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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:28.)
© 2001 American Heart Association, Inc.

Brief Reviews

Potassium Channel Function in Vascular Disease

Christopher G. Sobey

From the Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.

Correspondence to Christopher G. Sobey, PhD, Department of Pharmacology, The University of Melbourne, Parkville, Victoria 3010, Australia. E-mail cg.sobey{at}unimelb.edu.au

	Abstract

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
Abstract—Potassium ion (K⁺) channel activity is a major regulator of vascular muscle cell membrane potential (E_m) and is therefore an important determinant of vascular tone. There is growing evidence that the function of several types of vascular K⁺ channels is altered during major cardiovascular diseases, such as chronic hypertension, diabetes, and atherosclerosis. Vasoconstriction and the compromised ability of an artery to dilate are likely consequences of defective K⁺ channel function in blood vessels during these disease states. In some instances, increased K⁺ channel function may help to compensate for increased vascular tone. Endothelial cell dysfunction is commonly associated with cardiovascular disease, and altered activity of nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor could also contribute to changes in resting K⁺ channel activity, E_m, and K⁺ channel–mediated vasodilatation. Our current knowledge of the effects of disease on vascular K⁺ channel function almost exclusively relies on interpretation of data obtained by using pharmacological modulators of K⁺ channels. As further progress is made in the development of more selective drugs and through molecular approaches such as gene targeting technology in mice, specific K⁺ channel abnormalities and their causes in particular diseases should be more readily identified, providing novel directions for vascular therapy.

Key Words: hypertension • depolarization • endothelium-derived hyperpolarizing factor • hypercholesterolemia • hyperpolarization

	Introduction

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
When a potassium ion (K⁺) channel opens in the vascular smooth muscle cell membrane, K⁺ efflux increases, causing membrane potential (E_m) hyperpolarization, closure of voltage-activated calcium (Ca²⁺) channels, decreased Ca²⁺ entry, and vasodilatation (Figure 1). Conversely, closure of a K⁺ channel causes E_m depolarization, opening of voltage-activated Ca²⁺ channels, increased cytosolic Ca²⁺ concentration, and vasoconstriction (Figure 1). As a major regulator of vascular muscle cell E_m, K⁺ channel activity is therefore an important determinant of vascular tone and blood vessel diameter.¹

View larger version (30K): [in this window] [in a new window]   Figure 1. Schematic illustration of the key events involved in the vascular smooth muscle response to K+ channel activation (left) or inhibition (right). Left: Activation (opening) of a K+ channel (gray) in the cell membrane allows K+ to flux out of the cell, causing a decrease in Em (ie, hyperpolarization) and consequent inhibition (closure) of voltage-activated Ca2+ channels (white) and a decrease in cytosolic Ca2+ levels, resulting in vascular muscle relaxation (vasodilatation). Right: In the reverse case, inhibition of a vascular muscle K+ channel decreases K+ efflux and hence, increases Em (depolarization). Voltage-activated Ca2+ channels will open in response to the increased Em, allowing Ca2+ to enter the cell and to increase cytosolic Ca2+ levels resulting in vascular contraction (vasoconstriction).

The physiological roles and properties of K⁺ channels in arterial smooth muscle have recently been comprehensively reviewed.^{1 2 3 4 5 6} This Brief Review will first provide a short description of the functional characteristics of the 4 main types of vascular K⁺ channels and the likely physiological importance of these channels, as well as the phenomenon of K⁺ channel–mediated, endothelium-dependent vascular hyperpolarization. The majority of this review will then examine the evidence for altered K⁺ channel function in blood vessels in 3 major cardiovascular disease states.

While molecular biological studies are revealing a large diversity in the subtypes of K⁺ channels that are normally expressed in vascular muscle,⁷ it is noteworthy that there is still very little information available at the molecular level regarding regulation of K⁺ channel expression and function in vascular disease. Hence, our current knowledge of the effects of disease on vascular K⁺ channel expression is somewhat indirect and almost exclusively relies on interpretation of functional or electrophysiological data (eg, recordings of vessel tone or diameter, vascular muscle cell E_m, or whole-cell or single-channel currents in isolated myocytes under voltage-clamp conditions) obtained in the presence of pharmacological modulators of K⁺ channels.

	Calcium-Activated K+ Channels

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
Large conductance Ca²⁺-activated K⁺ (BK_Ca) channels are activated by intracellular Ca²⁺ and also by E_m depolarization and are particularly abundant in vascular smooth muscle cells.^{1 8} Physiological activation of vascular BK_Ca channels may be an important buffering mechanism to counteract vessel depolarization and constriction in response to some vasoconstrictors and to increased intravascular pressure. Because of the large conductance of BK_Ca channels, the activity of relatively few channels can exert a relatively large influence on E_m. Vasodilators that increase intracellular levels of cAMP or cyclic GMP,^{1 5} carbon monoxide,⁹ and epoxides of arachidonic acid¹⁰ may activate BK_Ca channels. Focal increases in subsarcolemma Ca²⁺ levels ("Ca²⁺ sparks") due to Ca²⁺ released through ryanodine receptors in the sarcoplasmic reticulum appear to play a fundamental role in regulating BK_Ca channel activity and hence, E_m and vascular tone.^{11 12} Pharmacological agents commonly used to inhibit BK_Ca channels include tetraethylammonium ion (1 mmol/L), charybdotoxin, and iberiotoxin. Based on the constrictor responses elicited by these inhibitors, it is thought that BK_Ca channel activity may be greater in large arteries versus microvessels under normal resting conditions.⁶

