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(Stroke. 1997;28:392-397.)
© 1997 American Heart Association, Inc.

Articles

Effect of Subarachnoid Hemorrhage on Cerebral Vasodilatation in Response to Activation of ATP-Sensitive K⁺ Channels in Chronically Hypertensive Rats

Christopher G. Sobey, PhD; Donald D. Heistad, MD Frank M. Faraci, PhD

the Departments of Internal Medicine (C.G.S., D.D.H., F.M.F.) and Pharmacology (D.D.H., F.M.F.), Cardiovascular Research Center, and Center on Aging, University of Iowa College of Medicine, Iowa City.

Correspondence to Dr Donald Heistad, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242-1081.

	Abstract

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Background and Purpose Cerebral vasodilatation in response to aprikalim, an opener of ATP-sensitive K⁺ channels, is selectively augmented after subarachnoid hemorrhage (SAH). Vasodilatation in response to activation of ATP-sensitive K⁺ channels, however, is impaired during chronic hypertension. Hypertension may contribute to a worse outcome after SAH, but the nature of the relationship between hypertension and SAH is uncertain. In the present study we examined responses of the basilar artery to aprikalim after SAH in normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP).

Methods In anesthetized WKY and SHRSP, we measured changes in diameter of the basilar artery in response to aprikalim and papaverine using a cranial window 2 days after injection of 0.3 mL saline or autologous blood into the cisterna magna.

Results Under control conditions, aprikalim (0.1 to 1 µmol/L) and papaverine (10 to 100 µmol/L) produced dilatation of the basilar artery. After SAH, responses to aprikalim were not significantly altered in WKY and were markedly increased in SHRSP compared with saline-injected control rats. In contrast, vasodilator responses to papaverine were not changed by SAH in either WKY or SHRSP, suggesting that augmented vasodilatation in response to aprikalim after SAH was selective.

Conclusions Responses of the basilar artery to aprikalim were greatly augmented in SHRSP after SAH. Because vasodilator responses to many stimuli are impaired after SAH and cerebral vasodilator responses to several stimuli are impaired by chronic hypertension, augmented responses to activation of K⁺ channels despite the presence of hypertension are unusual.

Key Words: basilar artery • hypertension • potassium channels • subarachnoid hemorrhage • vasodilatation • rats

	Introduction

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Subarachnoid hemorrhage produces several abnormalities of vascular function. After SAH, cerebral vascular muscle is partially depolarized,^{1 2} cerebral vasodilator mechanisms to several stimuli are impaired in experimental animals^{3 4 5 6 7} and humans,^{8 9} and cerebral vasospasm occurs frequently.¹⁰

Hypertension is up to 8 times more frequent in patients with SAH than in control subjects,¹¹ but the precise nature of the relationship between hypertension and SAH is uncertain.¹² Furthermore, there is evidence that humans with hypertension are at a higher risk than normotensives for poor outcome after SAH.^{13 14} The effects of SAH on cerebral vascular function during chronic hypertension are not known.

We recently found that dilatation of the basilar artery in response to aprikalim is augmented after SAH in normotensive Sprague-Dawley rats.⁷ Aprikalim produces vasodilatation by activation of ATP-sensitive K⁺ channels and hyperpolarization of vascular muscle.¹⁵ Thus, vascular hyperpolarization may be an effective mechanism to produce relaxation of cerebral vessels after SAH. The vasodilator potency of aprikalim is reduced, however, in basilar arteries of chronically hypertensive rats¹⁶ and hence might not be effective after SAH.

In this study we used a model of SAH in which responses of the basilar artery of rats could be evaluated in vivo using a cranial window preparation. The purpose of the study was to determine whether, after SAH, dilator responses of the basilar artery to aprikalim are augmented in SHRSP, as in Sprague Dawley rats,⁷ or whether impairment of responses to aprikalim in SHRSP¹⁶ would also be observed after SAH.

