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(Hypertension. 2000;35:173.)
© 2000 American Heart Association, Inc.

Workshop

Ion Channels and Vascular Tone

William F. Jackson

From the Department of Biological Sciences, Western Michigan University, Kalamazoo, Mich.

Correspondence to Dr William F. Jackson, Department of Biological Sciences, Western Michigan University, 3169 Wood Hall, Kalamazoo, MI 49008. E-mail jackson{at}wmich.edu

	Abstract

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
Abstract—Ion channels in the plasma membrane of vascular muscle cells that form the walls of resistance arteries and arterioles play a central role in the regulation of vascular tone. Current evidence indicates that vascular smooth muscle cells express at least 4 different types of K⁺ channels, 1 to 2 types of voltage-gated Ca²⁺ channels, 2 types of Cl^- channels, store-operated Ca⁺ (SOC) channels, and stretch-activated cation (SAC) channels in their plasma membranes, all of which may be involved in the regulation of vascular tone. Calcium influx through voltage-gated Ca²⁺, SOC, and SAC channels provides a major source of activator Ca²⁺ used by resistance arteries and arterioles. In addition, K⁺ and Cl^- channels and the Ca²⁺ channels mentioned previously all are involved in the determination of the membrane potential of these cells. Membrane potential is a key variable that not only regulates Ca⁺² influx through voltage-gated Ca²⁺ channels, but also influences release of Ca²⁺ from internal stores and Ca²⁺- sensitivity of the contractile apparatus. By controlling Ca²⁺ delivery and membrane potential, ion channels are involved in all aspects of the generation and regulation of vascular tone.

Key Words: muscle, smooth, vascular • arterioles • potassium channels • calcium channels • vascular resistance • vasoconstriction

	Introduction

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
Vascular tone, the contractile activity of vascular smooth muscle cells in the walls of small arteries and arterioles, is the major determinant of the resistance to blood flow through the circulation. Thus, vascular tone plays an important role in the regulation of blood pressure and the distribution of blood flow between and within the tissues and organs of the body. Regulation of the contractile activity of vascular smooth muscle cells in the systemic circulation is dependent on a complex interplay of vasodilator and vasoconstrictor stimuli from circulating hormones, neurotransmitters, endothelium-derived factors, and blood pressure. All of these signals are integrated by vascular muscle cells to determine the activity of the contractile apparatus of the muscle cells and hence the diameter and hydraulic resistance of a blood vessel. Ion channels play a central role in this process. Like all muscle cells, vascular smooth muscle uses Ca²⁺ as the trigger for contraction. Calcium influx through channels in the plasma membrane and Ca²⁺ release from intracellular stores are the major source of activator Ca²⁺. In addition, the movement of ions through ion channels determines, to a large extent, membrane potential. Membrane potential, along with cytosolic Ca²⁺ concentration, regulates and modulates the influx^{1 2} and release^{3 4 5} of Ca²⁺ through ion channels and the sensitivity of the contractile machinery to Ca²⁺.⁶ Vascular smooth muscle cells express 4 different types of K⁺ channels,^{7 8} 1 to 2 types of voltage-gated Ca²⁺ channels,^{1 2} 2 types of Cl^- channels,^{9 10 11} store-operated Ca⁺ channels,^{12 13} and stretch-activated cation channels^{14 15 16} in their plasma membranes, all of which may be involved in the regulation of vascular tone. These channels will serve as the focus of this review, with particular emphasis on regulation of vascular tone in the microcirculation. The reader is referred to several recent reviews for information about intracellular ion channels^{13 17 18} and ion channels in endothelial cells,¹⁹ which also are involved in the determination of vascular tone.

	Regulation of Vascular Tone by K+ Channels and Voltage-Gated Ca+ Channels

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
Potassium channels are the dominant ion conductive pathways in vascular muscle cells.^{7 8} As such, their activity importantly contributes to determination and regulation of membrane potential and vascular tone.^{7 8} The electrochemical gradient for K⁺ ions is such that opening of K⁺ channels results in diffusion of this cation out of the cells and membrane hyperpolarization (Figure 1). Closure of K⁺ channels has the opposite effect (Figure 1).

