Molecular and Cellular Emerging Role of Arterial Vascular Smooth Muscle Cells Potassium Channels in Chronic Hypertension Volume 47- Issue 5

Leta Melaku*

• Assistant Professor of Medical Physiology, Department of Biomedical Sciences, College of Health Sciences, Arsi University, Ethiopia

Received: December 16, 2022;   Published: January 05, 2023

*Corresponding author: Leta Melaku, Assistant Professor of Medical Physiology, Department of Biomedical Sciences, College of Health Sciences, Arsi University, Ethiopia

DOI: 10.26717/BJSTR.2023.47.007570

Abstract PDF

Background: Potassium (K+) ion channel activity is an important determinant of vascular tone by regulating cell membrane potential (MP). This study aims to describe the effect of hypertension on the physiological function of major potassium channels within blood vessels.
Method: Studies were accessed through an electronic web-based search strategy from PubMed, Cochrane Library, Google Scholar, Embase, PsycINFO, and CINAHL by using a combination of search terms.
Results/Discussion: Each of K⁺ channels (Voltage-dependent K⁺ (Kv), large-conductance Ca²⁺-activated K⁺ (BKCa), and ATP-sensitive K⁺ (KATP) channels) is responsive to a number of vasoconstrictors and vasodilators, which act through protein kinase C (PKC) and protein kinase A (PKA), respectively. Impaired Kv, KATP, and Kir channel function have been linked to a number of pathological conditions, like hypertension. 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 factors could also contribute to changes in resting K+ channel activity, Em, and K+ channel–mediated vasodilatation.
Conclusion/Perspectives: Potassium channels importantly contribute to the regulation of vascular smooth muscle (VSM) contraction and growth. Activation of K+ channels leads to membrane hyperpolarization and subsequently vasodilatation, while inhibition of the channels causes membrane depolarization and then vasoconstriction.

Keywords: Arterial Vascular Smooth Muscle Cells; Potassium Channels; Chronic Hypertension

Abbreviation:SHRs: Spontaneously Hypertensive Rats; VSMC: Vascular Smooth Muscle Cell; VOCC: Voltage-Operated Calcium Channel; Popen: Open Probability; NO: Nitric Oxide; CO: Carbon Monoxide; WKYs: Wistar-Kyoto Rats

Potassium channels are the dominant ion conductive pathways in vascular muscle cells. As such, their activity importantly contributes to the determination and regulation of membrane potential and vascular tone [1,2]. To date, four distinct types of K⁺ channels have been identified in vascular smooth muscle (Figure 1). The following depolarization and increase in [Ca²⁺]_i can activate K⁺ chan nels to buffer the vasoconstriction (shown with green arrows). See text for details. Blue arrow = effect; red arrow = deactivation; green arrow = activation. VOCC: voltage-activated calcium channel, V_m: membrane potential, SR: sarcoplasmatic reticulum, PKC: protein kinase C, IP₃: inositol trisphosphate, 20-HETE: 20-hydroxyeicosatetraenoic acid.

Figure 1.Pathways leading to vasoconstriction via deactivation of K+ channels in vascular smooth muscle cells (shown with red arrows).

Voltage-Dependent K+ Channels (K_V Channels)

KV channels consist of four α-subunits, each subunit is associated with an additional β-subunit influencing the characteristics of the channel. Conductances between ~ 4 and 70 pS have been reported for single K_V channels in vascular smooth muscle cells depending on preparation and experimental conditions [3,4]. Compared with the process of activation, K_V channel inactivation is relatively slow and involves an initial peak in the K_V current [5]. The various constituents of the K_V current have been identified and the K_V channels present in vascular smooth muscle have been divided into groups based on their voltage dependence and pharmacological data. K_V channels exhibit strong voltage dependence. Cell membrane depolarization leads to activation of K_V channels and an increased hyperpolarizing outward K⁺ current. The resulting hyperpolarization of the vascular smooth muscle cell (VSMC) inactivates voltage-operated calcium channel (VOCC) channels and consequently decreases VSMC tone (Figure 2) (1,6). The threshold for activation of K_V channels is approximately -50 mV. Sustained depolarization leads to inactivation of K_V channels. Inactivation is slower than activation, and the steady-state current via these channels is determined by the balance between these processes. Thus, the open probability (Popen) of these channels is a product of the probability that they are available (not inactivated) and the probability that they are activated [7,8]. K_V channels are also activated by the cAMP/PKA pathway and inactivated by PKC as well as by a decreased pH. Furthermore, Rho kinases have been reported to suppress K_V currents in rat cerebral arteries [9].

