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(Stroke. 1995;26:1713-1723.)
© 1995 American Heart Association, Inc.

Articles

Role of Potassium Channels in Cerebral Blood Vessels

Takanari Kitazono, MD, PhD; Frank M. Faraci, PhD; Hisao Taguchi, MD, PhD Donald D. Heistad, MD

From the Departments of Internal Medicine and Pharmacology, Cardiovascular Center and Center on Aging, University of Iowa College of Medicine, and Veterans Administration Medical Center, Iowa City.

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

	Abstract

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
Background Hyperpolarization of vascular muscle in response to activation of potassium channels is a major mechanism of vasodilatation. In cerebral blood vessels, four different potassium channels have been described: ATP-sensitive potassium channels, calcium-activated potassium channels, delayed rectifier potassium channels, and inward rectifier potassium channels.

Summary of Review Activation of ATP-sensitive and calcium-activated potassium channels appears to play a major role in relaxation of cerebral arteries and arterioles in response to diverse stimuli, including receptor-mediated agonists, intracellular second messengers, and hypoxia. Both calcium-activated and delayed rectifier potassium channels may contribute to a negative feedback system that regulates tone in large cerebral arteries. The influence of ATP-sensitive and calcium-activated potassium channels is altered in disease states such as hypertension, diabetes, and atherosclerosis.

Conclusions Activation of potassium channels is a major mechanism of cerebral vasodilatation. Alteration of activity of potassium channels and impairment of vasodilatation may contribute to the development or maintenance of cerebral ischemia or vasospasm.

Key Words: cerebral ischemia • potassium channels • vasodilation

	Introduction

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
Relaxation of blood vessels can be mediated by several mechanisms. One major mechanism of vasodilatation is activation of guanylate cyclase and increased production of cGMP^{1 2} (Fig 1). EDRF, which appears to be nitric oxide or a related compound,^{3 4 5} and natriuretic peptides⁶ are two endogenous stimuli that activate guanylate cyclases and thereby produce vasodilatation. A second major mechanism that mediates vasodilatation is activation of adenylate cyclase and production of cAMP (Fig 1). Vasodilatation produced by prostacyclin,⁷ ß-adrenergic agonists,⁸ and several peptides^{9 10 11 12} apparently is mediated by formation of cAMP.

View larger version (24K): [in this window] [in a new window]   Figure 1. Schematic diagram shows three major mechanisms of vasodilatation involving activation of adenylate cyclase, potassium channels, and guanylate cyclase. Both endothelium- dependent and endothelium-independent mechanisms can produce vasodilatation. Several peptides, ß-adrenergic agonists, and nitrovasodilators such as nitroglycerin act directly on vascular muscle to produce relaxation. Prostacyclin (PGI2), which is released from endothelium, ß-adrenergic agonists, and several peptides activate adenylate cyclase and thereby produce vasodilatation. Vasodilatation in response to EDRF (nitric oxide) is mediated by activation of guanylate cyclase. EDHF and potassium channel openers increase the open probability of potassium channels, hyperpolarize vascular muscle, and thereby relax blood vessels.

Recent evidence suggests that several types of potassium channels are present in cerebral blood vessels and that activation of these channels may be a third major mechanism of relaxation in cerebral blood vessels.^{13 14 15 16 17 18} Membrane potential of vascular muscle is a major determinant of vascular tone, and activity of potassium channels is a major regulator of membrane potential.¹⁷ Activation or opening of these channels increases potassium efflux, thereby producing hyperpolarization of vascular muscle. Membrane hyperpolarization closes voltage-dependent calcium channels and thereby causes relaxation of vascular muscle^{13 16 17 19 20 21 22 23 24 25 26} (Fig 1). Membrane potential of vascular muscle is typically in the range of -40 to -60 mV, and changes in this potential of only a few millivolts are associated with significant changes in vascular tone.¹⁷

In this review, we will summarize current evidence regarding the presence and influence of potassium channels in the cerebral circulation. This review will focus on (1) evidence for the presence of potassium channels in cerebral blood vessels, (2) mechanisms of activation of potassium channels, and (3) alterations in the influence of these channels in several disease states.