	Voltage-Dependent (Delayed Rectifier) K+ Channels

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
Voltage-dependent (K_V) channels in vascular smooth muscle are activated by membrane depolarization in the physiological range for E_m (approximately -35 to -55 mV) and are therefore also thought to serve an important buffering function against depolarization and vasoconstriction.¹ 4-Aminopyridine is widely used as a pharmacological blocker of K_V channels. 4-Aminopyridine causes arterial depolarization and constriction, suggesting that K_V channel activity exists in some blood vessels under basal conditions.^{13 14 15 16} cAMP^{17 18} and nitric oxide (NO)/cyclic GMP^{15 19 20} may activate K_V channels in some blood vessels, and these channels may be inhibited by protein kinase C.²¹

	ATP-Sensitive K+ Channels

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
ATP-sensitive K⁺ (K_ATP) channels are inhibited by intracellular ATP and are therefore likely to have a very low open probability in most vascular smooth muscle cells under normal conditions. Thus, glibenclamide, which is widely used as a selective inhibitor of K_ATP channels, generally has no effect on vascular E_m or tone, although there are examples of exceptions to this (eg, see References 3, 6, and 11^{3 6 11} ). Pharmacological agents that can induce glibenclamide-sensitive vascular relaxation by directly activating K_ATP channels include cromakalim, levcromakalim (lemakalim), aprikalim, nicorandil, and pinacidil.^{1 3 5} This phenomenon provides functional evidence that K_ATP channels are present in vascular muscle and can be activated to influence E_m and vascular tone. Endogenous vasodilator stimuli, such as hypoxia, acidosis, and mediators that increase intracellular cAMP levels (eg, adenosine, prostacyclin, and norepinephrine), may also exert their vascular effects, in part via activation of K_ATP channels.^{1 5}

	Inwardly Rectifying K+ Channels

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
When vascular myocyte E_m is varied experimentally by using electrophysiological techniques, one type of K⁺ channel displays "inward rectification." That is, because of the blocking effects of intracellular polyamines and magnesium ions, these inwardly rectifying K⁺ (K_IR) channels conduct K⁺ current into cells much more readily than they conduct outward K⁺ current.^{1 3 22} Importantly though, at physiological E_m, a small increase above the normal extracellular K⁺ concentration of 3 to 5 mmol/L leads to an increase in the resting outward K⁺ current through K_IR channels. Hence, a modest increase in extracellular K⁺ (eg, by <10 mmol/L), as may occur during neuronal or muscle activation,^{23 24 25} can paradoxically lead to substantial vascular hyperpolarization and vasorelaxation due to K⁺ efflux through K_IR channels.^{26 27 28 29 30 31} Reasonably selective block of K_IR channels can be achieved pharmacologically by using 100 µmol/L barium ion (Ba²⁺), and because this inhibitor causes vascular depolarization and constriction,^{26 28 29 31} it is thought that vascular K_IR channels may be active under resting conditions. Recent findings in gene-targeted mice indicate that Ba²⁺-sensitive, K⁺-induced vasorelaxation is mediated by activation of the K_IR2.1 channel³⁰ (see below).

	Endothelium-Dependent Hyperpolarization

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
Vascular smooth muscle relaxation in response to a signal initiated by stimulation of overlying endothelium is known as "endothelium-dependent relaxation" and involves the release of at least 1 "endothelium-derived relaxing factor" (EDRF). There appear to be several important EDRFs, the 2 most well understood of these being NO and prostacyclin. It is now well established that endothelium-dependent vascular relaxation is often accompanied by K⁺ channel–mediated hyperpolarization of the vascular smooth muscle. Because both NO and prostacyclin are known to be able to elicit vascular relaxation, at least in part, through activation of K⁺ channels^{1 5} (Figure 2), endothelium-dependent hyperpolarization may often simply reflect part of the mechanism of relaxation produced by NO and/or prostacyclin.³²

View larger version (30K): [in this window] [in a new window]   Figure 2. Some potential mechanisms involving K+ channel–mediated, endothelium-dependent hyperpolarization. Stimulation of endothelial cell receptors by agonists such as acetylcholine (ACh), bradykinin (BK), and substance P (SP) may cause release of several endothelium-derived relaxing factors. These include NO, EDHF(s), and prostacyclin (PGI2), each of which can induce relaxation of underlying vascular muscle through activation of K+ channels. In the case of NO and PGI2, this may involve the intracellular accumulation of a second messenger (cyclic GMP and cAMP, respectively). Like EDHF, NO may activate K+ channels directly. The production of EDHF may depend on the bioavailability of NO, such that EDHF release may be more significant under conditions in which NO production is impaired. The hyperpolarization occurring in response to K+ channel activation leads to vasodilatation, as described in Figure 1. Because all 3 endothelial factors may normally activate vascular K+ channels, endothelial dysfunction occurring during cardiovascular disease states may result in vascular depolarization and/or abnormal K+ channel function, leading to increased vascular tone and reduced blood flow.