Figure 2.Pathways leading to vasodilation via activation of K+ channels in endothelial cells or vascular smooth muscle.

Function of vascular K_V channels: Small-scale depolarization in vascular smooth muscle cells leads to an influx of Ca²⁺ through L-type Ca2+ channels and activation of the contractile machinery. K_V channels, also called the delayed rectifier, may contribute to the regulation of the resting membrane potential and thus the tone of VSMC (Figure 2) [10,11]. It is suggested that the physiological role of K_V channels is to buffer membrane depolarization to maintain resting vascular tone [1]. The presence of K_V channels in EC has been indicated, but their precise role in the control of EC function has yet to be clarified.

ATP-Sensitive K+ Channels (K_ATP Channels)

K_ATP channels are hetero-octameric complexes which consist of eight protein subunits; four α-subunits from the K_ir family (K_ir6.1 or Kir6.2) forming the pore and four regulatory subunits which belong to the family of sulfonylurea receptors (SUR1, SUR2A, and SUR2B) [12]. The molecular diversity that exists between species and tissues in terms of their K_ATP channels is magnified by the presence of multiple isoforms of SUR; however, they clearly fall into two distinct categories: small/medium conductance and large conductance [13]. Values between 7 and 15 pS have been reported for small/ medium-conductance K_ATP channels at 6 mM [K⁺]_o, whereas values between 20 and 25 pS have been reported at 60 mM [K⁺]_o; conductances in the range of 20 ~ 50 pS have been identified in symmetric high K+ in arterial smooth muscle cells [14]. The clinical implications of the inhibition of K_ATP by sulfonylureas relate to their use as oral agents in the therapy of maturity-onset diabetes mellitus [15]. K_ATP channels in smooth muscle are known to be inhibited by antidiabetic sulphonyl urea drugs, such as glibenclamide and tolbutamide. Glibenclamide is the most frequently used inhibitor of K_ATP channels in studies of arterial smooth muscle, with a half-inhibition value between 20 and 200 nM [16]. Tolbutamide, with a half-inhibition value of 350 μM in smooth muscle, is considerably less effective than glibenclamide as a hypoglycemic agent [17]. 4-morpholinecarboximidine- N-1-adamantyl-N’-cyclohexyl hydrochloride (U-37883A) and 5-hydroxydecanoate are selective inhibitors of nonvascular K_ATP channels with half inhibition values of 0.26 μM and 0.16 μM, respectively [18]. External Ba²⁺ also could be acting as an inhibitor of K_ATP channels in smooth muscle, with a half-inhibition value of 100 μM at -80 mV [19]. The K_ATP channels are not affected by iberiotoxin and are less sensitive to tetraethylammonium (TEA) [20]. The vasodilation induced by synthetic K⁺ channel activators, including cromakalim, levcromakalim, nicorandil, pinacidil, minoxidil, diazoxide, and BRL-55834 (a novel potassium channel activator), can be successfully blocked by glibenclamide; thus, they are believed to hyperpolarize the cells in vascular smooth muscle by targeting K_ATP channels [13]. However, other K+ channel blockers, such as iberiotoxin, apamin, or low concentrations of TEA are ineffective on K_ATP channels [21].

Function of vascular K_ATP channels: It has been shown both in vitro and in vivo that a block in K_ATP channels leads to vasoconstriction and membrane depolarization in various types of vascular smooth muscle (Figure 2) [22]. K_ATP channel activation is closely associated with several pathophysiological responses, including systemic arterial dilation during hypoxia, reactive hyperemia in the coronary and cerebral circulation, and acidosis and endotoxic shock-induced vasodilation. Moreover, the inhibition of K_ATP channels leads to impaired coronary and cerebral autoregulation [23]. K_ATP channels could be controlled by cell metabolism via the concentration of ATP and/or the ATP/ADP ratio, and it is possible that they have a role in the adaptation of vascular tone to the metabolic needs and partial pressure of oxygen (PO2) of the tissue [24]. Furthermore, since the channels are inhibited by PKC, there is a potential for mediation of the effect of vasoconstrictors like norepinephrine (NE) and ANG II [11]. Outward currents from these channels are stimulated by PKA and/or PKG, and it is suggested in some studies that this pathway mediates the vasodilatory action of adenosine [3]. ECs also expresses K_ATP channels and may participate in shear stress- and hyperosmolarity-mediated vasodilation [11].