	Properties of Potassium Channels in Blood Vessels

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
Several types of potassium channels, including ATP-sensitive potassium channels, calcium-activated potassium channels, delayed rectifier potassium channels, and inward rectifier potassium channels, have been identified in blood vessels. Some basic properties of these potassium channels are summarized below.

ATP-Sensitive Potassium Channels
ATP-sensitive potassium channels, which were defined by their sensitivity to intracellular ATP, were first described in cardiac muscle²⁷ and have also been found in skeletal muscle,²⁸ pancreatic ß cells,^{29 30} and neurons.³¹ Recently, ATP-sensitive potassium channels have also been identified in vascular muscle.^{18 20} These channels are closed by ATP binding to an intracellular site and are opened by the dissociation of ATP from this site.^{19 23} Thus, reduction of intracellular ATP opens the channels and produces vasodilatation. Because nonhydrolyzable analogues of ATP also effectively inhibit the activity of this channel, hydrolysis of ATP is not necessary to produce inhibition.³² Activity of ATP-sensitive potassium channels is also affected by other factors, including ADP³³ and reductions in PO₂ or pH.³⁴ Thus, activity of ATP-sensitive potassium channels may reflect the metabolic state of cells.

An important feature of ATP-sensitive potassium channels is that the channel can be activated by synthetic openers of potassium channel openers^{23 35 36 37 38 39 40} and inhibited by sulfonylureas^{19 23 24 26 41 42} (Table 1). Potassium channel openers are a chemically diverse group of compounds that produce hyperpolarization and thereby cause relaxation of vascular muscle.^{35 36 37 38 39 40} Potassium channel openers activate ATP-sensitive potassium channels primarily,^{35 36 37 38 39 40} but some of these compounds have additional effects in some blood vessels. For example, nicorandil appears to also activate cytosolic guanylate cyclase,⁴³ and cromakalim can inhibit uptake and release of intracellular Ca²⁺ stores.^{44 45} Sulfonylureas such as glibenclamide, which are hypoglycemic agents that are widely used in the treatment of diabetes mellitus, inhibit ATP-sensitive potassium channels in blood vessels.^{19 23 24 26 41 42} The exact mechanism by which sulfonylureas inhibit ATP-sensitive potassium channels is still not clear, but it has been suggested that the binding site for glibenclamide is coupled in a negative allosteric manner to the binding site for potassium channel openers.^{46 47}

View this table: [in this window] [in a new window]   Table 1. Potassium Channel Activators and Inhibitors

The primary structure of ATP-sensitive potassium channels is not known. Using photoaffinity labeling with [³H]glibenclamide, 140- and 150-kD polypeptides were identified from pancreatic ß cells⁴⁸ and brain,⁴⁹ respectively. An ATP-sensitive potassium channel has recently been cloned from cardiac tissue.⁵⁰

Calcium-Activated Potassium Channels
Large-conductance calcium-activated potassium channels were first described in skeletal muscle^{51 52} and chromaffin cells.⁵³ calcium-activated potassium channels are also found in vascular muscle.^{54 55 56} These channels are defined on the basis of their activation by intracellular calcium,^{16 17 19} and activity of these channels is also dependent on membrane potential.^{16 17 19} Increases in intracellular calcium in the physiological range increase the open probability of calcium-activated potassium channels.¹⁷ Thus, these potassium channels appear to be activated by membrane depolarization that occurs during vasoconstriction in response to increases in blood pressure^{15 17} or in response to vasoconstrictors such as angiotensin II, endothelin, and serotonin.¹⁷

Calcium-activated potassium channels are divided into at least three subtypes by their conductance: large (200 to 300 ps), intermediate (20 to 60 ps), and small (10 to 14 ps). Large-conductance calcium-activated potassium channels (maxi K channels) appear to be most important in regulation of vascular tone.¹⁹ Large-conductance calcium-activated potassium channels are blocked by extracellular TEA,^{55 57} charybdotoxin,⁵⁸ and iberiotoxin⁵⁹ (Table 1). Low concentrations of TEA (below 1 mmol/L) appear to be relatively selective for large-conductance calcium-activated potassium channels.^{55 57} Charybdotoxin blocks large-conductance calcium-activated potassium channels in vascular muscle (IC₅₀ 2 nmol/L),⁵⁹ although it may inhibit some other types of potassium channels in other tissues.⁶⁰ Iberiotoxin also blocks large-conductance calcium-activated potassium channels in vascular muscle (IC₅₀ 250 pmol/L), and it appears to be highly selective for large-conductance calcium-activated potassium chans.⁶⁰

