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(Stroke. 1997;28:2290-2295.)
© 1997 American Heart Association, Inc.

Articles

Mechanisms of Bradykinin-Induced Cerebral Vasodilatation in Rats

Evidence That Reactive Oxygen Species Activate K⁺ Channels

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

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

Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Background and Purpose Relatively little is know regarding mechanisms by which reactive oxygen species produce dilatation of cerebral arterioles. The goal of this study was to test the hypothesis that vasodilator responses of cerebral arterioles to bradykinin, which produces endogenous generation of reactive oxygen species, involve activation of calcium-dependent potassium channels.

Methods We used a cranial window in anesthetized rats to examine effects of catalase (which degrades hydrogen peroxide) on responses to bradykinin. In addition, we examined effects of tetraethylammonium (TEA) and iberiotoxin, inhibitors of calcium-dependent potassium channels, on responses of cerebral arterioles to hydrogen peroxide, bradykinin, and papaverine.

Results In cerebral arterioles (baseline diameter=40±1 µm) (mean±SE), hydrogen peroxide (10 and 100 µmol/L) produced concentration-dependent dilatation. TEA (1 mmol/L), an inhibitor of calcium-dependent potassium channels, produced marked inhibition of vasodilatation in response to hydrogen peroxide. For example, 100 µmol/L hydrogen peroxide dilated arterioles by 13±2% in the absence and 4±1% (P<.05 versus control) in the presence of TEA. Bradykinin (10 nmol/L to 1 µmol/L) also produced concentration-dependent dilatation of cerebral arterioles that was inhibited completely by catalase (100 U/mL). TEA or iberiotoxin markedly inhibited vasodilatation in response to bradykinin. For example, 100 nmol/L bradykinin dilated arterioles by 21±3% in the absence and 2±2% (P<.05 vs control) in the presence of iberiotoxin (50 nmol/L).

Conclusions These findings suggest that dilatation of cerebral arterioles in the rat in response to hydrogen peroxide, or hydrogen peroxide produced endogenously in response to bradykinin, is mediated by activation of calcium-dependent potassium channels. Thus, activation of potassium channels may be a major mechanism of dilatation in response to reactive oxygen species in the cerebral microcirculation.

Key Words: bradykinin • cerebral arteries • vasodilation • rats

	Introduction

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Activation of potassium channels is a major mechanism that produces relaxation of vascular muscle. Recent studies suggest that potassium channels in cerebral blood vessels are activated by diverse stimuli including receptor-mediated agonists, intracellular second messengers, and hypoxia.^1,2 The calcium-dependent potassium channel appears to be an important regulator of tone in cerebral blood vessels.^1,2

Reactive oxygen species, including hydroxyl radical and hydrogen peroxide, are produced in brain in response to vascular injury³ and are known to be vasodilators in the cerebral microcirculation.^4-8 Mechanisms by which reactive oxygen species produce dilatation of cerebral arterioles are not clear. Measurements of membrane potential in vitro and patch-clamp studies suggest that hydrogen peroxide and other oxidizing agents open calcium-dependent potassium channels in noncerebral vascular muscle.^9,10

Cerebral vasodilator responses to bradykinin are endothelium dependent¹¹ and receptor mediated¹² and can be inhibited by scavengers of reactive oxygen spe-cies,^7,8,13,14 which suggests that the response is mediated by reactive oxygen species. Responses of cerebral arterioles to bradykinin are also inhibited by indomethacin, suggesting that the source of reactive oxygen species is the cyclooxygenase pathway.^15,16 In the rat the mediator appears to be hydrogen peroxide, because dilatation of cerebral arterioles in response to bradykinin is inhibited by catalase, which degrades hydrogen peroxide,⁸ or indomethacin.¹⁵ The response to bradykinin in the rat also is potentiated by superoxide dismutase or deferoxamine,⁸ either of which tends to increase the concentration of hydrogen peroxide.

