Published online before print November 22, 2006, doi: 10.1161/01.STR.0000252157.93998.47
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(Stroke. 2007;38:124.)
© 2007 American Heart Association, Inc.
Original Contributions |
Postischemic Augmentation of Conducted Dilation in Cerebral Arterioles
From the Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington.
Correspondence to Al C. Ngai, PhD, Department of Neurological Surgery, Harborview Medical Center, Box 359914, 325 Ninth Avenue, Seattle, WA 98104-2499. E-mail ngai{at}u.washington.edu
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Abstract |
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Background and Purpose— Conducted vasomotor responses likely play an important role in cerebrovascular regulation, but it is unclear how these responses may be affected by ischemia. The purpose of this study was to evaluate the hypothesis that cerebral ischemia and reperfusion (I/R) alters vascular conduction in cerebral arterioles.
Methods— Middle cerebral artery occlusion (MCAO) was induced by an intraluminal filament technique in 4 groups of rats: (A) 2-hour MCAO/24-hour reperfusion (n=14); (B) 2-hour MCAO/1-hour reperfusion (n=7); (C) 1-hour MCAO/24-hour reperfusion (n=6); and (D) 1-hour MCAO/1-hour reperfusion (n=5). Neurological status and infarction (2,3,5-triphenyltetrazolium chloride staining) were evaluated after I/R. Conducted vasomotor responses were assessed in intracerebral branches of the MCA, by following the longitudinal spread of vasodilation or vasoconstriction to localized microapplication of ATP or adenosine.
Results— Local microapplication of ATP evoked a biphasic constriction (17±3%) and dilation (7±2%) response, whereas adenosine elicited only dilation (11±2%). These local responses spread longitudinally along sham-control arterioles (1 mm conduction distance) with rapid spatial decay. Ischemia followed by 24-hour reperfusion (groups A and C) led to a marked potentiation of conducted dilation responses: dilation to ATP conducted with virtually no decay in I/R arterioles. Augmentation of conductivity was not observed in the 1-hour reperfusion groups (B and D). Moreover, I/R did not alter conducted constriction.
Conclusions— Ischemia-reperfusion led to a specific augmentation of conducted vasodilation in cerebral arterioles. Presumably, enhanced conductivity may improve cerebral perfusion after ischemia.
Key Words: adenosine • ATP • focal ischemia • gap junction • middle cerebral artery occlusion
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Introduction |
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Proper cerebral perfusion requires the coordination of vasomotor responses among segments of the cerebral vasculature, where both arteries and arterioles contribute to the regulation of vascular resistance.1,2 An example of vascular communication is the retrograde dilation of pial arterioles observed during focal brain activity.3,4 Such upstream dilation of feeding vessels preserve microvascular perfusion pressure and increase blood flow to meet local energy demands.2 During focal ischemia, vascular communication may likewise contribute to the maintenance of perfusion pressure and collateral flow to ischemic regions.5
Vascular conduction may be the predominant mechanism of vascular communication in cerebral arterioles during regional brain activity.2,4,6 These responses involve cell-cell communication of vasomotor signals via gap junctions,7,8 and could be functionally assessed in blood vessels, including cerebral arterioles,9,10 by following the longitudinal spread of vasodilation or vasoconstriction to a localized stimulus. Because of its deleterious effect on vascular cells,11,12 ischemia and reperfusion (I/R) may adversely impact conducted vasomotor responses in cerebral vessels. However, no studies so far have evaluated the effect of I/R on vascular conduction in the cerebral circulation. In the present study, we therefore sought to determine the effect of I/R on conducted vasomotor responses in penetrating arterioles.
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Materials and Methods |
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Middle Cerebral Artery Occlusion Surgery
Experimental protocols in the present study were approved by the Institutional Animal Care and Use Committee at the University of Washington. Male Sprague Dawley rats (Charles River Laboratory; Wilmington, Mass; body weight, 300 to 350 g, n=38) were anesthetized by spontaneous inhalation of 1.5% halothane in a 30% oxygen/70% air mixture. Focal cerebral ischemia was induced by adapting an intraluminal filament technique,13 and animals were maintained at normothermia during surgery. In brief, a 4.0 monofilament surgical suture with a heat-blunted tip was inserted through the common and internal carotid arteries, and advanced to the anterior cerebral artery until a slight resistance was felt, thus occluding the middle cerebral artery. The suture was next secured in place, and anesthesia was discontinued. After occlusion, the suture was removed under brief anesthesia to allow reperfusion, and the animal allowed to recover.