	Materials and Methods

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Experimental Model of SAH
Procedures used on animals were approved by the Animal Care and Use Committee of the University of Iowa. Experiments were performed in 8- to 12-month-old (weight, 300 to 450 g) male WKY (n=13) and SHRSP (n=15). Animals were anesthetized with pentobarbital sodium (50 mg/kg IP), and atropine sulfate (15 µg/kg IP) was administered to inhibit airway secretions. Using aseptic technique, we placed a catheter in the left femoral artery for removal of blood. The animal was then placed in a stereotaxic frame, and the atlanto-occipital membrane was exposed. Saline or blood was injected into the CSF with the head in a nose-down position, and the superior plane of the parietal bone was tilted forward by approximately 30°. A 27-gauge hypodermic needle was mounted on the manipulating arm of a stereotaxic device, and the needle was inserted into the cisterna magna. Approximately 0.1 mL of CSF was gently aspirated. Saline or freshly drawn autologous nonheparinized blood (0.3 mL) was then injected into the cisterna magna in approximately 1 minute. After blood was removed, an equal volume of saline was injected into the arterial catheter. Thus, in this study the term SAH refers to an experimental model of SAH produced by injection of blood into the cisterna magna.

After injection of saline or blood into the cisterna magna, the rats were maintained in a 30° nose-down position for 30 minutes, the neck muscles were approximated, and the incision was closed with sutures. The catheter was then removed from the femoral artery, and the leg incision was closed. The procedure was completed within approximately 1 hour, and anesthesia was supplemented with 10 to 20 mg/kg IP if necessary. Animals were studied 2 days later.

Two days after injection of saline or blood into the cisterna magna, the animals were again anesthetized with pentobarbital sodium (50 mg/kg IP), and anesthesia was supplemented at 10 to 20 mg·kg^-1·h^-1. A tracheostomy was performed, and the animals were mechanically ventilated with room air and supplemental oxygen. Skeletal muscle paralysis was produced with gallamine triethiodide (5 to 10 mg/kg IV). Depth of anesthesia was evaluated by applying pressure to a paw or the tail and observing changes in heart rate or blood pressure. Additional anesthetic was administered when such changes occurred. We have shown previously that this rate of supplementation is sufficient to maintain anesthesia in nonparalyzed rats.¹⁷

A catheter was placed in the right femoral artery to measure systemic pressure and to obtain arterial blood. The right femoral vein was cannulated for infusion of supplemental anesthetic. Arterial blood gases were monitored and maintained within normal levels throughout the experiment. Body temperature was maintained at 37°C to 38°C with a heating pad.

A craniotomy was performed over the ventral brain stem as described in detail previously.⁷ The cranial window was suffused with artificial CSF (temperature, 37°C to 38°C) at 3 mL/min, and a portion of the dura mater was opened. In CSF sampled from the craniotomies, PCO₂ was 44±1 mm Hg, PO₂ was 55±2 mm Hg, and pH was 7.37±0.01. We measured the diameter of the basilar artery using a microscope equipped with a television camera coupled to a video monitor and an image shearing device.

One WKY and one SHRSP received a second injection of blood 2 days after the first injection of blood. The SHRSP died within 30 minutes after the second injection. The WKY survived, and when studied 2 days later (ie, on day 4) was found to have responses similar to those in animals that received one injection. Data from that rat were therefore included with data from the other WKY that were injected with blood.

Vascular Responses
We studied four groups of rats: (1) WKY that were injected with saline (n=7), (2) SHRSP that were injected with saline (n=6), (3) WKY that were injected with blood (n=6), and (4) SHRSP that were injected with blood (n=9).

Vasodilators were applied in a cumulative manner, by suffusion over the basilar artery, and the maximum change in diameter was recorded. We studied the dilator response of the basilar artery to aprikalim (10^-7, 3x10^-7, and 10^-6 mol/L) and papaverine (10^-5 and 10^-4 mol/L). Aprikalim is a direct activator of ATP-sensitive K⁺ channels.¹⁸ In the doses used, there was no effect of these drugs on blood pressure or heart rate.

