to PGE2
Arteriolar dilator responses before ischemia were similar for PGE2 (Table 3⇓, Fig 8⇓) and iloprost (Table 2⇑, Fig 5⇑). However, ischemia did not alter arteriolar dilator responses to PGE2 (Table 3⇓, Fig 8⇓).
Glibenclamide did not affect PGE2-induced dilation. Baseline diameter was 106±4 μm, and application of 0.1 and 1.0 μg/mL PGE2 increased diameter to 125±6 μm (19±9%) and 132±4 μm (25±7%), respectively (n=4; P<.05 for both responses compared with baseline). With coapplication of glibenclamide, baseline diameter was 105±4 μm, and application of 0.1 and 1.0 μg/mL PGE2 increased diameter to 121±4 μm (16±6%) and 133±6 μm (28±9%), respectively (P<.05 for responses compared with baseline; P>.05 for comparisons in the absence and presence of glibenclamide).
The major new finding is that 10 minutes of total global ischemia suppresses cerebral arteriolar responses to aprikalim or iloprost in a time-dependent fashion. Thus, arteriolar dilation to aprikalim is severely restricted at 1 hour after ischemia, but normal dilator responsiveness returns by 2 to 4 hours. Similar findings occurred for iloprost, but recovery of arteriolar dilation after ischemia was not as complete. In contrast, arteriolar dilation to PGE2, which does not activate ATP-sensitive K+ channels, is unaffected by ischemia. In addition, pretreatment with indomethacin before ischemia preserves arteriolar dilation to aprikalim and iloprost. Thus, ischemia has selective depressor effects on ATP-sensitive K+ channels, and reduced responsiveness is preventable with pharmacological intervention.
Cerebral Vascular ATP-Sensitive K+ Channels
Recent reports indicate that ATP-sensitive K+ channels are important in regulation of cerebral circulation. Selective agonists of these receptors, such as aprikalim and lemakalim,3 9 10 12 13 18 are potent promoters of cerebral vasodilation. In the present study, aprikalim dilated pial arterioles in piglets by amounts similar to those reported in rat basilar artery15 and in rabbit pial arterioles.6 Arteriolar dilation by aprikalim is inhibited by selective antagonists of ATP-sensitive K+ channels such as glibenclamide.5 10 11 12 13 14 Moreover, cerebral vasodilation to aprikalim has been reported to be unchanged by inhibitors of other K+ channels such as charybdotoxin and iberiotoxin or tetraethylammonium.12 Thus, it seems likely that aprikalim is a relatively selective activator of ATP-sensitive K+ channels, particularly at the doses used in the present study.
Several fundamental dilator responses of the cerebral circulation are mediated through ATP-sensitive K+ channels. For example, the majority of arteriolar dilation due to arterial hypoxia,3 6 prostacyclin,3 or CGRP1 4 7 is inhibited by drugs such as glibenclamide. Our results concerning iloprost, a prostacyclin agonist, confirm these previous findings.3 In contrast, arteriolar dilation to other substances such as sodium nitroprusside, acetylcholine, and PGE2 (present study) apparently does not involve activation of ATP-sensitive K+ channels.4
We realize that there is controversy surrounding the characterization of K+ channels in vivo when only pharmacological approaches are used. Thus, glibenclamide-sensitive and ATP-sensitive K+ channels may not always be equivalent. Nonetheless, the results of our study clearly indicate that function of these channels, as defined by aprikalim, iloprost, and glibenclamide, is severely impaired by anoxic stress.
Altered Responses After Ischemia
Very little is known about regulation of vascular ATP-sensitive K+ channels or aprikalim binding sites. Several investigators have shown that ATP-sensitive K+ binding sites are altered during chronic conditions such as arterial hypertension19 and diabetes mellitus.20 However, because of the multifactorial nature of these disease states, it is difficult to ascertain specific stimuli that could affect these binding sites. Our study is the first to demonstrate that direct impairment of ATP-sensitive K+ channel functioning can be achieved by an acute stimulus. Reduced arteriolar responsiveness after ischemia does not occur for all stimuli, since arteriolar dilation to topical isoproterenol, sodium nitroprusside, and PGE2 (present study) are normal after ischemia in piglets.21 22
We also determined whether reduced responsiveness to aprikalim and iloprost could be due to already increased activation of ATP-sensitive K+ channels by metabolites produced during ischemia and reperfusion. Previously, we have shown that arterioles dilate modestly after ischemia, but that diameter returns to baseline values by 1 hour.22 In the present study, baseline diameter at 1 hour after ischemia was not different from values from time control animals. Furthermore, administration of glibenclamide, at a dose sufficient to block effects of aprikalim and iloprost, fails to change arteriolar diameter significantly at 1 hour after ischemia. Thus, there appears to be minimal glibenclamide-sensitive cerebrovascular tone at this time.