We induced middle cerebral artery occlusion (MCAO) periods of 1 and 2 hours, with 1- and 24-hour reperfusion periods. Hence, MCAO was performed in 4 groups of animals: (A) 2-hour MCAO/24-hour reperfusion (n=14); (B) 2-hour MCAO/1-hour reperfusion (n=6); (C) 1-hour MCAO/24-hour reperfusion (n=7); and (D) 1-hour MCAO/1-hour reperfusion (n=5). Sham-operated animals underwent similar surgical procedures without filament insertion, and were studied at either 1 hour (1-hour sham, n=5) or 24 hours (24-hour sham, n=6) after surgery.
Neurological Evaluation and Infarct Assessment
Neurological evaluation was performed by a blinded investigator (T.N.) at the end of both the ischemic (1 and 2 hours) and reperfusion periods (1 and 24 hours). Neurological status was graded,13 with scores of 0, 1, 2 and 3 indicating no neurological deficit, failure to extend left forepaw (mild deficit), left circling (moderate deficit), and falling to the left (severe deficit), respectively. The rats were next anesthetized with pentobarbital (50 mg/kg, IP) and decapitated. The brain was rapidly removed from the skull, and a section of cerebral cortex, 
2-mm thick and containing the first portion of the middle cerebral artery, was dissected from the brain for the harvesting of penetrating arterioles. The brain was next sliced into 2-mm coronal sections for staining with 2% 2,3,5-triphenyltetrazolium chloride (TTC). Excision of tissue for vessel isolation precluded the direct quantitation of infarction volume. We therefore assessed infarction by a qualitative method, as described by Marrelli.14 Briefly, brain lesions were assigned nominal scores of 0, 1, 2, 3, indicating, respectively, no lesion, partial lesion in the striatum, lesion in most of the striatum, and lesion in both the striatum and cortex. Animals with no neurological deficit after MCAO, or brains with evidence of subarachnoid hemorrhage, were excluded from vascular studies.
In Vitro Vessel Preparation
In vitro vessel methodology has been described in detail in previous publications from our laboratory.15,16 After excision of a piece of cortex containing the proximal MCA, the pia mater was gently peeled from the cortical tissue to reveal the penetrating parenchymal arterioles. A segment of an arteriole, 80 µm diameter and 1.5 mm in length, was excised from the pia, and transferred to a temperature-controlled vessel chamber mounted on the stage of an inverted microscope. The isolated vessel was cannulated using a system of concentric glass pipettes. Both ends of the arteriole were cannulated to permit continuous perfusion of fluid through the vessel (2 µL/min). The luminal fluid contained 3-(N-morpholino)propanesulfonic acid (MOPS; Sigma) buffered saline buffer with 1% albumin. The vessel was pressurized to 60 mm Hg. Lumen diameter was measured with a video micrometer (Colorado Video), and passive (maximally dilated) vessel diameter was measured (confirmed at the end of the experiment with Ca2+ free buffer). On warming of the vessel bath (37°C), viable arterioles developed rhythmic vasomotion, and spontaneously contracted to 70% of passive diameter within 30 minutes. Baseline diameter was measured after the development of steady tone, and remained largely stable over a 4- to 6-hour period. We calculated spontaneous tone as: Baseline diameter/Passive (maximal) diameterx100%.
Vascular Reactivity and Conduction
In each experiment, the reactivity of each penetrating arteriole was first evaluated by global application of vasoactive agents. Nonendothlium-dependent dilation responses were assessed by extraluminal superfusion of acidic (pH 6.8) buffer, adenosine (Ado), 1 and 10 µmole/L and sodium nitroprusside, 10 µmole/L. Endothelium-dependent dilation was evaluated by luminal infusion of 10 and 100 µmole/L ATP (to selectively activate endothelium purinergic receptors).17,18 Vasoconstriction was evaluated by superfusion of alkaline (pH 7.6) buffer. Vessel diameter was monitored for 5 to 10 minutes between solution changes to measure steady state responses.