Drugs
Papaverine hydrochloride was obtained from Sigma Chemical Co and was dissolved and diluted in saline. Aprikalim [trans-(-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothio-pyran carbothiamide-1-oxide]¹⁸ was kindly supplied by Rhone-Poulenc Rorer. A 10^-3 mol/L stock solution of aprikalim and also glibenclamide (Sigma) was prepared by dissolving the drug in 50% dimethyl sulfoxide and 50% normal saline, and subsequent dilutions were made in saline. The vehicle for aprikalim and glibenclamide (0.05% dimethyl sulfoxide at 10^-6 mol/L of each agent) had no effect on diameter of the basilar artery.

Statistical Analysis
All comparisons were made with the use of unpaired t tests. Values are presented as mean±SE. A value of P<.05 was considered significant.

	Results

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During the 2 days after intracisternal injection of blood or saline, all animals except one appeared healthy with no detectable change in motor function or behavior. One SHRSP died 30 minutes after a single intracisternal injection of blood.

Two days after injection of blood, no thrombus was visible in the cranial window over the basilar artery in any of the rats. In some WKY and SHRSP in which blood had been injected, the CSF was red when the dura was opened but became clear after the cranial window was suffused with artificial CSF.

Mean arterial pressure was 117±2 and 106±3 mm Hg in saline- and blood-injected WKY, respectively. Mean arterial pressure was 180±5 and 170±13 mm Hg in saline- and blood-injected SHRSP, respectively. Diameter of the basilar artery was smaller in SHRSP than WKY (192±7 versus 229±6 µm; P<.05) and was not significantly altered by injection of blood in either WKY or SHRSP.

Responses to Aprikalim
Aprikalim produced dilatation of the basilar artery in saline-treated WKY (Fig 1). Dilator responses to aprikalim in WKY after SAH and in saline-treated WKY were not statistically significant (Fig 1).

View larger version (14K): [in this window] [in a new window]   Figure 1. Change in diameter of basilar artery in WKY and SHRSP in response to aprikalim 2 days after injection of saline (open bars) or blood (solid bars). Values are mean±SE. *P<.05 vs saline-treated rats. In WKY, vessel diameter was 229±6 µm in saline-injected and 241±12 µm in SAH rats (P>.05). In SHRSP, vessel diameter was 192±7 µm in saline-injected and 203±11 µm in SAH rats (P>.05). n=6 to 7 in each group.

Dilator responses of the basilar artery to aprikalim of saline-treated SHRSP (Fig 1) were not statistically different from those of saline-treated WKY (Fig 1; P=.06 for 10^-6 mol/L aprikalim in saline-treated WKY versus saline-treated SHRSP). Dilator responses of the basilar artery to aprikalim were markedly augmented in SHRSP after SAH (Fig 1) and were not significantly different from responses in either WKY group. In two blood-injected SHRSP, glibenclamide (10^-6 mol/L) had no effect on basilar artery diameter and inhibited dilator responses to 10^-6 mol/L aprikalim by more than 60% (data not shown).

Responses to Papaverine
Papaverine produced dilatation of the basilar artery in saline-treated WKY (Fig 2). After SAH in WKY, responses of the basilar artery to papaverine were not different than in saline-injected WKY (Fig 2).

View larger version (13K): [in this window] [in a new window]   Figure 2. Change in diameter of basilar artery in WKY and SHRSP in response to papaverine 2 days after injection of saline (open bars) or blood (solid bars) rats. Values are mean±SE; n=6 to 7 in each group.

Papaverine produced dilatation of the basilar artery in saline-treated SHRSP (Fig 2). After SAH in SHRSP, responses of the basilar artery to papaverine were not different than in saline-injected SHRSP (Fig 2). There was no difference between all groups in the response of the basilar artery to papaverine (Fig 2).

	Discussion

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The major new finding in the present study is that dilatation of the basilar artery in response to activation of ATP-sensitive K⁺ channels by aprikalim is markedly augmented in chronically hypertensive rats after injection of blood into the cisterna magna. Dilatation of the basilar artery to papaverine was unaffected by injection of blood in either WKY or SHRSP, which suggests that augmentation of vasodilatation to aprikalim after injection of blood in SHRSP is selective.