Inward Rectifier K⁺ Channels (K^ir Channels)

The K^ir channels are tetramers where each α-subunit has two transmembrane domains. Six families of K^ir channels are known (K^ir1– 6), where K^ir2 is the classical inward rectifier channel and K^ir6 is the ATP-sensitive channel [25]. A unique feature of K^ir channels is the small increase (~5–12 mM) in [K⁺]_o increasing the outward current (Figure 2). This mechanism is mediated by the interaction of K+ with polyamines and/or Mg²⁺ in the channel pore [26]. An increase in the single-channel conductance has recently been suggested to also contribute to the increased outward current [27]. The Nernst equation predicts that increased [K⁺]_o leads to a less negative EK, and thus a depolarization of the cell membrane is to be expected, but as the small elevation in [K⁺]_o also increases the outward K⁺ current, the net effect is a hyperpolarization of the cell membrane. If [K⁺]o is increased further (more than ~20 mM), the depolarizing effect dominates [28,29]. The single-channel conductance of the K^ir channels is reported to be ~20 pS [3]. They are coined “inward rectifier” channels because of their propensity for carrying current in the inward direction. Only a few papers have addressed the single-channel properties of K^ir channels in vascular smooth muscle [30]. Ba²⁺ is a general blocker of K⁺ channels, but at concentrations <100μM it is considered specific for K^ir channels with a reported half-maximal inhibition concentration of 2.2 μM at -60 mV. However, Ba²⁺ is much less effective on KATP channels (Kd, 200 μM at –60 mV), BKCa channels (Kd>10 mM), and KV channels (Kd >1 mM). Therefore, at concentrations below 50 μM, Ba²⁺ is a selective blocker of K^ir channels in vascular smooth muscle. Cs+, which acts from outside the cell, also inhibits K^ir currents in vascular smooth muscle with a Kd of 2.9 mM at –60 mV (13). External Ca2+ and Mg2+ partially block K^ir channels. For example, at –60 mV, 5 mM Ca2+ or Mg2+ reduced the K^ir current by 47% and 41%, respectively.

Function of vascular K_ir channels: K_ir channels are found predominantly in VSMC from microvessels, and the main isoform found is K_ir 2.1. However, Wu et al. suggested that the K_ir channels in cerebral arteries contain both K_ir2.1 and K_ir2.2 [31]. In addition, K_ir2.1 and K_ir2.4 expression has been detected in cultured human pulmonary arterial smooth muscle cells [30]. The K_ir channels in vascular smooth muscle cells mediate inward currents at membrane potentials that are negative relative to the EK and small outward currents at membrane potentials that are positive relative to the EK [32]. Given that the membrane potential of vascular smooth muscle is normally positive relative to the equilibrium potential (EK), a physiological role for the inward rectifier channel requires an outward current through the channel (Figure 2) [33]. Inward rectifier K+ channels are abundant in the smooth muscle of small-diameter resistance vessels [34]. Although the exact function of K_ir channels in vascular smooth muscle is still incomplete, there are two basic possibilities. First, K_ir channels contribute to the resting membrane potential and resting tone in small-diameter vascular smooth muscle [35]. Second, K_ir channel activation in response to moderate increases in the extracellular K+ concentration (up to 10–15 mM) may cause vasodilation [36,37]. In accord with the sensitivity to [K⁺]o described above, K_ir channels might participate in K+ induced vasodilation described in the metabolic regulation of blood flow and in the endothelium-derived hyperpolarizing factor (EDHF) response elicited by K+ release via small-conductance (SK_Ca) and intermediate- conductance (IK_Ca) calcium channels. It is also possible that part of the K+ induced hyperpolarization/vasodilation is mediated by activation of Na⁺-K⁺ ATPase. In addition to VSMC, K_ir channels are found in endothelial cells where K_ir 2.1 is supposed to be the main isoform [38].