In contrast to openers of ATP-sensitive potassium channels, few synthetic compounds appear to open calcium-activated potassium channels. Cromakalim has been reported to activate calcium-activated potassium channels in rat basilar artery⁶¹ and rabbit aorta⁶² in vitro. Other investigators, however, have found cromakalim to be without effect on calcium-activated potassium channels at concentrations that cause maximal relaxation of vascular muscle.^{16 55} Dehydrosoyasaponin I (a triterpenoid glycoside) increases the open probability of large-conductance calcium-activated potassium channels when applied to the intracellular but not extracellular side of the membrane of tracheal muscle.⁶³ NS 1619, a benzimidazolone, has also been reported to be an activator of large-conductance calcium-activated potassium channels in vascular muscle.⁶⁴ Dehydrosoyasaponin I and NS 1619 reportedly have no effect on ATP-sensitive potassium channels.^{63 64} If such compounds selectively activate large-conductance calcium-activated potassium channels, they may be useful in studies of the functional role for calcium-activated potassium channels in blood vessels.

Although calcium-activated potassium channels have not been cloned from vascular muscle, a closely related calcium-activated potassium channel has been cloned from the slo locus of Drosophila melangarta.^{65 66} Calcium-activated potassium channels are considered to belong to the superfamily of voltage-gated cation channels.^{67 68 69} The predicted peptide contains consensus structures of this superfamily characterized by the motif of six membrane-spanning segments, a putative voltage sensor, and an S5-S6 linker involved in ion conduction. It also contains a sequence that resembles the EF hand structure of calcium-binding proteins. The channels transcribed and expressed in Xenopus oocytes showed typical activities of large-conductance potassium channels that were gated by membrane potential and by intracellular calcium concentration.

Delayed Rectifier Potassium Channel
Delayed rectifier potassium channels have been described in nearly all excitable membranes⁷⁰ and have also been described in vascular muscle.^{71 72 73 74} The open probability of delayed rectifier potassium channels also increases with membrane depolarization, but open probability is independent of cytoplasmic calcium concentration.⁷⁰

When cells are depolarized, the potassium channels are activated after a short delay, and an outward current produced by activation of these potassium channels returns the membrane potential toward the resting level.⁷⁰ Thus, the delayed rectifier potassium channel appears to be a negative feedback system to regulate vascular tone. Delayed rectifier potassium channels are inhibited by 4-aminopyridine, cesium ion, and high concentrations of TEA but not by charybdotoxin or barium ion⁷⁰ (Table 1).

Inward Rectifier Potassium Channel
Inward rectifier potassium channels have been found in several tissues, including skeletal⁷⁵ and cardiac muscle,⁷⁶ neurons,⁷⁷ blood cells,^{78 79} and endothelium.⁸⁰ The channels have also been described in vascular muscle.^{81 82} Because inward rectifier potassium channels are opened by pronounced hyperpolarization and show sustained inward current, these potassium channels may play an important role in maintaining resting membrane potential and in regulating excitability of these cells. Extracellular cations such as barium and cesium ions block these potassium channels⁸² (Table 1). Recently, a cDNA encoding an inward rectifier potassium channel was cloned from a mouse macrophage cell line⁸³ and mouse brain.⁸⁴

	Presence of Potassium Channels in Cerebral Blood Vessels

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
Direct measurements of membrane potential and potassium current in vitro indicate that several different types of potassium channels are present in cerebral blood vessels. In addition, a number of pharmacological studies using activators and inhibitors have provided functional evidence that potassium channels, especially ATP-sensitive potassium channels and calcium-activated potassium channels, regulate tone of cerebral blood vessels in vitro and in vivo.