There were two goals of the present study. First, we tested the hypothesis that the vasodilator response of cerebral arterioles in rats to exogenous hydrogen peroxide is mediated by activation of calcium-dependent potassium channels. Because responses to hydrogen peroxide were inhibited by tetraethylammonium ion (TEA), we performed subsequent studies using a stimulus that causes endogenous (physiological) formation of reactive oxygen species. We therefore performed a second series of experiments using bradykinin, which causes endogenous formation of hydrogen peroxide in rats.⁸ Thus, the second goal was to test the hypothesis that dilatation of cerebral arterioles in response to bradykinin involves activation of calcium-dependent potassium channels.

	Materials and Methods

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Experimental Animals
Experiments were performed on 39 Sprague-Dawley rats (weight, 300 to 400 g). Animals were anesthetized with pentobarbital sodium (50 mg/kg IP). Pentobarbital was supplemented regularly at approximately 10 to 20 mg/kg per hour. The trachea was cannulated, and the animals were ventilated mechanically with air and supplemental oxygen. Arterial blood gases were as follows: PCO₂=39±2 mm Hg, PO₂= 127±2 mm Hg, and pH=7.40±0.01 (n=39). A femoral artery was cannulated for measurement of systemic pressure and to sample arterial blood. A femoral vein was cannulated for infusion of drugs. Depth of anesthesia was evaluated by applying pressure to a paw or the tail and observing changes in heart rate or blood pressure. When such changes occurred, additional anesthetic was administered. Arterial pressure averaged 100±1 mm Hg (n=39) in rats and was similar among the different experimental treatment groups.

A cranial window was placed over the left parietal cortex, as described previously.^7,8,15 The cranial window was filled with artificial cerebrospinal fluid warmed to 37°C. Diameters of cerebral arterioles were recorded with the use of a microscope equipped with a television camera coupled to a video monitor. Images were recorded on videotape, and vessel diameters were measured with an image analyzer. All drugs were applied topically over the cerebral vessels. Application of vehicle did not affect vessel diameter.

Experimental Protocols
Six groups of animals were studied. In all groups, the diameter of one arteriole per animal was measured under control conditions and during topical application of drugs.

Cerebral Vasodilator Responses to Exogenous Hydrogen Peroxide
Cerebral vasodilator responses to exogenous hydrogen peroxide were studied in two groups of rats. The diameter of cerebral vessels was measured under control conditions (immediately before application) and after 3 to 5 minutes during steady state responses to hydrogen peroxide. In group 1 (time controls; n=7), changes in arteriolar diameter were measured in response to hydrogen peroxide (10 and 100 µmol/L). A 60-minute recovery period was allowed, and application of hydrogen peroxide to the cranial window was then repeated. This group of animals acted as a time control to establish whether responses to hydrogen peroxide were reproducible.

In group 2 (TEA; n=6), changes in arteriolar diameter were measured in response to hydrogen peroxide (10 and 100 µmol/L). A 60-minute recovery period was allowed, and application of hydrogen peroxide to the cranial window was repeated in the presence of TEA (1 mmol/L). The cranial window was treated with TEA for 15 minutes before and during application of hydrogen peroxide. The purpose of these experiments was to determine whether TEA, a relatively selective inhibitor of calcium-dependent potassium channels at this concentration, inhibits vasodilator responses to hydrogen peroxide.

Cerebral Vasodilator Responses to Bradykinin
Four additional groups of rats were studied. The diameter of cerebral vessels was measured under control conditions (immediately before application of agonists) and after 3 to 5 minutes during steady state responses to agonists.

In group 3 (time controls; n=7), changes in arteriolar diameter were measured in response to bradykinin (10 nmol/L to 1 µmol/L) and papaverine (12.5 and 50 µmol/L). The concentrations of bradykinin and papaverine were applied in a cumulative manner, and the order of application of drugs was varied between experiments. At least 15 minutes was allowed for vessel diameter to recover to control levels between application of vasodilators. When both vasodilators had been applied, a 60-minute recovery period was allowed, and application of bradykinin and papaverine to the cranial window was then repeated in variable order. This group of animals acted as a time control to establish whether responses to bradykinin and papaverine were reproducible.