Conducted vasomotor responses were next evaluated by focal application of vasoactive agents via micropipettes. Vessel diameter was measured only at the upstream end of the arteriole (the "observe" site, see Figure 1). A "stimulating" micropipette containing either Ado (10 mmole/L) or ATP (10 mmole/L) was positioned adventitially next to the arteriolar wall. At this location, pressure-pulse ejection9 of Ado or ATP (randomized order) evoked a local vasomotor response. These purine metabolites were chosen because of their involvement in a plethora of physiological functions, including cerebral blood flow regulation.19 We next moved the micropipette downstream along the vessel, 500, 750 and 1000 µm from the observe site, where the same vasoactive stimulus evoked vasomotor responses that propagated back to the observation site. In preliminary studies, we established that vascular tone and reactivity were longitudinally uniform in both sham and ischemic arterioles.
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The magnitude of the local response to pressure-pulse ejection of an agonist is determined not only by the responsiveness of the vessel but also by the amount of agonist delivered, which in turn may be affected by a multitude of factors, including pipette tip diameter, proximity of pipette tip to the arteriole, ejectate concentration, ejection duration, and ejection pressure. In this study, ejection duration was kept constant at 0.5 s; micropipettes tips were pulled to within 2 to 3 µm, and positioned 5 µm away from the vessel wall. These ejection parameters were chosen to deliver a conical-shaped pulse that is highly localized (to a vascular segment <100 µm wide), and rapidly dispersed by the bath superfusate (as verified by ejectate dyed with 0.1% phenol red). At the local application site, a response of 10% could be consistently evoked by varying ejection pressure (2 to 5 psi) in sham and I/R arterioles, thus facilitating the comparison of conducted responses.20 Temporal response profiles to agonist microapplication were traced with the video micrometer. Peak diameter changes were used for data analysis. Figure 1 depicts representative recordings. The vessel bath was perfused with MOPS buffer at a rate of 1 mL/min, to instantaneously disperse the vasoactive stimuli. This prevents diffusion or convection of the vasoactive agent to the remote sites, which could otherwise cause a direct (ie, nonconducted) response.
Data Analysis
All data are expressed as mean±SE. Only one vessel was studied from each animal. For comparison of responses to vasoactive agents, internal vessel diameters were normalized as a percentage of basal diameters (diameters measured after the development of steady tone at 60 mm Hg of intraluminal pressure and 37°C). Data and statistical analyses were performed with GraphPad Prism 3.0 software. Neurological and infarction scores were analyzed by the Kruskal-Wallis test followed by Dunn test for differences between 2 groups. Differences in tone and reactivity to vasoactive agents between sham and I/R groups were evaluated by 1-way ANOVA, whereas vascular conduction in sham and IR vessel groups was analyzed by 2-way ANOVA (for multiple conduction distances). Bonferroni test was used for post hoc comparisons. A value of P<0.05 was considered significant.
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Results |
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Neurological and Infarction Scores
Results of neurological evaluation and infarct assessment are shown in Table 1. In general, MCAO duration (1 or 2 hours) did not influence neurological status. Neurological scores were higher during occlusion than reperfusion (data not shown), and tended to decrease further after 24-hour reperfusion. In contrast, infarction, as revealed by TTC staining, increased in both 24-hour reperfusion groups. Infarction scores tended to be higher with longer ischemic (2 hours) periods.
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Vascular Tone and Reactivity
All pressurized (60 mm Hg) penetrating arterioles in this study (n=38) developed spontaneous tone and constricted as the bathing medium was warmed to 37°C. Table 2 lists the number of vessels studied, passive diameter, vascular tone, and vessel diameter attained after the development of steady resting tone, in each of the 4 I/R and 2 sham vessel groups. Spontaneous vascular tone was similar among all groups of vessels studied regardless of MCAO and reperfusion durations. Thus, I/R did not seem to impact myogenic tone development in this study.
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We first assessed the reactivity of cerebral arterioles to global applications of vasoactive agents. In the 1-hour reperfusion group, vessel reactivity did not vary among sham, 1-hour MCAO and 2-hour MCAO groups (Figure 2A). In the 24-hour reperfusion groups, a significant impairment in dilator responses to both ATP and adenosine was noted with 2-hour MCAO, but only at the higher agonist concentrations (Figure 2B). Overall vessel reactivity in the 1-hour MCAO group was not different from that in the sham control group.