In addition, in many normal vascular preparations, a component of agonist-induced, endothelium-dependent relaxation appears to be mediated by a non-NO, nonprostanoid, hyperpolarization-related mechanism that involves activation of K⁺ channels³² (Figure 2). The chemical nature of this mediator(s), termed endothelium-derived hyperpolarization factor (EDHF), has still not been definitively identified, nor has the particular type(s) of K⁺ channel(s) activated by EDHF, but inhibition of its action appears to require coapplication of charybdotoxin and apamin, which may implicate a role for small conductance K_Ca, intermediate conductance K_Ca, and/or BK_Ca channels.³³ This particular combination of inhibitors may be necessary to block release of EDHF from endothelial cells, rather than to block the action of EDHF on vascular smooth muscle.³⁴ EDHF may play a greater role in the smaller resistance arteries of animals^{35 36 37} and humans^{38 39} and might therefore normally modulate systemic arterial pressure. It has been suggested that the vascular activity of EDHF is normally inhibited by NO, such that when NO synthesis is impaired in cardiovascular disease, EDHF production and/or function may increase^{40 41} (Figure 2). However, there is also evidence against this proposal in hypertension and diabetes (see the following sections).

	Use of Gene Targeting to Study Vascular K+ Channels

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
The biology of K⁺ channels is extremely complex, and we now know that there is enormous diversity at the molecular level in mammalian cells.⁷ The use of traditional pharmacological inhibitors has been invaluable for our initial understanding of the functional importance of major K⁺ channel types. However, this approach is likely to be of limited value in future research that will seek to discriminate between the functional roles of different K⁺ channel subtypes. Instead, it seems likely that a great deal more information will be gained by using the powerful approach of gene targeting in mice. The first example of such work was published recently by Zaritsky et al,³⁰ who found that K⁺-induced cerebral artery hyperpolarization and relaxation are absent in mice lacking the gene to express K_IR2.1 channels but are normal in K_IR2.2 channel–deficient mice, confirming that the K_IR2.1 channel isoform is critically and exclusively involved in K⁺-induced cerebral vasodilator responses. Although a number of studies of vascular function have already been performed in genetically altered mice, most have focused on the role of the endothelium,⁴² and this landmark study³⁰ is the first in which gene-targeted mice were used to examine the role of any ion channel in blood vessels.

	K+ Channels in Vascular Diseases

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
Altered vascular K⁺ channel function under pathological conditions could be either a cause (ie, involved in the pathogenesis) or an effect (ie, a secondary phenomenon or compensatory mechanism) of the disease. Vasoconstriction and the compromised ability of an artery to dilate are likely consequences of defective K⁺ channel function in blood vessels and may be due to a change in the number, unitary conductance, and/or open probability of the channel(s). Information at this level regarding K⁺ channel expression can currently be provided only by studies with molecular and/or patch-clamp approaches and hence, are restricted to studies of blood vessels or myocytes removed from their physiological environment. For this reason, where feasibility allows (ie, with the future availability of selective pharmacological tools or appropriate genetically modified animals), it will remain important to verify such findings with data regarding vascular K⁺ channel function obtained in the integrated physiological environment in vivo.

Very few published studies have so far examined the impact of disease states on the biophysical characteristics of K⁺ channels or channel subtypes. By contrast, as mentioned above, most of our knowledge of the effects of diseases on vascular K⁺ channel expression remains indirect and dependent on interpretation of the experimental data obtained by using K⁺ channel modulators that are thought to be relatively selective pharmacological agents. The following sections will review current evidence for the effects of 3 major cardiovascular diseases on the expression and function of K⁺ channels in blood vessels.

Chronic Hypertension
Chronic hypertension has been the most extensively studied cardiovascular disease state in terms of its effects on vascular K⁺ channel function, and there is now evidence for abnormal functioning of each of the 4 major K⁺ channel types during hypertension (Figure 3).

View larger version (33K): [in this window] [in a new window]   Figure 3. Altered vascular K+ channel function during chronic hypertension. Experimental evidence suggests that expression and/or activity of BKCa channels is enhanced during hypertension, whereas the function of KATP, KV, and KIR channels may be reduced. Increased activity of protein kinase (PKC) and increased cytosolic Ca2+ levels may inhibit activation of KATP and KV channels, as part of their proconstrictor effects, as shown. Inhibition of KV channel activity is likely to cause Em depolarization, which together with increased cytosolic Ca2+ levels, causes increased activity of BKCa channels. Increased function of BKCa channels will help to restrict increases in vascular tone and hence, arterial pressure.

Effects of Hypertension on E_m
The resting E_m of vascular smooth muscle cells is reported to be more depolarized in arteries from hypertensive versus normotensive animals^{43 44 45 46 47 48 49} (Figure 3). Increased vascular depolarization is associated with enhanced myogenic tone in arteries from hypertensive animals.^{50 51} The effect of hypertension on E_m may be more profound in smaller resistance vessels, especially in vascular beds that play a significant role in the regulation of peripheral resistance.⁵²