ATP-Sensitive Potassium Channels
Many studies using synthetic potassium channel openers and sulfonylurea inhibitors suggest that ATP-sensitive potassium channels are functional in cerebral blood vessels (Table 2). For example, cromakalim, pinacidil, and lemakalim have been reported to produce glibenclamide-sensitive relaxation of cerebral arteries in vitro.^{85 86 87 88 89 90 91 92 93 94 95 96} In addition, direct activators of ATP-sensitive potassium channels cause dilator responses in the basilar artery^{97 98 99} and in cerebral arterioles^{100 101 102 103 104 105 106 107} in vivo. Dilatation of pial vessels in response to nicorandil in vivo appears to be mediated in part by activation of glibenclamide-sensitive potassium channels.¹⁰⁸ Thus, a substantial body of evidence suggests that ATP-sensitive potassium channels are present and functional in cerebral vessels.

View this table: [in this window] [in a new window]   Table 2. Potassium Channels in Cerebral Vessels

In contrast to these findings, some studies failed to obtain functional evidence supporting the presence of ATP-sensitive potassium channels in some cerebral arteries^{90 109} and in cerebral microvessels.¹¹⁰ The reason for these differences is not completely clear but may relate, in part, to species differences⁹⁰ and to a heterogeneous distribution of ATP-sensitive potassium channels in the cerebral circulation.⁹⁰ The apparent absence of ATP-sensitive potassium channels in cerebral microvessels may be specific for this preparation, which typically contains primarily capillaries, so that less than 10% of vessels in this preparation contain smooth muscle.^110A

Our understanding of the role of ATP-sensitive potassium channels in intact cerebral vessels has been obtained primarily using activators and inhibitors of these potassium channels (Table 2). As with other studies that are based on pharmacological approaches, it is important to consider the specificity of the compounds (at the concentration used) in the model in question. Thus, although it is clear that substances such as cromakalim and aprikalim open ATP-sensitive potassium channels, some of these agonists may exert additional effects in some systems. For example, cromakalim opens calcium-activated potassium channels in rabbit aorta⁶² but not other vascular muscle (see Reference 17 for review). In contrast, aprikalim produces glibenclamide-sensitive dilatation of cerebral vessels^{97 98 102 105} that is not inhibited by charybdotoxin¹⁰² or iberiotoxin,¹⁰⁰ suggesting that aprikalim does not open calcium-activated potassium channels in the cerebral circulation.

Glibenclamide is the most frequently used inhibitor of ATP-sensitive potassium channels and appears to be selective at commonly used concentrations (3 µmol/L).¹⁷ Some findings suggest that higher concentrations of glibenclamide (10 µmol/L) may affect opening of calcium-activated potassium channels under some conditions.⁶²

Calcium-Activated Potassium Channels
Calcium-activated potassium channels have been identified in cerebral arteries with patch-clamp techniques^{15 60 111 112 113} (Table 2). These potassium currents show a large conductance and are inhibited by charybdotoxin and iberiotoxin. Application of TEA⁺, charybdotoxin, and iberiotoxin produces contraction of large cerebral arteries in vitro.^{15 114} TEA constricts the basilar artery in vivo,^{115 116} which suggests that potassium channels (possibly calcium-activated potassium channels) are active in large cerebral arteries under basal conditions.

Delayed Rectifier Potassium Channels
A delayed rectifier potassium current has been described in cat cerebral arteries¹³ and rat basilar artery^{61 112} (Table 2). The current was activated by depolarization and sensitive to 4-aminopyridine. Because reduction of intracellular pH increased this current,¹³ it has been suggested that these potassium channels may be important in mediation of cerebral vasodilatation during acidosis and/or hypercapnia.

Inward Rectifier Potassium Channels
An inward rectifier potassium current has been recorded in rat cerebral vessels^{14 81 82} (Table 2). The functional significance of these potassium channels in cerebral vessels is not clear, although it has been suggested that they may play a role in mediation of vasodilatation in response to modest elevations in extracellular potassium.^{14 82}

	Activation of Potassium Channels by Vasodilators

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
Several endothelium-dependent and endothelium-independent vasodilators produce hyperpolarization of smooth muscle and relaxation of cerebral blood vessels. Hyperpolarization of vascular muscle produced by activation of potassium channels appears to be an important mechanism of vasodilatation in response to several stimuli.

	Endogenous Vasodilators

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
ATP-Sensitive Potassium Channels
Several endogenous substances have been reported to produce hyperpolarization and relaxation of cerebral vascular muscle, which appear to be mediated by activation of ATP-sensitive potassium channels.