View larger version (28K): [in this window] [in a new window]   Figure 1. K+ channels and vascular tone. Schematic of a vascular smooth muscle cell (top) and cross sections through an arteriole (bottom) that shows that opening K+ channels leads to diffusion of K+ ions out of the cell, membrane hyperpolarization, closure of voltage-gated Ca2+ channels, decreased intracellular Ca2+, etc (see text), which leads to vasodilatation. Closure of K+ channels has the opposite effect. Modified from Jackson.8

Voltage-gated Ca²⁺ channels play a central role in the regulation of vascular tone by membrane potential^{1 2} : hyperpolarization closes these channels and leads to vasodilatation, whereas depolarization opens them, which results in vasoconstriction (Figure 1). Dihydropyridine-sensitive L-type voltage-gated Ca²⁺ channels appear to be dominant in most vascular muscle cells,^{1 2} although T-type Ca²⁺ channels have been reported.² In the microcirculation, L-type Ca²⁺ channels appear to play a particularly important role in myogenic reactivity^{20 21 22} and vasomotion.^{20 23 24} Voltage-gated Ca²⁺ channels are modulated by several signaling systems.² They appear to be activated by vasoconstrictors that activate the protein kinase C pathway.² Vasodilators that stimulate production of cAMP and activate protein kinase A have been reported to both activate and inhibit these channels.² Voltage-gated Ca²⁺ channels are inhibited by increases in intracellular Ca²⁺ and activation of cGMP-dependent protein kinase.² Thus, these ion channels are poised to contribute to an important degree to the neural, humoral, and local regulation of vascular tone.

Membrane potential not only regulates voltage-gated Ca²⁺ channels, but also appears to influence inositol 1,4,5-trisphosphate–induced release of Ca²⁺ from intracellular stores^{3 4 5} and the Ca²⁺ sensitivity of the contractile apparatus.⁶ Thus, by their dominance in setting membrane potential, K⁺ channels play a central role in determination and regulation of vascular tone. In the microcirculation, as in other vascular muscles, we have identified functional expression of 4 different classes of K⁺ channels (see Figure 1): ATP-sensitive K⁺ (K_ATP) channels, large-conductance Ca²⁺- activated K⁺ (BK_Ca) channels, voltage-activated K⁺ (K_V) channels, and inward rectifier K⁺ (K_IR) channels.^{8 25 26 27}

	KATP Channels and Vascular Tone

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
ATP-sensitive K⁺ channels were first described by Noma²⁸ in cardiac myocytes. Subsequent studies by other investigators have identified currents through similar channels in many other cell types, including vascular smooth muscle cells (see references ²⁹ through –³² for recent reviews). These channels close as intracellular ATP concentration increases; hence, their name. However, as mentioned below, K_ATP channels are also regulated by several signal transduction pathways independent from changes in ATP. Thus, other regulatory pathways may be more physiologically important.

Early studies showed that glibenclamide, a selective K_ATP channel blocker, caused arteriolar constriction in several microcirculatory beds in a number of species, including humans.^{33 34 35 36 37 38 39} These data support the hypothesis that K_ATP channels may be active in the microcirculation under resting conditions. Glibenclamide has been reported to have no effect on resting vascular resistance in several vascular beds.^{40 41 42 43} The reason for these differences is not obvious and has not been experimentally explored. The differences may indicate species or regional differences in the activity and regulation of these channels or methodological differences among the studies described above.

Several studies have shown that K_ATP channel agonists such as cromakalim and pinacidil dilate arterioles,^{7 31 33 34 44} which provides evidence that recruitable K_ATP channels also are present in arteriolar muscle cells. In addition, arteriolar dilation induced by adenosine, prostacyclin, and isoproterenol is mediated, in part, by opening of K_ATP channels.^{33 34} These functional studies provided evidence that this class of ion channel plays a crucial role in the regulation of vascular tone in the microcirculation.

The open K_ATP channels implied by the functional experiments noted above have recently been confirmed by electrophysiological measurements in single, isolated arteriolar muscle cells with the perforated patch technique.²⁷ Superfusion of either hamster or rat cremasteric arteriolar muscle cells with glibenclamide (1 µmol/L), inhibited currents between -60 and -30 mV (normal range of resting membrane potential), decreased whole-cell membrane conductance, and depolarized current-clamped cells by >10 mV.²⁷ These experiments provided the first direct evidence that open K_ATP channels exist in resting arteriolar muscle cells. Thus, K_ATP channels play an important role in the regulation of resting membrane potential and, hence, tone of arteriolar muscle cells. They also appear to participate in the mechanism of action of vasodilators such as adenosine and prostacyclin through cAMP/protein kinase A–dependent⁷ and –independent³⁴ mechanisms. Furthermore, some vasoconstrictors may act, in part, by closure of K_ATP channels through a mechanism that involves protein kinase C.^{7 36} K_ATP channels have been implicated in functional hyperemia,^{35 39 40} reactive hyperemia,^{37 41 42} and responses to reductions in blood flow⁴³ in several skeletal muscle models. Responses of arterioles and resistance arteries to K_ATP channel agonists are blunted during experimental diabetes mellitus,^{45 46 47 48} which suggests a role for these channels in the causation of or as a consequence of vascular complications present in this disease.