The basis for the present study is our earlier finding that arteriolar responses to CGRP are eliminated for up to 4 hours after ischemia.1 Since most of the arteriolar dilation to CGRP is through mechanisms involving activation of ATP-sensitive K+ channels, it seemed logical to examine functioning of these channels after ischemia. However, our results indicate a lack of concordance between cerebral arteriolar responses to CGRP and aprikalim after ischemia: while responses to both stimuli were reduced at 1 hour, responses to aprikalim but not CGRP returned to normal values at 2 to 4 hours. Thus, impaired cerebrovascular dilator responses to CGRP at 2 to 4 hours probably involve sites or mechanisms distinct from ATP-sensitive K+ channels. Although untested, it is possible that ischemic stress also altered CGRP receptor function or disrupted second messenger systems as well. The previous findings that arteriolar dilator responsiveness to sodium nitroprusside and isoproterenol is intact after ischemia indicate that general smooth muscle dysfunction is not present during these conditions. However, we cannot rule out possible involvement of ATP-sensitive K+ channels in reduced arteriolar responses to CGRP at 1 hour after ischemia.
The underlying basis for attenuation of arteriolar dilation to aprikalim and iloprost after ischemia may involve action of oxygen radicals. We have shown that substantial amounts of superoxide anion are produced in piglet cortex in the immediate postischemic period and that indomethacin pretreatment prevents production of these radicals.16 Oxygen radicals could alter vascular responses by several different mechanisms, including effects on ion channel complexes.23 The preservation of normal responsiveness to aprikalim with indomethacin but not with the coapplication of superoxide dismutase is similar to our earlier findings with CGRP and may indicate that oxygen radical–induced changes occur in the immediate postischemic period. However, the partial retention of dilator responses to aprikalim at 10−6 mol/L (but not at 10−8 mol/L) by superoxide dismutase at 1 hour after ischemia might indicate continued production of modest amounts of superoxide anion. We also considered that indomethacin administration might preserve responses to aprikalim after ischemia by other mechanisms such as prevention of prostaglandin production. High levels of prostacyclin for up to 1 hour after the beginning of reperfusion could result in preactivation of ATP-sensitive K+ channels and thus attenuate effects of subsequent administration of aprikalim. However, this possibility seems unlikely since administration of glibenclamide after ischemia fails to constrict arterioles.
Responses to Prostaglandins
An unexpected finding was that iloprost and PGE2 mediate cerebral arteriolar dilation through different mechanisms. Thus, dilation to the former but not the latter was sensitive to blockade of ATP-sensitive K+ channels. This finding is in apparent contrast to recent reports indicating that cerebral arteriolar dilation in piglets for both prostacyclin and PGE2 is predominantly through the effects of nitric oxide24 or that vasodilator effects of PGE2 are mediated through prostacyclin receptors coupled to adenylyl cyclase.25 In the case of ATP-sensitive K+ channels, we have shown that only a small amount of the dilation to aprikalim, a selective agonist of these channels, is due to activation of nitric oxide synthase.26
Although indomethacin has been shown to be a relatively selective inhibitor of prostaglandin H synthase, it has been reported that relatively high doses of indomethacin also block prostacyclin receptors.27 28 In one study27 simultaneous intravenous (5 mg/kg) and topical (10−4 mol/L) administration of indomethacin inhibited pial arteriolar dilation to iloprost. In the other study28 indomethacin inhibited iloprost binding in cultured cerebrovascular smooth muscle cells. However, substantial blockade (>20%) of iloprost binding in cultured smooth muscle cells only occurred at doses of indomethacin equal to or greater than 10−4 mol/L. In the present study intravenous administration of 5 mg/kg (Fig 7⇑) or 10 mg/kg (Fig 6⇑) indomethacin did not affect arteriolar dilation to iloprost, and these results confirm an earlier report from another laboratory.24 Furthermore, we have shown previously that administration of these doses of indomethacin is sufficient to almost totally block prostaglandin and superoxide anion production by the cerebral cortex under a variety of conditions.16 29 30 31 Thus, virtually complete inhibition of prostaglandin H synthase in cerebral cortex by indomethacin can be achieved without detectable inhibition of cerebrovascular prostacyclin receptors.