BK_Ca Channels in Hypertension
There is strong evidence that the functional role of BK_Ca channels is enhanced in vascular muscle during chronic hypertension. For example, pharmacological inhibitors of these channels cause augmented depolarization and constriction of arteries from hypertensive animals. This phenomenon occurs similarly in vessels from various anatomic regions, including aorta,^{53 54 55 56} carotid artery,^{57 58 59} and the mesenteric,⁵⁸ femoral,^{58 60} and cerebral^{61 62} vascular beds. Because increases in both Ca²⁺ influx and BK_Ca channel activity can be detected even in prehypertensive spontaneously hypertensive rats (SHRs),⁶⁰ genetic factors may play at least some role in these changes. However, increased BK_Ca channel function may also be a consequence of elevated blood pressure, as it can be induced over several weeks by surgical or pharmacological interventions that cause hypertension,^{53 61} and it can be reversed by antihypertensive therapy.⁵⁴ Therefore, BK_Ca channel function may be increased in arterial smooth muscle cells as a protective mechanism against progressive increases in blood pressure and may provide a negative-feedback mechanism that helps to restrict the increased pressure and vascular tone. Such a mechanism would therefore act to limit pressure-induced vasoconstriction and to preserve local blood flow.

Electrophysiological measurements obtained under voltage-clamp conditions in arterial myocytes isolated from hypertensive animals have confirmed that the whole-cell K⁺ current through BK_Ca channels is enhanced in comparison with currents recorded from normotensive myocytes.^{52 53 63} A comprehensive molecular, electrophysiological, and functional study in the cerebral circulation of SHRs has provided strong evidence for greater expression of BK_Ca channels per myocyte rather than any change in channel unitary conductance or open probability.⁶² Liu et al⁶² found that a 2- to 4-fold greater constriction of SHR versus Wistar-Kyoto rat (WKY) cerebral arteries in vivo in response to iberiotoxin was associated with a 4.7-fold higher density of BK_Ca channel current in SHRs (measured in myocytes by using whole-cell, patch-clamp techniques) and a 4.1-fold greater expression of the BK_Ca channel -subunit (ie, the pore-forming part of the channel) in SHRs (determined by Western blot analysis). Another study has reported that BK_Ca channel open probability may be increased in the renal vasculature owing to higher intracellular Ca²⁺ levels during hypertension.⁵² Thus, activity of the BK_Ca channel appears to be greater in hypertensive arteries (Figure 3), and it may be the primary determinant of resting K⁺ efflux and hence, vascular muscle E_m in hypertension.⁶⁴

K_V Channels in Hypertension
In contrast to the increased function of BK_Ca channels, there is evidence for a decreased function of arterial K_V channels in hypertension. Voltage-dependent current through K_V channels was found to be substantially lower in interlobar artery myocytes from both genetic (SHR) and nongenetic (deoxycorticosterone acetate-salt/nephrectomy regime) models of hypertension.⁵² Reduced function of K_V channels in hypertensive myocytes may seem surprising, given that vascular E_m appears to be more depolarized (see above), and the activity of K_V channels, like BK_Ca channels, is voltage dependent. However, in contrast to the effects on BK_Ca channels, a depolarized E_m and a higher intracellular Ca²⁺ level in myocytes from chronically hypertensive rats^{52 56 60 65 66} may represent a detrimental positive-feedback mechanism resulting in decreased vascular K_V channel activity, because (1) intracellular Ca²⁺ inhibits K_V channel activity⁶⁷ and (2) Ca²⁺ entry via voltage-activated Ca²⁺ channels will be further increased owing to the depolarizing effect of impaired K_V channel activity. Reduced K_V channel activity could therefore be an important factor underlying the depolarized E_m and enhanced myogenic vascular tone reported during chronic hypertension^{50 51} (Figure 3). A similar phenomenon may exist in cerebral arteries after subarachnoid hemorrhage (SAH), a cerebral vascular disease state that is also associated with vascular depolarization^{68 69 70} and increased intracellular Ca²⁺ levels⁷¹ and in which K_V channel function also appears to be impaired.¹⁶

Paracrine influences potentially underlying altered K⁺ channel activity in hypertension have not yet been extensively explored and could be numerous. One recent report suggested that parathyroid hypertensive factor, a circulating substance originating in the parathyroid gland and associated with some forms of experimental and human hypertension, inhibits K_V channels and causes depolarization of myocytes from rat tail artery.⁷² Parathyroid hypertensive factor is thought to increase Ca²⁺ influx into vascular muscle cells via L-type, voltage-activated Ca²⁺ channels (probably due to K_V channel inhibition) and consequently to enhance vascular responses to depolarizing and constrictor stimuli in vitro⁷³ and in vivo.⁷⁴ In an analogous manner, decreased K_V channel function in the pulmonary circulation is reported to cause depolarization and vasoconstriction in patients with primary pulmonary hypertension.⁷⁵ Because NO may activate K_V channels in some arteries,^{15 19 76 77} impaired bioavailability of endothelium-derived NO in hypertension and other cardiovascular disease states could lead to vascular depolarization and contraction that are partly due to inhibition or closure of K_V channels. Thus, increased knowledge of mediators that modulate K_V channel function could provide important insight into the mechanisms of increased vascular tone during chronic hypertension and may reveal novel targets for pharmacological prevention of vascular dysfunction.