VIP, which was originally isolated from porcine small intestine, is a potent vasodilator.^{9 117} Immunocytochemical studies have revealed that large cerebral arteries are innervated by VIP-containing nerves.¹¹⁷ Standen et al¹⁸ first reported that in the rabbit middle cerebral artery, VIP produces hyperpolarization of smooth muscle, which was inhibited by glibenclamide. These findings suggest that VIP produces relaxation of cerebral vessels by activation of ATP-sensitive potassium channels.

CGRP is an extremely potent vasoactive peptide.¹¹⁸ In the cerebral circulation, major arteries and pial arterioles are innervated by CGRP-containing nerve fibers.¹¹⁹ CGRP produces hyperpolarization of cerebral vascular muscle in vitro.^{18 120} Dilator responses of cerebral arterioles and the basilar artery to CGRP are inhibited by glibenclamide and thus appear to be mediated by activation of ATP-sensitive potassium channels in vivo.^{104 121}

Cerebral blood vessels are richly innervated by sympathetic nerves.¹²² Norepinephrine produces dilatation, not constriction, of rat basilar artery, which is mediated by activation of ß-adrenergic receptors.¹²³ Vasodilatation produced by norepinephrine is inhibited modestly by glibenclamide.¹²³ Thus, norepinephrine-induced dilatation of rat basilar artery appears to be mediated in part by activation of ATP-sensitive potassium channels in vivo.

Both a cAMP-dependent mechanism and a direct action of GTP-binding protein (G_i or G_o) have been proposed as physiological modulators of ATP-sensitive potassium channels in nonvascular tissues.^{124 125 126} VIP, CGRP, adenosine, pituitary adenylate cyclase–activating peptide, and norepinephrine activate adenylate cyclase in cerebral vessels.^{8 12 127 128 129} Thus, a cAMP-dependent mechanism may be involved in activation of ATP-sensitive potassium channels in cerebral blood vessels. In support of this hypothesis is the finding that forskolin, a direct activator of adenylate cyclase, produces marked dilatation of the basilar artery in vivo, which is inhibited in part by glibenclamide.¹²³ This concept is supported by the observation, made using patch-clamp techniques, that cAMP-dependent protein kinase activates ATP-sensitive potassium channels of smooth muscle from porcine coronary arteries and rabbit mesenteric arteries.^{130 131} In contrast, relaxation of the carotid artery in vitro¹³² and dilatation of the basilar artery^{97 99 121 123} and cerebral arterioles in vivo^{102 105 108 133} in response to nitrovasodilators are not affected by glibenclamide. Thus, a cAMP-dependent mechanism, but not a cGMP-dependent mechanism, may be involved in activation of ATP-sensitive potassium channels in cerebral arteries (Fig 2).

View larger version (19K): [in this window] [in a new window]   Figure 2. Schematic diagrams show possible functions of potassium channels in endothelium and smooth muscle. Vasodilator may activate receptors that open potassium channels and produce hyperpolarization of endothelium. Because endothelium does not express voltage-sensitive calcium channels, hyperpolarization of endothelium enhances calcium influx through receptor-operated calcium channels. Increase in cytoplasmic calcium concentration leads to production of EDRF and/or prostacyclin (PGI2) from endothelium. Receptor-mediated hyperpolarization of smooth muscle (eg, by norepinephrine and CGRP) reduces open probability of voltage-sensitive calcium channels and decreases cytoplasmic calcium concentration of vascular muscle. Decreases in cytoplasmic calcium concentration reduce calcium-dependent contraction of vascular muscle and produce vasodilatation.

Calcium-Activated Potassium Channels
ß-Adrenergic agonists activate calcium-activated potassium channels in airway smooth muscle, and calcium-activated potassium channels may contribute to relaxation of airway smooth muscle in response to ß-adrenergic stimulation.¹³⁴ Results of patch-clamp techniques suggest that calcium-activated potassium channels in smooth muscle from rat aorta and porcine coronary arteries are activated by cAMP-dependent protein kinase.^{135 136} Thus, vasodilator substances that activate adenylate cyclase may also activate calcium-activated potassium channels in vascular muscle. We have found that dilatation of cerebral arterioles in response to forskolin, a direct activator of adenylate cyclase, and cAMP is inhibited by charybdotoxin and iberiotoxin.¹⁰⁰ Isoproterenol-induced dilatation of rat cerebral arterioles is also inhibited by charybdotoxin,¹⁰² suggesting that adenylate cyclase–mediated activation of calcium-activated potassium channels may be an important mechanism of dilatation in cerebral blood vessels in vivo. These findings are similar to those described for coronary arteries in vitro.¹³⁷