In group 4 (catalase; n=4), changes in arteriolar diameter were measured in response to bradykinin (10 nmol/L to 1 µmol/L) and papaverine (12.5 and 50 µmol/L). When both vasodilators had been applied, a 60-minute recovery period was allowed, and application of bradykinin and papaverine to the cranial window was repeated in the presence of catalase (100 U/mL). The cranial window was treated with catalase for 15 minutes before and during application of vasodilators. The purpose of these experiments was to determine whether catalase, which degrades hydrogen peroxide, inhibits vasodilator responses to bradykinin.

In group 5 (TEA; n=11), changes in arteriolar diameter were measured in response to bradykinin (10 nmol/L to 1 µmol/L) and papaverine (12.5 and 50 µmol/L). When both vasodilators had been applied, a 60-minute recovery period was allowed, and application of bradykinin and papaverine to the cranial window was repeated in the presence of TEA (1 mmol/L). The cranial window was treated with TEA for 15 minutes before and during application of vasodilators. The purpose of these experiments was to determine whether TEA, a relatively selective inhibitor of calcium-dependent potassium channels at this concentration, inhibits vasodilator responses to bradykinin.

In group 6 (iberiotoxin; n=4), changes in arteriolar diameter were measured in response to bradykinin (10 nmol/L to 1 µmol/L) and papaverine (12.5 and 50 µmol/L). When both vasodilators had been applied, a 60-minute recovery period was allowed, and application of bradykinin and papaverine to the cranial window was repeated in the presence of iberiotoxin (50 nmol/L). The cranial window was treated with iberiotoxin for 15 minutes before and during application of vasodilators. The purpose of these experiments was to determine whether iberiotoxin, a highly selective inhibitor of calcium-dependent potassium channels, inhibits vasodilator responses to bradykinin.

Drugs
Bradykinin, catalase, hydrogen peroxide, papaverine hydrochloride, and tetraethylammonium chloride were obtained from Sigma Chemical Co and dissolved in saline. Iberiotoxin was obtained from Research Biochemicals International and was dissolved in distilled water and diluted in saline.

Statistical Analysis
To examine the effects of antagonists on baseline vessel diameter, paired t tests were used on absolute values (not percent change). For comparison of percent change data in the absence and presence of inhibitors, statistical analysis was also performed with the use of paired t tests. All values are expressed as mean±SE. A value of P<.05 was considered significant.

	Results

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Effects of Exogenous Hydrogen Peroxide
Under control conditions, baseline diameter of cerebral arterioles was similar in the different groups and averaged 40±1 µm. Baseline cerebral arteriolar diameter was stable throughout the time control experiments. Catalase, TEA, and iberiotoxin did not affect the baseline diameter of pial arterioles.

Hydrogen peroxide produced dilatation of cerebral arterioles that was reproducible in response to two application of hydrogen peroxide. Hydrogen peroxide (10 and 100 µmol/L, respectively) increased arteriolar diameter by 9±2% and 14±1% during the first application and 8±2% and 13±2% during the second application (n=7).

Dilator responses to hydrogen peroxide were inhibited by TEA (Fig 1). Thus, these data suggest that cerebral vasodilatation in response to exogenous hydrogen peroxide in rats is dependent on activation of calcium-dependent potassium channels.

View larger version (14K): [in this window] [in a new window]   Figure 1. Vasodilatation in response to hydrogen peroxide was inhibited by TEA. Percent change in diameter of rat cerebral arterioles in response to hydrogen peroxide in the absence (control) and presence of TEA (1 mmol/L; n=6) is shown. Baseline diameter of cerebral arterioles was 38±2 and 39±2 µm in the absence and presence of TEA (P>.05). Values are mean±SE. *P<.05 vs control response.