K_ATP Channels in Hypertension
Findings from several studies suggest that the function of vascular K_ATP channels is impaired during hypertension. Synthetic K_ATP channel activators are less potent dilators in vivo in both large^{78 79} and small⁸⁰ cerebral vessels of chronically hypertensive rats. This alteration seems likely to involve an impaired membrane hyperpolarization response to these agents, as analogous findings from patch-clamp studies indicate that a glibenclamide-sensitive K⁺ current activated by levcromakalim is decreased in mesenteric artery smooth muscle cells of chronically hypertensive animals.⁸¹ Cromakalim-induced relaxation of isolated mesenteric artery is similarly impaired in hypertension induced by chronic NO synthase inhibition.⁸² Because vascular K_ATP channels are thought to be inactive under most normal basal conditions,^{1 3} increased vascular tone during chronic hypertension is unlikely to be related to impaired K_ATP channel function.⁷⁸ By contrast, 1 study reported evidence for enhanced K_ATP channel function in chronic hypertension, finding an increased vasodilator effect of cromakalim and greater contraction by glibenclamide in carotid arteries from stroke-prone SHRs versus normotensive WKY rats.⁸³

The vasodilator response associated with cerebral blood flow autoregulation during systemic hypotension, which is mediated by K_ATP channel activation,^{84 85 86} is impaired in chronically hypertensive rats.⁸⁷ Thus, although most studies of vascular K_ATP channel function during hypertension have examined the effects of synthetic channel openers, these findings^{86 87} suggest that the K_ATP channel dysfunction may also interfere with vascular responsiveness to endogenous vasodilator stimuli.

Impaired K_ATP channel–mediated vascular effects may not necessarily occur for all endogenous K_ATP channel activators, however, because responses to some vasodilators that increase intracellular cAMP levels (ie, forskolin and norepinephrine) are preserved in the basilar artery of hypertensive rats.⁷⁸ Thus, a defect in only a particular aspect of K_ATP channel function could account for the abnormal responses during hypertension. Moreover, increased effects of angiotensin II and protein kinase C are associated with various forms of chronic hypertension, and both mediators may inhibit K_ATP channel function in vascular smooth muscle^{88 89 90 91} (Figure 3). An important goal of future studies will be to investigate the molecular basis for K_ATP channel dysfunction in hypertension. Importantly, several studies have clearly demonstrated that impairment of K_ATP channel–mediated vascular responses can be restored to near-normal levels by long-term treatment of high blood pressure.^{80 81 82 87} These findings emphasize the importance of antihypertensive therapy for correcting many abnormalities in vascular smooth muscle function.

There is very little information currently available on the effects of hypertension on K_ATP channel function in human blood vessels, with data from just 1 study reporting preserved dilator responses of isolated mesenteric arteries to cromakalim.⁹² Some studies of mesenteric arteries from hypertensive animals have also reported unchanged effects of K_ATP channel openers.^{47 93} It will be especially important to clarify whether this phenomenon occurs in humans; if it is restricted to certain vascular beds, this knowledge may then be critical in predicting the viability of using K_ATP channel openers as a potential new class of antihypertensive therapy.

Surprisingly, K_ATP channel function is augmented in cerebral vessels after exposure to subarachnoid blood,^{70 79 94} and this is particularly pronounced in hypertensive animals.⁷⁹ Furthermore, although responses to many vasodilators are generally impaired in cerebral arteries after SAH, the effects of calcitonin gene–related peptide (which activates K_ATP channels) are preserved or augmented,^{94 95 96 97} and treatment with calcitonin gene–related peptide can prevent development of cerebral vasospasm after experimental SAH.^{98 99} K_ATP channel openers may therefore represent a promising therapeutic strategy for treatment of depolarized and spastic cerebral arteries after SAH, which is up to 8 times more likely to occur in the presence of hypertension.¹⁰⁰

K_IR Channels in Hypertension
There is indirect evidence that vascular K_IR channel function may be altered during chronic hypertension. McCarron and Halpern¹⁰¹ reported that Ba²⁺-sensitive vasodilator responses to >7 mmol/L K⁺ were impaired in posterior cerebral arteries isolated from stroke-prone SHRs in comparison with vessels from WKYs, perhaps suggesting impaired K_IR channel function in the cerebral circulation during hypertension. Earlier studies reported that K⁺-induced vascular relaxation was either augmented^{45 102} or impaired¹⁰³ in several models of hypertension. Our laboratory has recently found that dilator responses of the basilar artery to K⁺ in vivo, which are largely Ba²⁺ sensitive in normotensive rats,³¹ are moderately enhanced and Ba²⁺ insensitive in SHRs (S. Chrissobolis et al, unpublished observations, 1999). Thus, it is possible that chronic hypertension leads to decreased expression and/or function of vascular K_IR channels (Figure 3) and expression of a compensatory vasodilator mechanism(s) that is upregulated. K_IR channel–mediated dilatation of cerebral arteries is also reported to be impaired after cerebral ischemia and reperfusion.¹⁰⁴

EDHF in Hypertension
Endothelium-dependent vascular relaxation is impaired in many animals models of hypertension and in hypertensive humans, and this is thought to be due, at least in part, to impaired endothelial NO production or activity.^{105 106} Consistent with the idea that EDHF may compensate during impaired vascular production of NO (Figure 2), findings made in endothelial NO synthase–deficient mice (which are moderately hypertensive¹⁰⁷ ) suggest that EDHF(s) mediates endothelium-dependent relaxation of saphenous, mesenteric, and skeletal muscle arterioles, whereas the same functional responses are mediated by NO in normal mice.^{108 109} This phenomenon may be specific to certain vascular beds, however, because no such compensation by EDHF occurs in aorta or the carotid, pulmonary, cerebral, or coronary arteries of endothelial NO synthase–mutant mice^{107 110 111 112 113} or in cerebral arterioles¹¹⁴ of normal mice treated with inhibitors of NO synthase or soluble guanylate cyclase.