	BKCa Channels and Vascular Tone

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
Large-conductance BK_Ca channels are found in most cells.⁴⁹ These channels are activated by increases in intracellular Ca²⁺ and membrane depolarization.^{7 50} In small arteries that display myogenic tone, activity of BK_Ca channels has been reported to contribute to resting membrane potential: blockade of the channels with iberiotoxin or tetraethyl ammonium (TEA) ions leads to membrane depolarization and vasoconstriction.^{1 7 51 52} Nelson and colleagues have championed the idea that BK_Ca channels play a central role in the regulation of vascular tone due to focal increases in subsarcolemmal Ca²⁺ (ie, Ca²⁺ sparks) by Ca²⁺ released through ryanodine receptors in the sarcoplasmic reticulum.^{17 51 53}

In the microcirculation, despite substantial resting myogenic tone, BK_Ca channels appear to be silent^{25 27 54 55} ; application of iberiotoxin or TEA has no effect on resting arteriolar diameter in vivo,^{25 54 55} and neither agent affects membrane potential or whole-cell K⁺ currents in single cells in vitro.^{8 27} This lack of apparent BK_Ca channel activity appears to arise because the channels present in the membranes of these cells have a high calcium threshold. That is, high levels of Ca²⁺, on the order of 3 to 10 µmol/L, are required for channel activity in the physiological range of membrane potentials (-60 to -30 mV) in relaxed cells.²⁵ Despite this high threshold, these channels are activated in the microcirculation during active vasoconstriction by agents such as norepinephrine and elevated oxygen tension.²⁵ Thus, BK_Ca channels appear to play a negative feedback role to limit active vasoconstriction and prevent vasospasm. In addition, these channels may be activated by vasodilators that act through the cGMP and cAMP cascades,^{7 54} epoxides of arachidonic acid⁵⁶ and CO.^{57 58 59} These channels may be closed by 20-OH arachidonic acid produced by cytochrome P450_4a.⁶⁰ Furthermore, vasodilators and vasoconstrictors may influence the frequency and amplitude of Ca²⁺ sparks and thus influence BK_Ca channel activity.^{53 61 62} Finally, expression of BK_Ca channels in vascular smooth muscle membranes is increased during hypertension^{63 64 65 66 67} and has been proposed to occur as a negative feedback response to the increased vascular reactivity observed in hypertension.⁶⁷ Thus, BK_Ca channels play an important role in regulation of vascular tone in both health and disease.

	KV Channels and Vascular Tone

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
Voltage-activated K⁺ channels, inhibited by 4-aminopyridine (also known as delayed rectifier channels), are another ubiquitous class of K⁺ channels expressed by vascular smooth muscle cells.⁷ These channels are activated by membrane depolarization with threshold potentials for substantial activation of -30 mV. Studies of small arteries and arterioles in vitro and vascular muscle cells isolated from arteries and arterioles have provided evidence that these channels may participate in the regulation of resting membrane potential and vascular tone.^{7 8 27} K_V channels may also participate in the mechanism of action of both vasodilators and vasoconstrictors^{7 68 69} : vasodilators that act via the cAMP signaling cascade may open these channels, and vasoconstrictors may close K_V channels by mechanisms that involve elevated intracellular Ca²⁺ and protein kinase C. Their role in vivo has not been explored, largely because of the lack of availability of inhibitors selective for the channels expressed in vascular muscle cells. However, electrophysiological studies indicate a decreased functional expression of K_V channels in vascular muscle cells from hypertensive animals, which may contribute to depolarization and an increase in vascular tone in this disease.⁷⁰