Hypoxic-ischemic insult is a serious problem during the perinatal period and is associated with neurological sequelae. One mechanism that could contribute to neuronal damage is impaired vascular function in the immediate, postanoxic period. First, normal responsiveness to dilator stimuli would be reduced, and thus basal blood flow may not be adequate for metabolic rate. Second, appropriate cerebrovascular responses might be impaired during secondary pathological events that may follow an initial anoxic episode. These secondary insults include apnea, seizure activity, increased intracranial pressure, and arterial hypotension. For example, impaired functioning of cerebrovascular ATP-sensitive K+ channels to seizure activity would lead to inadequate oxygen delivery to cerebral tissues and result in enhanced neuronal cell death.
Selected Abbreviations and Acronyms
|aCSF||=||artificial cerebrospinal fluid|
|CGRP||=||calcitonin gene–related peptide|
This study was supported by grants HL-30260, HL-46558, and HL-50587 from the National Institutes of Health. We thank Merck, Sharpe, and Dohme for providing the indomethacin, Rhône-Poulenc Rorer S. A. for supplying aprikalim, and Berlex Laboratories for supplying iloprost.
- Received April 19, 1996.
- Revision received June 3, 1996.
- Accepted June 25, 1996.
- Copyright © 1996 by American Heart Association
Louis TM, Meng W, Bari F, Errico RA, Busija DW. Ischemia reduces CGRP-induced cerebral vascular dilation in piglets. Stroke. 1996;27:134-139.
Faraci FM, Breese KR, Heistad DD. Cerebral vasodilation during hypercapnia: role of glibenclamide-sensitive potassium channels and nitric oxide. Stroke. 1994;25:1679-1683.
Fredericks DT, Yanpig L, Rusch NJ, Lombard JH. Role of endothelium and arterial K+ channels in mediating hypoxic dilation of middle cerebral arterioles. Am J Physiol. 1994;267:H580-H586.
Kitazono T, Heistad DD, Faraci FM. Role of ATP-sensitive K+ channels in CGRP-induced dilatation of basilar artery in vivo. Am J Physiol. 1993;265:H581-H585.
Kitazono T, Faraci FM, Heistad DD. Effect of norepinephrine on rat basilar artery in vivo. Am J Physiol. 1993;264:H178-H182.
Taguchi H, Heistad DD, Kitazono T, Faraci FM. ATP-sensitive K+ channels mediate dilatation during hypoxia. Circ Res. 1994;74:1005-1008.
Kitazono T, Faraci FM, Taguchi H, Heistad DD. Role of potassium channels in cerebral blood vessels. Stroke. 1995;26:1713-1723.
Faraci FM. Editorial comment. Stroke. 1996;27:139.
Aloup JC, Farge D, James C, Mondot S, Cavero I. 2-(3-Pyridyl)-tetrahydrothiopyran-2-carbonthiamide derivatives and analogues: a novel family of potent potassium channel openers. Drugs Future. 1990;15:1097-1108.
Standen NB, Quayle JM, Davies NW, Brayden JE, Huang Y, Nelson MT. Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science. 1989;245:177-180.
Taguchi H, Heistad DD, Kitazono T, Faraci FM. Dilatation 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.
Clapp LH, Gurney AM. ATP-sensitive K+ channels regulate resting potential of pulmonary arterial smooth muscle cells. Am J Physiol. 1992;262:H916-H920.
Faraci FM, Heistad DD. Role of ATP-sensitive potassium channels in the basilar artery. Am J Physiol. 1993;264:H8-H13.
Armstead W, Mirro R, Busija DW, Leffler CW. Postischemic generation of superoxide anion by newborn pig brain. Am J Physiol. 1988;255:H401-H403.
Nelson CW, Wei EP, Povlishock JT, Kontos HA, Moskowitz MA. Oxygen radicals in cerebral ischemia. Am J Physiol. 1992;263:H1356-1362.