Interestingly, impaired production of EDHF, and not NO, may sometimes contribute to reduced endothelium-dependent vascular relaxation during chronic hypertension, and in some instances, basal NO synthesis may be upregulated.¹¹⁵ There are now several reports that the contribution of EDHF to endothelium-dependent vasorelaxation is greatly reduced, whereas that of NO is preserved or increased, in a number of models of genetic and nongenetic hypertension.^{47 48 49 93 116 117 118} Thus, more work is clearly needed, not only to clarify the chemical identity of EDHF(s) and the molecular details of its K⁺ channel–mediated mechanism of hyperpolarization, but also to understand the relationship between the bioavailability and function of EDHF and NO in normal and diseased arteries.

Diabetes
There is a 2- to 4-fold increase in the risk of coronary heart disease, cerebrovascular disease, congestive heart failure, and other cardiovascular complications due to diabetes.^{119 120 121} Moreover, abnormalities of vascular function are thought to contribute to the etiology of many diabetic complications, including neuropathy, retinopathy, and myopathy. Functional changes occurring in blood vessels during diabetes include endothelial cell dysfunction⁵ but may also involve altered ion channel function in vascular smooth muscle.

K_ATP Channels in Diabetes
Most information currently available regarding vascular K⁺ channel function in diabetes concerns K_ATP channels. As for chronic hypertension, there are now several reports of impaired vascular relaxant responses to synthetic openers of K_ATP channels in long-term diabetes. These studies have mostly utilized the streptozotocin-injected rat model of diabetes and have examined vessels at 2.5 to 4 months after streptozotocin treatment. In this model in which plasma glucose levels are increased 3- to 4-fold, impaired relaxation of the isolated aorta^{122 123 124} and mesenteric vascular bed¹²⁵ and reduced dilatation of large¹²⁶ and small¹²⁷ cerebral arteries in vivo typically develop. These changes are thought to be the result of a decreased number of vascular K_ATP channels and/or reduced sensitivity of these channels to synthetic openers. Nonspecific cytotoxic effects of streptozotocin seem an unlikely cause of these changes because, like other manifestations of vascular dysfunction, abnormal vasodilator responses to K_ATP channel openers are prevented by treatments that prevent or reverse the hyperglycemia.¹²³ Streptozotocin-induced diabetes may also alter the functional response of K_ATP channels in other tissues, including pancreatic ß-cells¹²⁸ and ventricular myocytes,¹²⁹ indicating that hyperglycemia-induced impairment of K_ATP channels is not restricted to the vasculature. Because diabetes is associated with elevated plasma levels of LDL cholesterol and triglycerides, it is conceivable that some vascular abnormalities of diabetes are not directly related to hyperglycemia per se but could instead be a consequence of an altered plasma lipid profile.¹³⁰

The period of experimental hyperglycemia appears to be an important determinant of the observed effects of diabetes on vascular K_ATP channel function because, by contrast, responses to K_ATP channel activation are reported to be enhanced in the early diabetic state. For example, cromakalim-induced dilatation of large coronary arteries in the dog are augmented 1 week after treatment with alloxan, and responses of the small coronary arteries are unaltered.¹³¹ Similarly, only 2 weeks after streptozotocin injection, activators of K_ATP channels cause enhanced dilator responses of rat isolated renal afferent arterioles.¹³² Moreover, because glibenclamide may cause marked constriction of those vessels, increased expression and basal activation of K_ATP channels may both occur in the renal circulation early during diabetes.¹³² This condition could contribute to the increases in glomerular filtration rate and renal plasma flow (ie, "hyperfiltration"), which occur in early stages of diabetes in both clinical and experimental settings.¹³³ An increased K_ATP channel activity at this time may therefore reflect a very high metabolic state (ie, low ATP levels) of vascular smooth muscle cells relatively soon after the initiation of hyperglycemia. Increased K_ATP channel activity in blood vessels during metabolic stress, such as during ischemia, could be beneficial for maintaining tissue perfusion. Hence, tissues could be more susceptible to ischemic damage after extended periods of diabetes owing to impaired function of K_ATP channels.

On the other hand, mixed effects on K_ATP channel function are reported to occur at 4 to 8 weeks after induction of hyperglycemia, presumably in part reflecting a gradual deterioration of vascular mechanisms during progression of the disease. For example, Bouchard et al¹²⁵ reported that vasorelaxant responses to lemakalim are impaired in coronary resistance vessels, but not in the mesenteric vascular bed or the aorta, after 2 months of hyperglycemia. Likewise, pinacidil-induced hyperpolarization of the mesenteric artery was reported to be preserved after 8 to 12 weeks.¹³⁴ Zimmerman et al¹³⁵ reported that dilator responses to K_ATP channel openers were impaired in cerebral arteries from 4- to 8-week-diabetic rats as a consequence of reduced basal release of endothelium-derived NO. K_ATP channel function could be restored in those diabetic vessels by application of an NO donor drug.¹³⁵ However, such a mechanism of endothelial NO-dependent K_ATP channel activation may not always occur in other preparations, as others have found no evidence of a role for NO in the dilator responses of rat cerebral vessels to K_ATP channel openers in vivo,^{127 136} and K_ATP channel–mediated relaxant responses are impaired even in endothelium-denuded vessels after slightly longer periods of diabetes.^{122 124}