	KIR Channels and Vascular Tone

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
Inward rectifier K⁺ channels were first identified by Katz in skeletal muscle⁷¹ and subsequently have been found in both excitable and nonexcitable cells (see references 31, 72, and 73 for further examples). These ion channels pass inward K⁺ current much more readily than outward current with physiological ion gradients and also show a parallel rightward shift in the potential at which rectification appears (activation potential) and a large increase in conductance with increases in the extracellular K⁺ concentration. Very little is known about the role played by K_IR channels in the regulation of resting membrane potential and tone, and data that are available are difficult to interpret. Superfusion of guinea pig submucosa in vitro with Ba²⁺ ions causes depolarization of arterioles from -70 to -40 mV.^{74 75 76} These data suggest that K_IR channels may be active under resting conditions and contribute to resting membrane potential in this preparation. The relevance of these observations to other preparations and normal physiological conditions is not known. Membrane potential in submucosal arterioles is very negative relative to what has been measured in other vascular preparations under resting, unstimulated conditions.^{7 77} It is possible that due to the conditions of the preparation (isolated, unperfused tissue with unpressurized vasculature), K_IR channels are activated. In vascular muscle cells isolated from rat ventricular septal arteries, 100 µmol/L Ba²⁺ causes a small inhibition of outward current at -50 mV, which suggests that K_IR channels may be active at resting membrane potential in these cells.⁷⁸ Despite this supporting evidence, studies of isolated, cannulated, septal arteries have failed to identify a significant role for K_IR channels in the regulation of resting membrane potential and tone.⁷⁹ Preliminary studies suggest that 50 µmol/L Ba²⁺ causes constriction of rat arterioles in cremaster muscle in vivo.⁵⁵ In contrast, studies of hamster cremasteric arteriolar muscle cells have found no effect of Ba²⁺ on currents around the resting membrane potential.²⁶ These data are inconsistent with the hypothesis that K_IR channels are active under resting conditions. Thus, the role played by K_IR channels in the regulation of resting membrane potential and tone remains unclear.

In cerebral, coronary, and skeletal muscle vascular beds, elevated extracellular K⁺, as might arise from increases in nerve or muscle activity, causes vasodilation that is associated with hyperpolarization of the vascular smooth muscle membrane.^{7 31 79 80} Two mechanisms have been proposed to explain this K⁺-induced hyperpolarization: activation of Na⁺/K⁺ ATPase and activation of K_IR channels. Early studies showed that K⁺ -induced vasodilation could be inhibited by ouabain, which suggests that Na⁺/K⁺ ATPase might be involved in this process.^{77 80} However, more recent evidence suggests that K_IR channels mediate K⁺-induced vasodilation in cerebral and coronary resistance arteries.^{7 31 79 81 82 83} Preliminary data support a role for K_IR channels in K⁺-induced dilation of arterioles in cremaster muscle.⁵⁵ However, previous studies in this preparation have shown that K⁺ induced dilation can be inhibited by millimolar concentrations of ouabain.⁸⁴ Thus, the role played by K_IR channels in K⁺-induced vasodilation of skeletal muscle arterioles remains unclear.

	Cl- Channels and Vascular Tone

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
Chloride channels have also been proposed to regulate vascular tone.^{9 10 11} As with K⁺ ions, the electrochemical gradient for Cl^- is such that opening of Cl^- channels will result in efflux of Cl^- from vascular muscle cells (Figure 2). However, because of the negative charge, this efflux will result in depolarization and vasoconstriction (Figure 2). Closing the Cl^- channels will have the opposite effect (Figure 2). Vascular muscle cells appear to express 2 different types of chloride channels: Ca²⁺-activated Cl^- (Cl_Ca) channels⁹ and volume-regulated Cl^- (Cl_VR) channels.^{10 11} Like BK_Ca channels, Cl_Ca channels are activated by increases in intracellular Ca²⁺, and several studies have proposed that these channels are activated by vasoconstrictors and participate in the depolarization that is associated with vasoconstrictor-induced tone.⁹ However, other investigators have argued that Cl_Ca channels could have little effect on membrane potential because of the high density of BK_Ca channels and their large conductance.⁸⁵

View larger version (26K): [in this window] [in a new window]   Figure 2. Cl- channels and vascular tone. Schematic of a vascular smooth muscle cell (top) and cross sections through an arteriole (bottom) that shows that opening of Cl- channels leads to diffusion of Cl- ions out of the cell, membrane depolarization, opening of voltage-gated Ca2+ channels, increased intracellular Ca2+, etc (see text), which leads to vasoconstriction. Closure of Cl- channels has the opposite effect.

More recently, interest has been generated in Cl_VR channels. Nelson and colleagues¹⁰ demonstrated that Cl^- channel blockers dilated and hyperpolarized myogenically active cerebral arteries, which supports a role for Cl^- channels in regulation of resting membrane potential and myogenic tone. The pharmacological profile that they found was inconsistent with Cl_Ca channels, so they hypothesized that Cl_VR channels were involved. Subsequently, expression of a Cl_VR channel (ClC-3) was documented in canine pulmonary arteries,¹¹ which further supports a role for this class of ion channel in the regulation of vascular tone.