In noncerebral blood vessels, nitric oxide and other agonists that activate guanylate cyclase have been suggested to activate^{138 139 140 141} or have no effect^{137 141 142} on calcium-activated potassium channels. Patch-clamp studies suggest that, under some conditions, nitric oxide produced by the inducible form of nitric oxide synthase may activate calcium-activated potassium channels in vascular muscle.¹⁴³

In isolated cerebral vascular muscle, patch-clamp experiments suggested that calcium-activated potassium channels are activated by cGMP (Fig 1).¹⁴⁴ In contrast, nitric oxide (which increases cGMP) does not hyperpolarize vascular muscle in large cerebral arteries.^{145 146} Dilatation of cerebral arterioles in rabbits in response to nitroprusside and acetylcholine is not inhibited by iberiotoxin and charybdotoxin,¹⁰⁰ suggesting that cerebral vasodilation in response to stimulation of guanylate cyclase is not dependent on activity of calcium-activated potassium channels. Whether there are species or segmental differences in the effects of cGMP on activity of calcium-activated potassium channels in cerebral vessels is not known.

Endothelium-Derived Hyperpolarizing Factor
Many stimuli that produce hyperpolarization bind to receptors on vascular muscle and activate potassium channels through an endothelium-independent mechanism. Some agonists, however, produce relaxation of vascular muscle by endothelium-dependent hyperpolarization.^{147 148} Several lines of evidence have suggested that a substance, which is distinct from nitric oxide (EDRF) or prostanoids, is released from endothelium and produces hyperpolarization of vascular muscle.^{149 150} The chemical nature of this substance, which is called EDHF, is still not clear.¹⁴⁸

Several groups^{18 145 146 151 152 153} have shown that acetylcholine hyperpolarizes and relaxes cerebral blood vessels in vitro. This hyperpolarization is not inhibited by hemoglobin,¹⁵² which binds EDRF, but is dependent on the presence of intact endothelium and is inhibited by glibenclamide.^{146 152} Dilatation of rabbit cerebral arterioles in response to acetylcholine is also inhibited in part by glibenclamide.¹³³ Thus, acetylcholine-induced relaxation of cerebral blood vessels may be mediated, in part, by EDHF.

Recent studies suggest that prostacyclin may act as an EDHF that produces relaxation of the middle cerebral artery by activation of a glibenclamide-sensitive potassium channel.¹⁵⁴ Because some cerebral vessels do not appear to produce EDHF, the influence of EDHF may not be homogeneous throughout the cerebral circulation.^{151 155 156 157}

	Hypoxia, Hypercapnia, and Hypotension

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
Hypoxia
Hypoxia is a strong dilator stimulus in the cerebral circulation.¹⁵⁸ Decreases in arterial PO₂ produce relaxation of cerebral arteries in vitro and in vivo that may involve activation of potassium channels. In vitro, relaxation of carotid arteries and large cerebral arteries in response to hypoxia is inhibited by glibenclamide or TEA,^{154 159 160} which implies a role for ATP-sensitive potassium channels and calcium-activated potassium channels. In vivo, hypoxia-induced dilatation of cerebral arterioles in response to hypoxia is inhibited by glibenclamide,¹⁰⁵ and increases in cerebral blood flow during hypoxia are attenuated by tolbutamide, another inhibitor of ATP-sensitive potassium channels.¹⁶¹ Overall, these findings suggest that activation of potassium channels is an important mechanism in mediating relaxation of cerebral blood vessels during hypoxia. Because inhibitors may not always completely differentiate between different (sub)types of potassium channels, the relative importance of ATP-sensitive potassium channels versus calcium-activated potassium channels in responses to hypoxia is not clearly defined.