Ca²⁺-Activated K⁺ Channels (BK_Ca Channels)

Similar to KV channels, BK_Ca channels are comprised of a pore-forming α-subunit and a regulatory β-subunit. The α-subunits contain six transmembrane-spanning domains (S1–S6), including a voltage sensor (S4), which form the pore. Furthermore, the α-subunits produced from a gene slo contain an additional seventh transmembrane region (S0) at the exoplasmic NH2 terminus [39]. There are also four β-subunit isoforms (β1-4), each with two transmembrane domains, which may be associated with the α-subunits in a 1:1 ratio [40]. Of the four isoforms, the β1 subunit is the predominant isoform in vascular smooth muscle. The major function of the β-subunits is to enhance the Ca2+ sensitivity of the channel [41,42]. BK_Ca channel is also known as KCa²⁺ (Slo) and their conductance is between 200 –250 pS [43]. These channels are voltage sensitive, and the voltage sensitivity is modulated by [Ca²⁺]_I (Figure 2). BK_Ca channels are activated by changes in the intracellular Ca2+ concentration and membrane depolarization [41,44]. The efflux of K+ that results from BK_Ca channel activation can be used to counteract pressure- or chemical-induced depolarization and vasoconstriction. They are also activated by protein kinases including cAMPand cGMP-dependent protein kinases (PKA and PKG) [45,46]. Most studies indicate that PKC inhibits BK_Ca channels, but one study has shown that PKC via cGMP activates BK_Ca. As nitric oxide (NO) stimulates the cGMP/PKG pathway, activation of nitric oxide (NO) synthase might lead to increased BK_Ca activity [47]. Moreover, carbon monoxide (CO) has been reported to activate BK_Ca channels via a PKG dependent mechanism or by binding to a heme group on the channel. Pharmacologically, BK_Ca channels may be blocked by external TEA, iberiotoxin, and charybdotoxin at half inhibition values of 200 μM, < 10 nM, and ~ 10 nM, respectively [48,49]. Of these blockers, iberiotoxin is the most selective blocker; it has a very low half-inhibition value and its value is ineffective on other types of K+ channels [40]. Charybdotoxin has been used as a selective BK_Ca channel blocker; however, it also affects KV channels as well as intermediate conductance Ca²⁺-activated K+ channels [41]. BK_Ca channels are not affected by glibenclamide, Ba2+, or apamin, which blocks low-conductance Ca2+-activated K⁺ channels at their working concentrations [1]. Both NS-004 (an activator of Ca²⁺-dependent K+ Channels) and NS-1619 (a selective large conductance Ca2+-activated K+-channel activator) have been used to stimulate BK_Ca channels in smooth muscle, but they are of limited value given their nonspecific inhibitory effects on L-type Ca2+ channels [50].

Function of vascular BK_Ca: At negative Vm, activation requires [Ca2+]i in the range of 1–10μM, which exceeds that found in the bulk cytoplasm under resting conditions. It is, therefore, controversial whether BK_Ca channels are active at resting Vm and VSMC [Ca²⁺] i (Figure 2). However, BK_Ca channels have an important function by buffering vasoconstrictor responses [1]. The increase in VSMC [Ca²⁺]i, resulting from agonist stimulation or activation of the myogenic mechanism, activates BK_Ca channels, attenuates depolarization, and opposes vasoconstriction [51]. The increase in [Ca²⁺]i necessary for activating BK_Ca need not be global, but may be restricted to so-called microdomains within the cell. Ca²⁺ recruitment via entry and release from intracellular stores may cause localized elevations in [Ca²⁺]i, so-called Ca²⁺ sparks, able to activate BK_Ca channels. Recent evidence shows that BK_Ca channels and voltage-operated calcium channels (VOCC) form complexes in the cell membrane, which could provide an efficient mechanism for attaining local Ca²⁺ concentrations of a magnitude necessary to activate BK_Ca channels [52]. In isolated coronary and cerebral arterial myocytes from rabbits, it is shown that BK_Ca channels open simultaneously with the L-type Ca²⁺ channels [53]. In addition, Ca²⁺ released via ryanodine- sensitive Ca2+ channels in the sarcoplasmic reticulum attenuates vasoconstriction via activation of BK_Ca channels. It is reported that vasoconstrictors could exert their effect by PKC-mediated inhibition of BK_Ca channels [54].