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Conduction of Adenosine and ATP-induced Responses
Micropipette application of Ado evoked a transient local dilation in penetrating arterioles, consisting of a rapid rise to a peak followed by a slow decline and return to baseline diameter within 10 to 12 s (Figure 1). The same stimulus applied at remote sites elicited dilation that propagated back to the observation site. During conduction, the entire vessel appeared to dilate concordantly with little lag between local and distant responses. The magnitude of the dilation response diminished rapidly with distance in sham vessels (Figures 1 and 3
). In the 1-hour reperfusion group, ischemia (1- or 2- hour MCAO) did not affect adenosine-induced conduction (Figure 3A). In contrast, in the 2-hour MCAO/24-hour reperfusion group (Figure 3B), conduction was markedly augmented, with little or no decay. Conduction in the 1-hour MCAO/24-hour reperfusion group also exhibited less decay, although the trend was not significant.
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Micropipette application of ATP elicited a biphasic response, consisting of an initial constriction and a subsequent dilation (Figure 1). Both ATP constriction and dilation responses traveled along the vessel, and displayed attenuation with increasing conduction distance (Figures 1 and 4). Ischemia followed by 1-hour reperfusion had no appreciable effect on the conduction of ATP-induced dilation (Figure 4A), because the decay of the conducted dilation component was similar to sham controls, regardless of ischemic severity (1- or 2-hour MCAO). In striking contrast, both MCAO/24-hour reperfusion groups (Figure 4B) displayed a marked augmentation of the conducted dilation response; the dilation component conducted with virtually no attenuation in I/R arterioles. This postischemic augmentation of vascular conduction was not seen in the constriction component of the response. I/R had no effect on conduction of constrictor responses to ATP, regardless of occlusion or reperfusion duration.
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Discussion |
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The present study tested the hypothesis that I/R alters conducted vasomotor responses in cerebral arterioles. There are 2 major findings. First, reactivity to vasoactive agents, represented by steady state responses to global drug application, was mostly unaffected by I/R. Only in the 2-hour ischemia/24-hour reperfusion group did we observe impairment of vascular responses to dilator agents. Second, ischemia did not attenuate conducted vasomotor responses, initiated by focal, transient application of adenosine and ATP. Rather, I/R markedly potentiated conducted dilation, 24 hours after the onset of reperfusion. Conduction occurred with virtually no loss in these I/R arterioles, in contrast to the rapid longitudinal decay of conducted responses seen in sham-control vessels. This postischemic augmentation of vasomotor conduction is apparently specific for dilation, because I/R did not alter conducted constriction to ATP, and moreover was not observed after an acute (1 hour) reperfusion period.
Ischemia and reperfusion can cause abnormal vascular reactivity,11 dilation of pial arterioles,21 as well as injury to both vascular smooth muscle and endothelial cells.12 Moreover, vascular abnormalities may evolve over time after I/R.22 We therefore examined the effects of both 1-hour and 24-hour reperfusion periods on the vascular function of penetrating arterioles. In the present study, reactivity to vasoactive agents, including adenosine, ATP, nitroprusside (a nitric oxide donor), and pH changes, was on the whole unaffected by I/R. Only in the 2-hour ischemia/24-hour reperfusion group did we observe attenuated dilator responses to adenosine and to ATP. In the cerebral vasculature, the dilating action of adenosine involves activation of smooth muscle A2A receptors,16 whereas ATP acts on smooth muscle P2X1 receptors to evoke constriction,23 and on endothelium P2Y124 and P2Y223 receptors to cause dilation. Thus, our reactivity findings indicate that severe I/R may disturb both smooth muscle– and endothelium-dependent responses.
Previous studies revealed that ATP-induced dilation in cerebral arteries and arterioles is mediated by both nitric oxide (NO) and endothelium-dependent hyperpolarizing factors (EDHF).17 P2Y1 receptor activation leads to NO release, whereas stimulation of P2Y2 receptors causes production of both NO and EDHF.14,25 In the MCA, I/R (2-hour MCAO followed by 24 reperfusion) may markedly upregulate either the EDHF component only,18 or both NO and EDHF components, apparently by augmenting the endothelial Ca2+ responses to purinoreceptor stimulation.14 In contrast, penetrating arterioles in this study did not exhibit enhanced reactivity to ATP. Rather, responses were either unchanged (1-hour MCAO/24-hour reperfusion), or significantly impaired (2-hour MCAO/24-hour reperfusion). Based on these findings, we conclude that that I/R may have differential effects on cerebral arteries and penetrating arterioles.