Effect of SAH on Cerebral Dilatation
Aprikalim produces relaxation of cerebral vessels.^{7 16 19 20} In the present study, dilator responses of the basilar artery to aprikalim in WKY were preserved after SAH. Surprisingly, vasodilator responses to aprikalim were markedly augmented in SHRSP after SAH. Aprikalim dilates the basilar artery through activation of ATP-sensitive K⁺ channels.^{7 16 19} Cerebral vasodilatation in response to aprikalim is inhibited by glibenclamide, an inhibitor of ATP-sensitive K⁺ channels,^{7 19} but not by iberiotoxin,²⁰ which inhibits calcium-activated K⁺ channels. Glibenclamide inhibits vasodilatation in response to aprikalim after SAH,⁷ which indicates that augmented dilator responses to aprikalim after SAH are mediated by ATP-sensitive K⁺ channels.

The mechanism that accounts for enhanced vasodilatation in response to activation of ATP-sensitive K⁺ channels after SAH in SHRSP is not clear. Increased dilatation in response to activation of ATP-sensitive K⁺ channels after SAH may be related in part to depolarization of cerebral vascular muscle. Changes in responsiveness of the basilar artery after SAH were observed in the absence of vasospasm in the present study, which suggests that vessels were not significantly depolarized. Hence, we have observed marked alterations in dilator mechanisms of the basilar artery after SAH in SHRSP that are not an indirect effect that is related to increased vasoconstrictor tone.

In rats, intracisternal injection of 0.3 to 0.5 mL of blood produces an extensive thrombus over the ventral brain surface within 1 hour.⁷ Consistent with our previous findings⁷ and those of others²¹ in rats, we found that minimal or no thrombus was visible over the basilar artery 2 days after a single injection of blood. In some WKY and SHRSP in which blood had been injected, the CSF was still red when the dura was opened. We do not know the duration that blood remained in contact with the basilar artery before clot lysis, but it seems likely that there was prolonged exposure of the basilar artery to blood or blood components in the CSF.

Several substances are present in CSF after SAH that may contribute to changes in responses of the basilar artery after exposure to blood. For example, oxyhemoglobin from lysed red blood cells may penetrate the walls of cerebral arteries after SAH.²² Oxygen radicals produced from oxyhemoglobin²³ and bilirubin (a breakdown product)²⁴ may alter both constrictor and dilator responses of cerebral arteries. To our knowledge, effects of blood components on expression and function of K⁺ channels in brain arteries have not been reported, but some of these blood components could contribute to augmented dilator response of the basilar artery to aprikalim.

Several cerebral vasodilator mechanisms are impaired after SAH in animals^{3 4 5 6 7} and humans.^{8 9} Depolarization and vasospasm are inhibited in vitro and in vivo by nicorandil,² a vasodilator that activates both K⁺ channels and guanylate cyclase.²⁵ Our data suggest that selective openers of ATP-sensitive K⁺ channels (and perhaps other K⁺ channels) may be efficacious vasodilators after SAH. Dilator responses of the basilar artery to calcitonin gene–related peptide, an endogenous activator of ATP-sensitive K⁺ channels, are augmented after SAH in Sprague-Dawley rats.⁷ One might anticipate that responses to an endogenous activator of ATP-sensitive K⁺ channels would be similarly enhanced in SHRSP. Thus, we suggest that the effect of SAH on dilatation in response to activation of ATP-sensitive K⁺ channels may be of pathophysiological relevance.

The present data do not allow us to determine whether activity of ATP-sensitive K⁺ channels is increased or if vascular responsiveness to hyperpolarization is enhanced after SAH. Activation of K⁺ channels hyperpolarizes smooth muscle membranes and inhibits contraction to several agonists and also to low concentrations (<30 mmol/L) of potassium chloride.²⁶ When vascular muscle is moderately depolarized, such as after SAH, hyperpolarization would be expected to produce a greater decrease in vascular tension.²⁷ The present and previous⁷ findings support the concept that vasodilator effects of a selective activator of K⁺ channels, or perhaps other vasodilators that act through hyperpolarization of vascular muscle, might be augmented in moderately depolarized cerebral arteries after SAH.