Hypercapnia
Increases in [H⁺] or partial pressure of carbon dioxide have a pronounced relaxant effect on cerebrovascular muscle.¹⁵⁸ Several different mechanisms, including formation of nitric oxide, have been proposed to mediate hypercapnia-induced dilatation of cerebral blood vessels.^{4 133 158} Dilatation of cerebral arterioles in response to moderate hypercapnia are inhibited modestly by glibenclamide.¹³³ Thus, activation of ATP-sensitive potassium channels may contribute to hypercapnia-induced dilatation of cerebral blood vessels but does not appear to be a major mediator. The finding that the open probability of ATP-sensitive potassium channels increases with reduction in intracellular pH³⁴ supports this concept.

The delayed rectifier potassium channel also may contribute to relaxation of vascular muscle during hypercapnia. Peak outward current through delayed rectifier potassium channels from cat cerebral arterioles increases more than threefold during reduction of pH from 7.43 to 7.20.¹¹²

Hypotension
A reduction in arterial pressure decreases cerebral vascular resistance, which helps to maintain cerebral blood flow near normal levels during moderate hypotension.¹⁵⁸ Several mechanisms may contribute to autoregulation of cerebral blood flow. Recently, dilator responses of rat cerebral arterioles during graded hypotension were observed to be inhibited by glibenclamide.¹⁰⁷ Thus, ATP-sensitive potassium channels may be involved in the autoregulatory response of cerebral arterioles during hypotension.

	Potassium Channels in Vascular Endothelium

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
Endothelium plays an important role in regulation of vascular tone by releasing several substances, including EDRF, EDHF, and prostacyclin.^{3 7 147 162} Production of some endothelium-derived vasoactive substances, is dependent on the concentration of cytoplasmic Ca²⁺.^{3 7} Because endothelium does not express voltage-dependent calcium channels, increases in cytoplasmic Ca²⁺ concentrations in endothelium are achieved by mobilization of Ca²⁺ from intracellular stores and/or Ca²⁺ entry through receptor-operated cation channels. Ca²⁺ influx through receptor-operated Ca²⁺ entry is activated by membrane hyperpolarization, which may be achieved by activation of potassium channels.^{163 164 165 166}

Both ATP-sensitive potassium channels and calcium-activated potassium channels have been described in aortic endothelium. In pig coronary arteries, acetylcholine produces hyperpolarization of endothelium, which is inhibited by charybdotoxin.¹⁶³ ATP-sensitive potassium channels have also been described in brain microvascular endothelial cells.¹⁶⁷ Thus, activation of potassium channels in endothelium may be an important mechanism that contributes to dilatation of cerebral arteries in response to several endothelium-dependent stimuli (Fig 2).

	Potassium Channels in Disease States

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
Chronic Hypertension
ATP-Sensitive Potassium Channels
Endothelium-dependent relaxation of cerebral blood vessels is impaired during chronic hypertension.^{168 169 170 171 172} In contrast, endothelium-independent dilator responses of cerebral arteries are generally normal in chronically hypertensive animals.^{98 169 170 171 172}

Dilatation of the basilar artery in response to aprikalim, a direct activator of ATP-sensitive potassium channels, is impaired in stroke-prone SHR compared with normotensive Wistar-Kyoto rats.⁹⁸ Thus, activity of ATP-sensitive potassium channels in the basilar artery appears to be reduced during chronic hypertension. This finding suggests that vascular muscle, as well as endothelium, may be abnormal in cerebral blood vessels of stroke-prone SHR. Because forskolin-induced dilatation of the basilar artery is similar in stroke-prone SHR and Wistar-Kyoto rats, the cAMP-responsive site on ATP-sensitive potassium channels may not be altered during chronic hypertension.⁹⁸

Calcium-Activated Potassium Channels
In addition to mediating relaxation in response to cAMP,^{100 137} calcium-activated potassium channels seem to be part of a negative feedback system to regulate vascular tone.^{15 16 17 19} Because myogenic arterial tone appears to be enhanced in SHR,¹⁷³ one might anticipate that calcium-activated potassium channels in vascular muscle are activated in the resting state of arteries during chronic hypertension. Myogenic tone and ⁸⁶Rb efflux, which is an index of potassium efflux, in the resting state of arteries are greater in SHR than Wistar-Kyoto rats.^{173 174 175 176} Charybdotoxin produces more arterial contraction and blocks the enhanced ⁸⁶Rb efflux in SHR.^{173 176 177} Thus, in contrast to ATP-sensitive potassium channels, which appear to have reduced activity, calcium-activated potassium channels are highly activated in the carotid artery of SHR, presumably to compensate for enhanced myogenic tone.