Blue arrow = effect; red arrow = inhibition; green arrow = activation. ER: endoplasmic reticulum, Cyt P450: cytochrome P450, NOS: nitric oxide synthase, Vm: membrane potential, EET: epoxyeicosatrienoic acids, MEGJ: myoendothelial gap junctions, K^{+ +}:K_EC released from the endothelial cell, cGMP: cyclic GMP, PKG: protein kinase G, VOCC: voltage-activated calcium channel, PKA: protein kinase A.

PubMed, Cochrane Library, Google Scholar, CINAHL, Embase, and PsycINFO database were used for studies reporting the molecular and cellular emerging role of arterial vascular smooth muscle cells potassium channels in chronic hypertension from study conception to May 2021. Zotero reference management software for Windows was used to download, organize, review and cite the articles. I also manually searched cross-references in order to identify additional relevant articles. A comprehensive search was performed using the following search terms: “role of potassium channels”, “pathobiology of hypertension”, and “molecular and cellular emerging role potassium channels in chronic hypertension”. Boolean operators like “AND” and “OR” were used to combine search terms.

BKCa Channels in Hypertension

There is strong evidence that the functional role of BKCa channels is enhanced in vascular muscle during chronic hypertension in vessels from various anatomic regions. Increases in both Ca²⁺ influx and BKCa channel activity can be detected even in prehypertensive spontaneously hypertensive rats (SHRs) [55], so genetic factors may play at least some role in these changes. Increased BKCa channel function may be also a consequence of elevated blood pressure, as it can be induced over several weeks by surgical or pharmacological interventions that cause hypertension [56], and it can be reversed by antihypertensive therapy [57]. Therefore, BKCa 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 BKCa channels is enhanced in comparison with currents recorded from normotensive myocytes [56,58]. Another study has reported that BKCa channel open probability may be increased in the renal vasculature owing to higher intracellular Ca²⁺ levels during hypertension. Thus, activity of the BKCa channel appears to be greater in hypertensive arteries, and it may be the primary determinant of resting K⁺ efflux and hence, vascular muscle Em in hypertension [59].

K_V Channels in Hypertension

Unlike BKCa channels, there is a decreased function of arterial K_V channels in hypertension given that vascular Em appears to be more depolarized and the activity of K_V channels, like BKCa channels, is voltage dependent [60]. However, a depolarized Em and a higher intracellular Ca2+ level in myocytes from chronically hypertensive rats may represent a detrimental positive feedback mechanism resulting in decreased vascular K_V channel activity. Reduced K_V channel activity could therefore be an important factor underlying the depolarized Em and enhanced myogenic vascular tone reported during chronic hypertension [61,62]. Paracrine also influences potentially underlying altered K+ channel activity in hypertension have not yet been extensively explored and could be numerous. 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 [63,64]. 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. Because NO may activate K_V channels in some arteries [65], impaired bioavailability of endothelium-derived NO in hypertension could lead to vascular depolarization and contraction that are partly due to inhibition or closure of K_V channels. Accordingly, 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

Several studies suggest that the function of vascular K_ATP channels is impaired during hypertension. The vasodilator response associated with cerebral blood flow autoregulation during systemic hypotension, which is mediated by K_ATP channel activation, is also impaired in chronically hypertensive rats [66,67]. These findings suggest that 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 [68]. Thus, a defect in 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. Importantly, impairment of K_ATP channel– mediated vascular responses can be restored to near-normal levels by long-term treatment of high blood pressure [67,69]. These findings emphasize the importance of antihypertensive therapy for correcting many abnormalities in vascular smooth muscle function. However, there is very few information available currently on the effects of hypertension on K_ATP channel function in human blood vessels. 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.

K_ir Channels in Hypertension

There is indirect evidence that vascular K_ir channel function may be altered during chronic hypertension. Earlier studies reported that K+-induced vascular relaxation was either augmented or impaired in several models of hypertension. McCarron and Halpern [70] also reported that Ba₂₊-sensitive vasodilator responses to >7 mmol/L K⁺ were impaired in posterior cerebral arteries isolated from stroke-pronespontaneously hypertensive rats (SHRs) in comparison with vessels from Wistar-Kyoto rats (WKYs), perhaps suggesting impaired K_ir channel function in the cerebral circulation during hypertension. Thus, it is possible that chronic hypertension leads to decreased expression and/or function of vascular K_ir channels and expression of a compensatory vasodilator mechanism(s) that is upregulated.