Dilatation of the basilar artery in response to papaverine was similar among all groups of rats. The exact mechanism(s) by which papaverine produces vasodilatation is not well understood. Papaverine inhibits voltage-gated calcium channels²⁸ but may also inhibit phosphodiesterases.²⁹ Enhanced vasodilator responses to aprikalim and preserved responses to papaverine after SAH suggest that augmented vasodilatation by aprikalim may be selective for agents that activate K⁺ channels.

Hypertension and SAH
Chronic hypertension is associated with abnormalities of cerebral vascular function, including impaired endothelial function and impaired vasodilator responses mediated by activation of ATP-sensitive K⁺ channels.¹⁶ Hypertension is reported to be up to 8 times more frequent among patients with SAH,^{30 31} but the nature of the relationship between hypertension and aneurysmal SAH is uncertain.¹²

The effects of SAH on cerebral vascular function during chronic hypertension are not well understood. The finding that cerebral vasodilator responses to aprikalim after SAH are markedly augmented in SHRSP was unexpected. One interpretation of these results might be that responses of the basilar artery to aprikalim, which are usually impaired in SHRSP, are normalized after SAH. The mechanism of these changes could involve an increase (to normal levels) in number or affinity of ATP-sensitive K⁺ channels in the basilar artery. The mechanism of augmentation or normalization of responses to aprikalim after SAH in SHRSP did not involve normalization of arterial pressure in SHRSP, because arterial pressure did not decrease significantly after SAH. We speculate that activation of ATP-sensitive K⁺ channels may be useful for cerebral vasodilatation after SAH, especially in hypertensive patients, for the maintenance of cerebral perfusion and possibly for treatment of vasospasm.

Diameter of Basilar Artery After SAH
The time course of decreases in diameter of the basilar artery after SAH in rats has been described previously with the use of angiography. The peak reduction in vessel diameter occurred 2 days after SAH.³² In our previous study⁷ and preliminary experiments, we found that abnormalities of basilar artery dilator responses are similar, and not greater, when examined either 2 days after a single injection or on day 4, after a second injection of blood is given on day 2. Thus, we suggest that 2 days after SAH is an appropriate time to evaluate cerebral vascular abnormalities in rats.

In Sprague-Dawley rats we found only a 10% reduction in basilar artery diameter after SAH.⁷ In the present study we found no significant reduction in mean diameter of the basilar artery after SAH in either WKY or SHRSP. These observations raise the question of the value of this rat model for studies of vasomotor changes after SAH. It should be noted that vasospasm after SAH is inconsistent among different species: vasospasm is profound in dogs,³³ variable in rabbits,^{34 35} and modest in rats.^{7 32} In humans, approximately one half of SAH patients do not develop vasospasm.¹⁰ Several features of the rat model of SAH resemble those of human SAH, such as impaired dilator responses mediated by endothelium-dependent and cyclic GMP–mediated mechanisms.^{9 36} We therefore suggest that the absence of vasospasm after SAH in the present study does not detract from the conclusions that vasodilator responses to aprikalim are selectively augmented after SAH, especially in chronically hypertensive rats. Because several cerebral vasodilator mechanisms are impaired by either hypertension or SAH alone, the finding that vasodilator responses to aprikalim are markedly augmented after SAH in hypertensive rats is indeed unusual.

In summary, dilator responses of the basilar artery to aprikalim after SAH are substantially augmented in SHRSP rats. In contrast, responses to papaverine are unchanged after SAH. These findings suggest that responsiveness of the basilar artery to activation of ATP-sensitive K⁺ channels is increased after SAH and that this alteration is dramatic and potentially useful in chronic hypertension.