Effects of Bradykinin
Bradykinin and papaverine produced concentration-dependent dilatation of cerebral arterioles that was reproducible. Bradykinin (10 nmol/L, 100 nmol/L, and 1 µmol/L, respectively) increased arteriolar diameter by 10±1%, 15±2%, and 28±4% during the first application and 12±2%, 23±3%, and 38±5% during the second application (n=7). Papaverine (10 and 55 µmol/L, respectively) increased arteriolar diameter by 10±3% and 23±4% during the first application and 13±5% and 25±6% during the second application (n=3).

Dilator responses to bradykinin were inhibited completely by catalase (Fig 2). In contrast, catalase had no effect on responses to papaverine (Fig 2).

View larger version (10K): [in this window] [in a new window]   Figure 2. Vasodilatation in response to bradykinin was inhibited by catalase. Percent change in diameter of rat cerebral arterioles in response to bradykinin (left, n=4) and papaverine (right, n=4) in the absence (control) and presence of catalase (100 U/mL) is shown. Baseline diameter of cerebral arterioles was 49±4 and 51±3 µm in the absence and presence of catalase (P>.05). Values are mean±SE. *P<.05 vs control response.

TEA markedly inhibited dilator responses of cerebral arterioles to bradykinin (Fig 3). This effect of TEA was selective, because responses to papaverine were not affected by TEA (Fig 3). Similarly, iberiotoxin caused marked inhibition of vasodilator responses to bradykinin, and this effect was selective (Fig 4). These findings suggest that responses of cerebral arterioles to bradykinin involve activation of calcium-dependent potassium channels.

View larger version (10K): [in this window] [in a new window]   Figure 3. Vasodilatation in response to bradykinin was inhibited by TEA. Percent change in diameter of rat cerebral arterioles in response to bradykinin (left, n=7 to 11) and papaverine (right, n=3 to 6) in the absence (control) and presence of TEA (1 mmol/L) is shown. Baseline diameter of cerebral arterioles was 40±2 and 42±2 µm in the absence and presence of TEA (P>.05). Values are mean±SE. *P<.05 vs control response.

View larger version (11K): [in this window] [in a new window]   Figure 4. Vasodilatation in response to bradykinin was inhibited by iberiotoxin. Percent change in diameter of rat cerebral arterioles in response to bradykinin (left, n=4) and papaverine (right, n=4) in the absence (control) and presence of iberiotoxin (50 nmol/L). Baseline diameter of cerebral arterioles was 34±2 and 37±3 µm in the absence and presence of iberiotoxin (P>.05). Values are mean±SE. *P<.05 vs control response.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
There are two major new findings of this study. First, dilatation of cerebral arterioles in response to exogenous hydrogen peroxide in rats is inhibited selectively by TEA. This finding suggests that hydrogen peroxide causes activation of calcium-dependent potassium channels in cerebral arterioles. Second, bradykinin-induced dilatation of cerebral arterioles in the rat, which appears to be mediated by hydrogen peroxide, is selectively inhibited by TEA and iberiotoxin. These findings suggest that endogenous formation of hydrogen peroxide also causes dilatation of cerebral arterioles through activation of calcium-dependent potassium channels. Thus, these studies provide new insight into mechanisms that mediate cerebral vasodilatation in response to endogenous production of reactive oxygen species.

Effects of Hydrogen Peroxide in Cerebral Blood Vessels
Previous studies have shown that reactive oxygen species, either applied directly in the case of hydrogen peroxide or generated with the use of preparations such as xanthine plus xanthine oxidase, produce dilatation of cerebral arterioles in several species.^4-6,8,17 Similar results were obtained in the present experiments. We found that hydrogen peroxide produced dilatation of cerebral arterioles.

We considered the possibility that hydrogen peroxide could potentially damage blood vessels. It seems unlikely that cerebral arterioles were damaged by hydrogen peroxide in the present study because vessel diameter returned to the control level after application of hydrogen peroxide and the vasodilator response to hydrogen peroxide was reproducible.