Other K⁺ Channels in Diabetes
Information is still generally lacking regarding the effects of diabetes on the function of other types of K⁺ channels. Diabetes, like several other vascular diseases, is recognized as a condition in which there is increased oxidant stress.¹³⁷ Hence, with increased production of reactive oxygen species in the vascular wall and consequently, a decreased bioavailability of NO (eg, due to inactivation of NO by superoxide anion), activation of BK_Ca or K_V channels by NO/cyclic GMP might be expected to be decreased under resting or stimulated conditions. Moreover, there is recent evidence that peroxynitrite, which is formed by the reaction of superoxide anion with NO, can cause vasoconstriction (and presumably, E_m depolarization) by inhibition of BK_Ca channels in cerebral vascular muscle cells.^{138 139} Consistent with this notion, there is evidence that E_m is more depolarized than normal in cerebral arteries of genetic¹⁴⁰ and nongenetic¹³⁵ models of diabetes, although it is not altered in mesenteric arteries of streptozotocin-injected rats.¹³⁴ A reduced hyperpolarizing influence of basally released endothelium-derived NO may contribute to cerebrovascular depolarization in some cases.¹³⁵ In addition, there is preliminary evidence for an overall decrease in the outward K⁺ current in cerebral myocytes from spontaneously diabetic BB rats, which may involve decreased BK_Ca channel function and increased K_V channel function.¹⁴⁰ Finally, K⁺-induced relaxation is impaired in mesenteric arteries from diabetic rats,¹³⁰ perhaps reflecting an altered K_IR channel function.

EDHF in Diabetes
Recent findings suggest that the role of EDHF may be diminished in diabetic arteries. The component of endothelium-dependent relaxation that is resistant to NO synthase inhibition but sensitive to vascular depolarization is reduced in mesenteric vessels from diabetic rats, whereas the NO-mediated component is preserved or augmented.¹³⁰ Consistent with this finding, direct measurements of E_m in vascular muscle cells have confirmed that the endothelium-dependent hyperpolarization by EDHF is markedly reduced in mesenteric arteries from diabetic rats.¹³⁴ Thus, impaired production and/or effects of EDHF may account for the diminished endothelium-dependent relaxant responses of diabetic mesenteric arteries.

Hypercholesterolemia and Atherosclerosis
It is well established that vascular dysfunction occurs in hypercholesterolemia and atherosclerosis. In particular, this disease is associated with impairment of endothelial function, and reduced vascular activity of endothelium-derived NO is likely to play a major role in the development of atherosclerosis.¹⁴¹ As a consequence, arteries may exhibit an increased vascular tone under basal conditions and may respond inadequately to endothelium-dependent vasodilator agonists. Under such conditions of altered vascular reactivity, K⁺ channel activity or function may also be abnormal.

BK_Ca Channels in Hypercholesterolemia and Atherosclerosis
Najibi and colleagues^{142 143} have reported functional evidence of an enhanced role for BK_Ca channels in the vasodilator responses of carotid arteries from hypercholesterolemic rabbits. These investigators found that although the magnitude of endothelium-dependent relaxation was preserved, the responses of hypercholesterolemic but not of normal arteries were sensitive to charybdotoxin.¹⁴² Similarly, acetylcholine-induced relaxation is inhibited by charybdotoxin in aortic rings of atherosclerotic but not of normal mice.⁷⁶ Initially, the findings of Najibi et al were interpreted as being evidence for upregulation of an EDHF-mediated compensatory component during impaired NO production in hypercholesterolemia.¹⁴² However, subsequent studies by those workers revealed that the mechanism of the vasorelaxant response to exogenous NO becomes charybdotoxin sensitive despite an impaired production of cyclic GMP after cholesterol feeding,¹⁴³ suggesting that the functional role of BK_Ca channels in vascular muscle is markedly increased during hypercholesterolemia. These observations could be explained, in part, by a lower level of basal BK_Ca channel activity (and hence, increased BK_Ca channel availability for opening) under conditions of impaired activity of endothelium-derived NO. Analogous evidence for an increased role of BK_Ca channels in vasodilator responses to NO has been reported in cerebral arteries during NO synthase inhibition¹³⁶ and after SAH.¹⁴⁴ Interestingly, recent patch-clamp studies have found that the activity of BK_Ca channels is significantly higher in smooth muscle cells from human coronary atherosclerotic plaques than in medial smooth muscle cells, possibly suggesting a role for BK_Ca channels in the development of human atherosclerosis.¹⁴⁵