	Selected Abbreviations and Acronyms

 

CSF = cerebrospinal fluid SAH = subarachnoid hemorrhage, or experimental model of subarachnoid hemorrhage produced by injection of blood into the cisterna magna SHRSP = stroke-prone spontaneously hypertensive rats WKY = Wistar-Kyoto rats

	Acknowledgments

 
These studies were supported by National Institutes of Health grants HL-16066, NS-24621, HL-14388, AG-10269, and HL-38901; by Research Funds from the Veterans Administration; and by a Grant-in-Aid from the American Heart Association (95014510). Dr Sobey is the recipient of a C.J. Martin Fellowship from the National Health and Medical Research Council of Australia and a Michael J. Brody Fellowship in Basic Cardiovascular Research from the University of Iowa. Dr Faraci is an Established Investigator of the American Heart Association. We acknowledge the technical assistance of Cynthia Lynch. We thank Arlinda LaRose for secretarial assistance.

Received March 28, 1996; revision received October 21, 1996; accepted October 24, 1996.

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Editorial Comment

David R. Harder, PhD, Guest Editor

Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wis

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 
The accompanying article by Sobey et al suggests that K⁺ channel openers may be effective in dilating cerebral arteries after SAH in certain forms of hypertension. Cerebral vasospasm is often a complication of SAH and is notoriously resistant to treatment with Ca²⁺ channel blockers. While this report does not directly demonstrate efficacy of K⁺ channel activators on reversing vasospasm in a rat model of SAH in that no spasm was observed after cisternal injection of blood, it does demonstrate that exposure to subarachnoid blood significantly enhances the sensitivity of basilar arteries of SHRSP to the K⁺ channel opener aprikalim. This is an interesting finding in light of the fact that this laboratory had recently reported that the sensitivity of cerebral arteries to pharmacological manipulation of ATP-sensitive K⁺ channels (K_ATP) was reduced in SHRSP (see "Discussion").

The mechanism by which subarachnoid blood enhances the response of basilar arteries of hypertensive rats to aprikalim can only be speculated in that very little has been done with respect to the cellular mechanisms of cerebral vasospasm at the single ion channel level. However, recent patch-clamp studies have found that the activity of the large-conductance Ca²⁺-activated K⁺ channel (K_Ca) is markedly augmented in vascular muscle of spontaneously hypertensive rats.^1R In rat portal vein, pharmacological manipulation by known effectors of the K_ATP channel has been shown to affect K_Ca rather than K_ATP.^2R It is possible that in certain vascular beds or under specific pathological influence a suspected modulator of specific K⁺ channel subtype may modulate a different K⁺ channel in a nonspecific manner. There are many genetically based inherent differences in signal transduction mechanisms between genetically hypertensive animals and their normotensive counterparts.^3R It is quite possible that some component of SAH modulates ion channel activity or isoform subtype in genetically hypertensive animals differently than in a genetically dissimilar normotensive animal. The present study may set an important precedent for studying altered ionic-mediated signal transduction pathways in the hypertensive cerebral circulation.

	Selected Abbreviations and Acronyms

 

CSF = cerebrospinal fluid SAH = subarachnoid hemorrhage, or experimental model of subarachnoid hemorrhage produced by injection of blood into the cisterna magna SHRSP = stroke-prone spontaneously hypertensive rats WKY = Wistar-Kyoto rats

	References

Top Abstract Introduction Materials and Methods Results Discussion References Introduction  References

 

1. England SK, Wooldridge TA, Stekiel WJ, Rusch NJ. Enhanced single-channel K⁺ current in arterial membranes from spontaneously hypertensive rats. Am J Physiol.. 1993;264:H1337-H1345.[Abstract/Free Full Text]
2. Hu SL, Kim HS, Okolie P, Weiss GB. Alterations by glyburide of effects of BRL 34915 and P 1060 on contraction, 86Rb efflux and the maxi-K⁺ channel in rat portal vein. J Pharmacol Exp Ther.. 1990;253:771-777.[Abstract/Free Full Text]
3. Glasgow Genetics Symposium. Hypertension.. 1996;28:895-918.[Abstract/Free Full Text]

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