Kitazono T, Heistad DD, Faraci FM. ATP-sensitive potassium channels in the basilar artery during chronic hypertension. Hypertension. 1993;22:677-681.
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.
Busija DW, Meng W, Bari F, McGough PS, Errico R, Tobin JR, Louis TM. Effects of ischemia on cerebrovascular responses to N-methyl-D-aspartate in piglets. Am J Physiol. 1996;270:H1225-H1230.
Leffler CW, Beasley DG, Busija DW. Cerebral ischemia alters cerebral microvascular reactivity in newborn pigs. Am J Physiol. 1989;257:H266-H271.
Armstead W M. Role of nitric oxide and cAMP in prostaglandin-induced pial arterial vasodilation. Am J Physiol. 1995;268:H1436-H1440.
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. In press.
Parfenova H, Zuckerman S, Leffler CW. Inhibitory effect of indomethacin on prostacyclin receptor mediated cerebral vascular responses. Am J Physiol. 1995;268:H1884-H1890.
Parfenova H, Hsu P, Leffler CW. Dilator prostanoid-induced cyclic AMP formation and release by cerebral microvascular smooth muscle cells: inhibition by indomethacin. J Pharmacol Exp Ther. 1995;272:44-52.
Shibata M, Leffler CW, Busija DW. Prostanoids attenuate pial arteriolar dilation induced by cortical spreading depression in rabbits. Am J Physiol. 1991;261:R828-R834.
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Dilation of cerebral blood vessels in response to many exogenous and endogenous stimuli appears to be mediated in part by activation of ATP-sensitive K+ channels.1R 2R 3R Previous studies from this laboratory have shown that cerebral ischemia/reperfusion impairs dilation of cerebral arterioles in response to exogenous application of CGRP.4R The cellular mechanism that accounts for the effects of ischemia/reperfusion on CGRP-induced dilation of cerebral arterioles, however, was unclear. In light of recent studies which suggest that CGRP-induced dilation of cerebral blood vessels may be mediated by the activation of ATP-sensitive K+ channels,5R 6R the goal of the present study was to determine whether ischemia/reperfusion alters dilation of cerebral arterioles in response to activation of ATP-sensitive K+ channels.
Using intravital microscopy, the authors examined dilation of pial arterioles in newborn pigs in response to activators of ATP-sensitive potassium channels (aprikalim and iloprost) before and after global cerebral ischemia. Before ischemia/reperfusion, exogenous activation of ATP-sensitive K+ channels produced dose-related dilation of cerebral arterioles. In contrast, dilation of cerebral arterioles in response to activation of ATP-sensitive K+ channels was profoundly impaired 1 hour after a 10-minute period of global cerebral ischemia. In addition, pretreatment with indomethacin preserved normal arteriolar dilation to activation of ATP-sensitive K+ channels.
Thus, the findings of the present study suggest that cerebral ischemia/reperfusion transiently impairs dilation of cerebral arterioles to activation of ATP-sensitive K+ channels. Since indomethacin prevented impaired dilation of cerebral arterioles to activation of ATP-sensitive K+ channels following ischemia/reperfusion, it appears that prostaglandin receptor activation may play an important role in this process. The findings of this study may have important implications for the maintenance of cerebral perfusion after cerebrovascular trauma.
Selected Abbreviations and Acronyms
|aCSF||=||artificial cerebrospinal fluid|
|CGRP||=||calcitonin gene–related peptide|
Kitazono T, Faraci FM, Taguchi H, Heistad DD. Role of potassium channels in cerebral blood vessels. Stroke.. 1995;26:1713-1723.
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.
Faraci FM, Breese KR, Heistad DD. Cerebral vasodilation during hypercapnia: role of glibenclamide-sensitive potassium channels and nitric oxide. Stroke.. 1994;25:1697-1683.
Louis TM, Meng W, Bari F, Errico RA, Busija DW. Ischemia reduces CGRP-induced cerebral dilation in piglets. Stroke.. 1996;27:134-139.
Kitazono T, Heistad DD, Faraci FM. Role of ATP-sensitive K+ channels in CGRP-induced dilatation of basilar artery in vivo. Am J Physiol.. 1993;265:H581-H585.
Hong KW, Pyo KM, Lee WS, Yu SS, Rhim BY. Pharmacological evidence that calcitonin gene-related peptide is implicated in cerebral autoregulation. Am J Physiol.. 1994;266:H11-H16.