However, the picture has become considerably more cloudy. Indanyloxyacetic acid, used in the functional studies mentioned above,¹⁰ has recently been shown to block voltage-gated, dihydropyridine-sensitive Ca²⁺ channels in vascular muscle cells in the same concentration range as it inhibits tone.⁸⁶ Indanyloxyacetic acid has also been shown to activate TEA- and glibenclamide-sensitive K⁺ currents in vascular muscle cells.⁸⁷ Another chloride blocker, 5-nitro-2-(3-phenylpropylamino)benzoic acid not only blocks L-type Ca²⁺ channels,⁸⁶ but has also been demonstrated to inhibit currents through other calcium influx pathways in endothelial cells.⁸⁸ These additional effects confound simple interpretation of results obtained with Cl^- channel blockers. Thus, further research will be required to establish the role played by Cl^- channels in the regulation of vascular tone.

	Store-Operated and Stretch-Activated Ca2+ Channels and Vascular Tone

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
Calcium not only enters vascular muscle cells through voltage-gated Ca²⁺ channels, but also through store-operated Ca²⁺ (SOC) channels^{12 13} and stretch-activated cation (SAC) channels.^{14 15 16} SOC channels are activated when intracellular calcium stores empty through an as yet not well defined signaling pathway.¹³ In other cell types, this pathway provides a means to refill the stores. Recent evidence suggests that this pathway may also be important in the regulation of vascular tone.¹² However, these ion channels have not been investigated in resistance arteries or arterioles.

Calcium may also enter vascular muscle cells through SAC channels.^{14 15 16} Studies in isolated porcine coronary muscle cells have provided evidence for SAC channels permeable to Ca²⁺ that are responsible, in part, for stretch-induced depolarization of these vascular muscle cells¹⁴ and that result in an influx of Ca²⁺ sufficient to increase intracellular Ca²⁺ even when dihydropyridine-sensitive channels are inhibited.¹⁵ Similar results were recently obtained in mesenteric resistance arteries from guinea pig.¹⁶ These data support the hypothesis that SAC channels may be involved in the regulation of myogenic tone. Their role in vivo has not been examined.

	Summary

Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 
The brief outline presented above clearly demonstrates that ion channels play a central role in the regulation of vascular tone. As depicted in Figure 3, Ca²⁺ influx through voltage-gated Ca²⁺, SOC, and SAC channels provides a major source of activator Ca²⁺ used by resistance arteries and arterioles. In addition, K⁺ and Cl^- channels and the Ca²⁺ channels mentioned previously all are involved in the determination of the membrane potential of these cells (Figure 3). In turn, membrane potential, with intracellular Ca²⁺, regulates and modulates Ca²⁺ influx and Ca²⁺ release and Ca²⁺ sensitivity of the contractile machinery (Figure 3). In addition, although this is not covered in detail in the present review, functions of many of these channels are modulated by the signals and signaling pathways depicted in Figure 3. Thus, ion channels are involved to an important degree in the generation of vascular tone and in neural, humoral, and local regulation of this critical variable.

View larger version (25K): [in this window] [in a new window]   Figure 3. Ion channels and vascular tone. Schematic of a cross section through part of a vascular muscle cell. Along the top membrane are shown KIR, KATP, KV, and BKCa channels. Also shown are voltage-gated Ca2+ channels, 2 types of Cl- channels (see text), SOC channels (SOCC), and SAC channels (SACC). Shown in the membranes of the sarcoplasmic reticulum (SR) are ryanodine receptors (RyR) and inositol 1,4,5-trisphosphate receptors (IP3R). Bottom, A few of the signals that are known to modulate the function of the ion channels depicted. AC indicates adenylate cyclase; PKA, cAMP-dependent protein kinase; sGC, soluble guanylate cyclase; PKG, cGMP-dependent protein kinase; EETs, epoxyeicostetraenoic acid (epoxides of arachidonic acid; see text); PLC,phospholipase C; DAG,diacylglycerol; PKC=protein kinase C; and 20-HETE, 20-OH-arachidonic acid. See text for details.

	Acknowledgments

 
This work was supported by Public Health Service grant HL-32469.

	Footnotes

 
Received September 13, 1999; first decision October 20, 1999; revision accepted October 26, 1999.

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Top Abstract Introduction Regulation of Vascular Tone... KATP Channels and Vascular... BKCa Channels and Vascular... KV Channels and Vascular... KIR Channels and Vascular... Cl- Channels and Vascular... Store-Operated and Stretch... Summary References

 

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