K_ATP Channels in Hypercholesterolemia and Atherosclerosis
Relatively few studies have examined the effects of hypercholesterolemia and atherosclerosis on the functioning of non-BK_Ca K⁺ channels in blood vessels, with no electrophysiological data reported so far to the author’s knowledge. However, available evidence suggests that there may be regional variations in any associated changes to K_ATP channels, perhaps with more marked effects occurring in the larger vessels, which are also more susceptible to atherosclerotic lesion development. In carotid arteries from atherosclerotic monkeys, aprikalim-induced relaxation is impaired (as is acetylcholine-induced relaxation), whereas relaxant responses to the NO donor sodium nitroprusside are generally preserved.¹⁴⁶ Similarly, relaxation of atherosclerotic rabbit aortic rings is impaired in response to nicorandil, an agent that possesses properties of both K_ATP channel openers and NO donors.¹⁴⁷ Because responses to NO donors are commonly preserved in atherosclerotic vessels, this finding may reflect an impairment of K_ATP channel–mediated vasodilatation in the atherosclerotic aorta. By contrast, dilatation of small coronary arteries in vivo in response to aprikalim is preserved in atherosclerotic monkeys,¹⁴⁸ and relaxation of rabbit carotid and mesenteric arteries in response to K_ATP channel openers or hypoxia is unaffected by hypercholesteremia, whereas responses to acetylcholine are attenuated.^{149 150} Interestingly, unlike the reduction of endothelium-dependent relaxation, impairment of K_ATP channel function in atherosclerotic vessels may not be readily reversible by dietary treatment.¹⁴⁶

K_V Channels in Hypercholesterolemia and Atherosclerosis
4-Aminopyridine induces contraction and rhythmic activity of aortic rings from atherosclerotic but not control mice.⁷⁶ Because it is thought that basal NO release from endothelial cells may activate K_V channels on vascular smooth muscle^{15 19 20} and that NO activity is reduced in atherosclerotic arteries,¹⁴¹ it was suggested that the findings were evidence for reduced basal K_V channel activity in atherosclerotic vessels.⁷⁶ An alternative interpretation might be that increased effects of a K_V channel inhibitor reflect an increased basal influence of these channels during atherosclerosis, whereby inhibition of channel activity might be expected to have an increased influence on vascular muscle E_m and tone. In another study, 4-aminopyridine was found to inhibit endothelium-dependent, NO-mediated relaxation in response to acetylcholine in normal rabbit cerebral arteries, but it had no effect on the impaired responses to acetylcholine in vessels from cholesterol-fed rabbits,⁷⁷ consistent with a reduced role for K_V channels in the relaxant responses of atherosclerotic vessels.

EDHF in Hypercholesterolemia and Atherosclerosis
Few studies have so far tested the effects of hypercholesterolemia and atherosclerosis on EDHF function. Lysophosphatidylcholine, which is elevated in oxidatively modified LDL, is reported to inhibit different components of endothelium-dependent relaxation mediated by either NO or EDHF,¹⁵¹ suggesting that responses to both endothelium-derived factors may be sensitive to hypercholesterolemia. Similarly, EDHF-mediated relaxation of human isolated gastroepiplopic arteries was reduced during hypercholesterolemia.³⁸ By contrast, EDHF-mediated (ie, NO synthase– and cyclooxygenase-independent), endothelium-dependent relaxation of the rabbit renal artery was increased during hypercholesterolemia despite an impaired endothelium-dependent relaxant response overall in the absence of inhibitors, consistent with an enhanced role for EDHF in helping to maintain vascular function during reduced NO activity¹⁵² (Figure 2).

	Concluding Remarks and Future Directions

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 
As we have seen, many complex alterations in vascular K⁺ channel functions have been described in several major diseases. Although there is no firm evidence that vascular K⁺ channel dysfunction is genetic in origin, the progression of human cardiovascular disease states—which are probably caused by complex interactions between genetic and environmental factors—may nevertheless lead to secondary effects on K⁺ channel function that could perhaps be protective or that may further exacerbate the consequences of the disease.

Only a very modest amount of data currently exists at the molecular level regarding vascular K⁺ channel function in disease. As further progress is made, particularly through molecular and electrophysiological approaches, in unraveling the relationship between K⁺ channel structure and function, we will obtain a clearer picture of the ways in which channel expression and function are normally regulated. We can then use this information in seeking to identify specific K⁺ channel abnormalities and their causes in particular diseases. Increased appreciation of the diversity of vascular cell types present throughout the circulation and the relevance of specific K⁺ channel functions in different cell types and in different segmental regions may prove very important for understanding vascular K⁺ channel biology as well as pathology.⁴ With the development of more selective pharmacological modulators, activation of vascular K⁺ channels would seem to be a very promising direction for therapy in numerous vascular disease states associated with vascular constriction and depolarization. In particular, the utilization of gene targeting technology in mice will very likely provide major advances in our understanding of the function of vascular K⁺ channel subtypes in isolated vessel preparations (as in Reference 30³⁰ ) and ultimately, in the intact circulation in vivo in both health and disease.

	Acknowledgments

 
The author thanks Prof Frank Faraci, Prof James Angus, and Sophocles Chrissobolis for their helpful comments during preparation of this manuscript. Dr Sobey is a Senior Research Officer of the National Health and Medical Research Council of Australia.

Received September 13, 2000; accepted October 5, 2000.

	References

Top Abstract Introduction Calcium-Activated K+ Channels Voltage-Dependent (Delayed... ATP-Sensitive K+ Channels Inwardly Rectifying K+ Channels Endothelium-Dependent... Use of Gene Targeting... K+ Channels in Vascular... Concluding Remarks and Future... References

 

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