Conducted vasomotor responses, triggered by a focal, transient stimulus, was first systematically investigated in the peripheral vasculature.26 These responses have since been characterized in various vascular beds, including cerebral vessels. Past studies have documented the in vivo presence of conducted constriction in mouse pial arterioles.27 More recently, conducted vasomotor responses have been described in isolated penetrating arterioles to various vasoactive agents, including adenosine and ATP.9,10
Cerebral arterioles in the present study exhibited rapid conducted vasomotor responses to adenosine and ATP. During conduction, the entire vessel appeared to dilate or constrict concordantly with little lag between local and distant responses. Accumulating evidence suggests that this behavior is mediated mainly by the longitudinal transmission of hyperpolarizing or depolarizing current, in endothelial or smooth muscle cells that constitute the vessel wall.7,8 The decay of the conducted vasomotor responses therefore may vary with transmembrane and axial resistances.28 Because gap junctions provide the pathway for intercellular coupling, their function and expression could determine axial resistance and thus vascular conduction. In addition to gap junctions, other cellular mechanisms, such as regenerative ionic channels, could either strengthen,28 or directly mediate29 vascular conduction.
In the present study, augmentation of conducted dilation in this study was observed in 24-hour reperfusion vessels and not acutely in 1-hour reperfusion vessels. The timing of this observation implies an alteration in the expression of cellular mechanisms involved in conduction vasodilation, including gap junctions. The lack of decay in the 24-hour postischemic–conducted dilation responses also suggests the involvement of amplifying mechanisms, such as inward rectifier K+ channels,28,29 that may reinforce the spread of hyperpolarization along the vessel wall. Although conducted vasodilation may involve EDHF,30 our reactivity data indicate that the responses of penetrating arterioles to ATP (which involve EDHF14,25) were not enhanced by I/R. Thus, postischemic augmentation of vascular conduction in cerebral arterioles appeared to be independent of an EDHF-related mechanism. Clearly, further studies are needed to determine the precise mechanisms underpinning the enhanced ability of postischemic cerebral arterioles to conduct vasomotor responses.
The augmentation of vasomotor conduction may be an adaptive response to restore cerebral perfusion after ischemia.31 Both pial and intracerebral arterioles contribute to the regulation of cerebral vascular resistance.1 Thus, enhanced conduction of dilation responses (to upstream pial arterioles and arteries) could compensate for postischemic hypoperfusion,11 incurred by occlusion or reduced vascular reactivity at the intracerebral level. On the other hand, unaugmented propagation of vasoconstriction could conceivably also be protective, by migitating the potentially deleterious effect of severe vasoconstriction, which may occur during peri-infarct depolarization.32 Vascular communication is also potentially important in the opening of collateral vessels and subsequent regulation of local perfusion pressure.5 These factors control residual perfusion, and therefore are key determinants of infarct development and stroke outcome.33
In the present study, ischemia followed by 1-hour reperfusion did not alter conducted dilation and constriction responses in isolated intracerebral arterioles. Although our report represents the first study on conducted vasomotor responses in cerebral arterioles after I/R, previous studies have examined the effect of ischemia on vasomotor conduction in noncerebral vasculature.20,34,35 These studies were performed in vivo, and involved occlusion of a feeding artery. Our results appeared to be consistent with the finding by De With et al20 in hamster retractor muscle, in which ischemia and acute reperfusion (1 to 2 hours) did not disrupt conducted dilation, but differ with the reported impairment of conducted vasoconstriction in the hamster cheek pouch,34 and in mouse cremaster muscle after ischemia.35 Such comparisons are difficult to interpret, however, because of disparity in experimental design and methods, including ischemic model (focal cerebral ischemia versus feed artery occlusion) and vessel methodology (isolated vessel versus in vivo preparation). Moreover, these previous studies did not evaluate the effect of prolonged reperfusion on vasomotor conduction, and it is thus unknown whether augmented conduction also occurs in noncerebral vasculature after I/R.
In summary, the present study defined the I/R conditions that may lead to potentiation of conducted dilation responses to adenosine and ATP. Although the mechanisms underlying this effect remain to be defined, the present findings suggest that vascular conduction may be involved in the restoration of cerebral blood flow during and after cerebral ischemia.
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Acknowledgments |
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Sources of Funding
This study was supported in part by the American Heart Association (0255703N, to A.C.N.), and by the American Association of Neurological Surgeons (to G.W.B.).
Disclosures
None.
Received September 12, 2006; accepted September 29, 2006.
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