Vasodilator Responses of Cerebral Vessels to Bradykinin
Dilator responses of cerebral arterioles to bradykinin are endothelium dependent.^11,18 Thus, it seems likely that the vasodilator response to bradykinin is a direct vascular response and unlikely that indirect effects on parenchymal tissue contribute to dilatation of cerebral arterioles in response to bradykinin. In previous studies responses of cerebral arterioles to bradykinin were inhibited by indomethacin or superoxide dismutase plus catalase.^13-16 Thus, responses of cerebral arterioles to bradykinin are dependent on intact endothelium and cyclooxygenase activity and are mediated by reactive oxygen species.

In the present study bradykinin-induced cerebral vasodilatation was completely inhibited by catalase, which degrades hydrogen peroxide, confirming our previous finding in rats.⁸ In cats and mice, cerebral vasodilatation in response to bradykinin is inhibited by superoxide dismutase plus catalase or deferoxamine and thus may be mediated by hydroxyl radical.^13,14 In contrast, in rats, deferoxamine, an iron chelator that inhibits generation of hydroxyl radical from hydrogen peroxide, and superoxide dismutase enhance rather than inhibit cerebral vasodilatation induced by bradykinin.⁸ This pharmacological profile suggests that bradykinin-induced cerebral vasodilatation in rats is mediated by endogenous formation of hydrogen peroxide.

In studies with application of exogenous hydrogen peroxide, cerebral vasodilatation could potentially be due to generation of hydroxyl radical. In the presence of iron, hydrogen peroxide can be catalyzed, by means of the Haber-Weiss reaction, to hydroxyl radical, which is vasoactive.^4,5 Because hydroxyl radical is extremely reactive and essentially cannot diffuse from its site of formation,¹⁹ generation at its site of action is required to mediate vasodilatation. This mechanism does not seem to be present in rats, because cerebral vasodilator responses to bradykinin are blocked by catalase and augmented by superoxide dismutase and deferoxamine.⁸ We recognize that there are limitations in precisely defining, using pharmacological approaches, which reactive oxygen species mediate responses of cerebral arterioles. Considering the present findings and previous studies, we conclude that dilatation of cerebral arterioles in response to bradykinin is mediated by reactive oxygen species, but we cannot solely implicate a particular species.

Role of Potassium Channels
Large-conductance potassium channels have been described in cerebral blood vessels.^1,2,20 Activity of these channels can be inhibited with TEA, iberiotoxin, or charybdotoxin.¹ Recent studies suggest that activation of these potassium channels mediates cerebral vasodilatation in response to isoproterenol,^21,22 calcitonin gene–related peptide,²³ and activation of adenylate cyclase (increases in cAMP).^21,24

Hydrogen peroxide inactivates calcium pumps in sarcoplasmic reticulum and plasma membranes of vascular ²⁵ and thus may produce an increase in the concentration of intracellular calcium. Patch-clamp studies and measurement of membrane potential suggest that hydrogen peroxide increases activity of calcium-dependent potassium channels in noncerebral vascular muscle.^9,26 Oxidizing agents such as 5,5'-dithio-bis(2-nitrobenzoic acid) and oxidized glutathione also increase activity of calcium-dependent potassium channels in vascular muscle.¹⁰ Based on these studies, we anticipated that dilator responses of cerebral arterioles to hydrogen peroxide may be mediated by activation of calcium-dependent potassium channels. We found that dilatation of cerebral arterioles in response to exogenous hydrogen peroxide and bradykinin was inhibited by TEA and iberiotoxin. These findings suggest that dilatation of cerebral arterioles in response to exogenous hydrogen peroxide or endogenous hydrogen peroxide formed in response to bradykinin is mediated by activation of calcium-dependent potassium channels.