Diabetes Mellitus, Atherosclerosis, and Subarachnoid Hemorrhage
Endothelium-dependent responses of cerebral arteries are impaired in diabetic animals.^{178 179 180 181} Dilator responses of the basilar artery⁹⁹ and cerebral arterioles¹⁰² to aprikalim are also impaired in streptozocin-induced diabetic rats. Thus, diabetes mellitus appears to alter functional responses of cerebral arteries and arterioles both to endothelium-dependent stimuli and to activation of ATP-sensitive potassium channels.

Atherosclerosis is associated with impaired endothelium-dependent responses.^{132 182 183} Relaxation of the carotid artery in response to aprikalim is not impaired in hypercholesterolemic rabbits¹⁵⁹ but is impaired in atherosclerotic monkeys,¹³² which suggests that atherosclerosis may cause impairment of ATP-sensitive potassium channels. Atherosclerosis also alters the activity of calcium-activated potassium channels in human aorta.¹⁸⁴ Thus, several mechanisms lead to impairment of dilator responses of atherosclerotic arteries.

Cerebral vascular muscle is depolarized during vasospasm after subarachnoid hemorrhage.^{185 186} Depolarization may contribute to prolonged constriction of cerebral arteries, which often occurs after subarachnoid hemorrhage. Because cromakalim reverses the depolarization, it has been suggested that depolarization of cerebral vascular muscle after subarachnoid hemorrhage may be due to inactivation of potassium channels.¹⁸⁵ Nicorandil, which produces relaxation of cerebral vessels in part by activation of glibenclamide-sensitive potassium channels,¹⁰⁸ partially reverses vasospasm after subarachnoid hemorrhage.¹⁸⁵ Preliminary findings suggest that dilatation of the basilar artery in response to aprikalim, an activator of ATP-sensitive potassium channels, is enhanced following experimental subarachnoid hemorrhage in rats.¹⁸⁷ These findings suggest that activators of potassium channels in vascular muscle may have beneficial effects during vasospasm after subarachnoid hemorrhage.

	Summary

Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
Several types of potassium channels have been described in the cerebral circulation. Hyperpolarization of vascular muscle produced by activation of ATP-sensitive potassium channels and calcium-activated potassium channels may be a major mechanism that mediates relaxation of cerebral arteries and arterioles in response to several stimuli. Activation of ATP-sensitive potassium channels may be mediated, in part, by a cAMP-dependent mechanism, and activation of calcium-activated potassium channels is mediated by either cAMP-dependent or cGMP-dependent mechanisms. Both calcium-activated and delayed rectifier potassium channels appear to be negative feedback systems to regulate vascular tone.

Activity of ATP-sensitive potassium channels and calcium-activated potassium channels is altered in several disease states, including hypertension, diabetes, and atherosclerosis. Alterations of these potassium channels and impairment of vasodilatation may possibly contribute to the development or maintenance of cerebral ischemia or vasospasm.

	Selected Abbreviations and Acronyms

 

cAMP = cyclic AMP cGMP = cyclic GMP CGRP = calcitonin gene–related peptide EDHF = endothelium-derived hyperpolarizing factor EDRF = endothelium-derived relaxing factor SHR = spontaneously hypertensive rats TEA = tetraethylammonium ion VIP = vasoactive intestinal peptide

	Acknowledgments

 
Original studies by the authors that were described in this review were supported by National Institutes of Health grants HL-38901, HL-16066, HL-14388, NS-24621, and AG-10269; by a medical investigatorship and research funds from the Department of Veterans Affairs; and by a Grant-in-Aid from the American Heart Association (95014510). F.M. Faraci is an Established Investigator of the American Heart Association. We thank Dr Erwin F. Shibata (University of Iowa) for helpful discussion and critical reading of this manuscript.

Received March 31, 1995; revision received June 12, 1995; accepted June 16, 1995.

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Top Abstract Introduction Properties of Potassium Channels... Presence of Potassium Channels... Activation of Potassium Channels... Endogenous Vasodilators Hypoxia, Hypercapnia, and... Potassium Channels in Vascular... Potassium Channels in Disease... Summary References

 
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