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. Current evidence indicates that vascular smooth muscle cells express at least 4 different types of K⁺ channels (i.e., BK_Ca, K_ir, K_V, and K_ATP channels). 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. As further progress is made, particularly through molecular and electrophysiological approaches, in unravelling the relationship between K+ channel structure and function, we will obtain a clearer picture of the ways in which vascular smooth muscle cell K+ channels are affected by different pathophysiological conditions like hypertension. 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.

Ethics Approval and Consent to Participate:Not applicable.

Consent for Publication:Not applicable.

Availability of Data and Material:The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing Interests:The authors declare that there is no conflict of interests regarding the publication of this paper.

Funding:Nil support in financial or other manner

Authors’ Contributions:LM had participated in the design of the study, data analyses, and manuscript preparation; and the authors could have read and approved the final manuscript.

Acknowledgements:The Author is grateful to College of Health Sciences Research and Community Office of Arsi University as well as researchers who their documents were used in the preparation of the review.

1. Nelson M, Quayle J (1995) Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol 268: C799-C822.
2. Jackson W (1998) Potassium channels and regulation of the microcirculation 5(2-3): 85-90.
3. Ko E, Han J, Jung I, Park W (2008) Physiological roles of K+ channels in vascular smooth muscle cells. J Smooth Muscle Res 44(2): 65-81.
4. Vazquez Garcia M, Reyes Guerrero G (2009) Three types of single voltage dependent potassium channels in the sarcolemma of frog skeletal muscle. J Membr Biol 228(1): 51-62.
5. Cox R, Petrou S (1999) Ca(2+) influx inhibits voltage-dependent and augments Ca(2+)-activated K(+) currents in arterial myocytes. Am J Physiol 277(1): C51-63.
6. Korovkina V, England S (2002) Molecular diversity of vascular potassium channel isoforms. Clin Exp Pharmacol Physiol 29(4): 317-323.
7. Betts L, Kozlowski R (2000) Electrophysiological effects of endothelin-1 and their relationship to contraction in rat renal arterial smooth muscle. Br J Pharmacol 130(4): 787-796.
8. Glazebrook P, Ramirez A, Schild J, Shieh C, Doan T, et al. (2002) Potassium channels KV1.1, Kv1.2, and Kv1.6. influence excitability of rat visceral sensory neurons. J Physiol 541(pt 2): 467-482.
9. Luykenaar K, Brett S, Wu B, Wiehler W, Welsh D (2004) Pyrimidine nucleotides suppress KDR currents and depolarize rat cerebral arteries by activating Rho kinase. Am J Physiol Heart Circ Physiol 286(3): H1088-1100.
10. Cheong A, Dedman A, Xu S, Beech D (2001) K(V)alpha1 channels in murine arterioles: differential cellular expression and regulation of diameter. Am J Physiol Heart Circ Physiol 281(3): H1057-H1065.
11. Jackson W (2005) Potassium channels in the peripheral microcirculation. Microcirculation 12(1): 113-127.
12. Teramoto N (2006) Physiological roles of ATP-sensitive K+ channels in smooth muscle. J Physiol Lond 572(pt 3): 617-624.
13. Quayle J, Nelson M, Standen N (1997) ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev 77(4): 1165-1232.
14. Teramoto N, Brading A (1996) Activation by levcromakalim and metabolic inhibition of glibenclamide-sensitive K channels in smooth muscle cells of pig proximal urethra. Br J Pharmacol 118(3): 635-642.
15. Standen N, Quayle J, Davies N, Brayden J, Huang Y, et al. (1989) Hyperpolarising vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle. Science 245(4914): 177-180.
16. Xu X, Lee K (1994) Characterization of the ATP-inhibited K+ current in canine coronary smooth muscle cells. Pflügers Arch 427(1-2): 110-120.