It is unlikely that inhibitory effects of iberiotoxin or TEA on dilatation of cerebral arterioles were nonspecific. Iberiotoxin is considered to be highly selective for calcium-dependent potassium channels.¹ We have shown in a previous study in rabbits that iberiotoxin does not inhibit dilatation of cerebral arterioles in response to sodium nitroprusside, acetylcholine, and aprikalim, a direct activator of ATP-sensitive potassium channels.²⁴ The findings with acetylcholine indicate that iberiotoxin does not produce nonspecific impairment due to effects on ion channels in endothelium. Furthermore, in the present study we found that neither iberiotoxin nor TEA inhibited dilator responses of cerebral arterioles to papaverine. Thus, there is considerable evidence that the effect of iberiotoxin (and TEA) on responses of cerebral arterioles to hydrogen peroxide was specific.

A recent study suggests that dilatation of feline pial vessels to hydrogen peroxide is mediated by activation of ATP-sensitive potassium channels.²⁷ Thus, our findings in the present study and those obtained recently²⁷ support the concept that activation of potassium channels is a major mechanism of relaxation of cerebral vessels in response to reactive oxygen species. It is possible that the specific potassium channel (ATP sensitive versus calcium dependent) that is activated by hydrogen peroxide may differ in different species. The novel aspect of the present experiments is that these are the first data to suggest that endogenously formed (ie, physiological levels of) reactive oxygen species produce relaxation of vascular muscle by activation of potassium channels.

Inhibitors of calcium-dependent potassium channels produce depolarization and contraction of cerebral arteries in vitro²⁰ and constriction of the basilar artery in vivo.²⁸ In contrast, inhibitors of calcium-dependent potassium channels had no significant effect on baseline diameter of cerebral arterioles (cerebral microvessels) in the present and previous studies in vivo.^{23,24,27,29,30} In the rat, we studied arterioles with a mean baseline diameter of approximately 40 µm. We are not aware of any data in vitro in which inhibitors of calcium-dependent potassium channels produced depolarization and contraction in small cerebral microvessels. The explanation for the finding that inhibitors of calcium-dependent potassium channel constrict large cerebral arteries (in vitro and in vivo) but not cerebral microvessels is not clear. We speculate that there may be segmental differences (large arteries versus microvessels) in the influence of inhibitors of calcium-dependent potassium channels on basal tone. There may also be segmental differences in the activity of calcium-dependent potassium channels under basal conditions. Because membrane potential was not measured in these arterioles, there is no direct evidence concerning whether depolarization occurred in response to the inhibitors of potassium channels. However, because baseline diameter was unchanged by these inhibitors, it seems reasonable to assume that the vessels were not significantly depolarized.

There are potential limitations in interpretation of data concerning function of ion channels with the use of pharmacological approaches in vivo. Interpretation of such data is dependent on several factors, perhaps the most important being selectively of the inhibitors used. To this end, we have used relatively selective inhibitors and tested specificity. Although in vivo approaches to study the functional importance of potassium channels have limitations, compared with studies of isolated vessels in vitro, studies in vivo also have potential advantages. Variables such as blood pressure, pulse pressure, and blood flow probably are important determinants of membrane potential, which may be a determinant of responses to potassium channel activators and inhibitors. In addition, cerebral microvessels can be studied routinely in vivo. We are not aware of any laboratory that routinely measures membrane potential in cerebral microvessels in vitro or membrane potential of cerebral vessels in vivo.

In conclusion, these findings suggest that dilatation of cerebral arterioles in response to hydrogen peroxide is mediated in large part by activation of calcium-dependent potassium channels. This mechanism appears to be of physiological relevance because cerebral vasodilator responses to bradykinin are mediated by endogenous hydrogen peroxide and are also markedly reduced by inhibitors of calcium-dependent potassium channels. Thus, our findings provide evidence that reactive oxygen species may modulate cerebral vascular tone in vivo through activation of potassium channels.

	Acknowledgments

 
This study was supported by National Institutes of Health grants HL 38901, HL 16066, NS 24621, HL 14355, and AG 10269; by Research Funds from the Veterans Administration; and by a Grant-In-Aid from the American Heart Association (95014510). Dr Faraci is an Established Investigator of the American Heart Association. 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. The authors thank Dale Kinzenbaw for excellent technical assistance.

Received June 3, 1997; revision received August 5, 1997; accepted August 19, 1997.

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