17. Quayle J, Bonev A, Brayden J, Nelson M (1995) Pharmacology of ATP-sensitive K+ currents in smooth muscle cells from rabbit mesenteric arteries. Am J Physiol 269(5): C1112-C1118.
18. Guillemare E, Honore E, De Weille J, Fosset M, Lazdunski M, et al. (1994) Functional receptors in Xenopus oocytes for U-37883A, a novel ATP-sensitive K+ channel blocker: comparison with rat insulinoma cells. Mol Pharmacol 46(1): 139-145.
19. Bonev A, Nelson M (1993) ATP-sensitive potassium channels in smooth muscle cells from guinea pig urinary bladder. Am J Physiol 264(5): C1190-C1200.
20. Davies N, Spruce A, Standen N, Stanfield P (1989) Multiple blocking mechanisms of ATP-sensitive potassium channels of frog skeletal muscle by tetraethylammonium ions. J Physiol Lond 413: 31-48.
21. Brayden J (2002) Functional roles of KATP channels in vascular smooth muscle. Clin Exp Pharmacol Physiol 29: 312-316.
22. Nakashima M, Vanhoutte P (1995) Isoproterenol causes hyperpolarization through opening of ATP-sensitive potassium channels in vascular smooth muscle of the canine saphenous vein. J Pharmacol Exp Ther 272(1): 379-384.
23. Hong K, Pyo K, Lee W, Yu S, Rhim B (1994) Pharmacological evidence that calcitonin gene-related peptide is implicated in cerebral autoregulation. Am J Physiol 266: H11-H16.
24. Ngo A, Jensen L, Riemann M, Holstein Rathlou N, Torp-Pedersen C (2010) Oxygen sensing and conducted vasomotor responses in mouse cremaster arterioles in situ. Pflügers Arch 460(1): 41-53.
25. Loussouarn G, Rose T, Nichols C (2002) Structural basis of inward rectifying potassium channel gating. Trends Cardiovasc Med 12(6): 253-258.
26. Guo D, Ramu Y, Klem A, Lu Z (2003) Mechanism of rectification in inward-rectifier K+ channels. J Gen Physiol 121(4): 261-276.
27. Liu T, Chang H, Shieh R (2011) Extracellular K+ elevates outward currents through Kir2.1 channels by increasing single-channel conductance. Biochim Biophys Acta 1808(6): 1772-1778.
28. Jantzi M, Brett S, Jackson W, Corteling R, Vigmond E, et al. (2006) Inward rectifying potassium channels facilitate cell-to-cell communication in hamster retractor muscle feed arteries. Am J Physiol Heart Circ Physiol 291(3): H1319-H1328.
29. Smith P, Brett S, Luykenaar K, Sandow S, Marrelli S, et al. (2008) KIR channels function as electrical amplifiers in rat vascular smooth muscle. J Physiol 586(pt 4): 1147-1160.
30. Tennant B, Cui Y, Tinker A, Clapp L (2006) Functional expression of inward rectifier potassium channels in cultured human pulmonary smooth muscle cells: evidence for a major role of Kir2.4 subunits. J Membrane Biol 213(1): 19-29.
31. Wu B, Luykenaar K, Brayden J, Giles W, Corteling R, et al. (2007) Hyposmotic challenge inhibits inward rectifying K+ channels in cerebral arterial smooth muscle cells. Am J Physiol 292(2): H1085-H1094.
32. Quayle J, McCarron J, Brayden J, Nelson M (1993) Inward rectifier K+ currents in smooth muscle cells from rat resistance-sized cerebral arteries. Am J Physiol 265(5): C1363-C1370.
33. Robertson B, Bonev A, Nelson M (1996) Inward rectifier K+ currents in smooth muscle cells from rat coronary arteries: block by Mg2+, Ca²⁺, and Ba2+. Am J Physiol 271(2): H696-H705.
34. Quayle J, Dart C, Standen M (1996) The properties and distribution of inward rectifier potassium currents in pig coronary arterial smooth muscle. J Physiol Lond 494(pt 3): 715-726.
35. Park W, Ko J, Kim N, Son Y, Kang S, et al. (2007) Increased inhibition of inward rectifier K+ channels by angiotensin II in small-diameter coronary artery of isoproterenol-induced hypertrophied model. Arterioscler Thromb Vasc Biol 27(8): 1768-1775.
36. Chrissobolis S, Ziogas J, Chu Y, Faraci F, Sobey C (2000) Role of inwardly rectifying K(+) channels in K(+)-induced cerebral vasodilation in vivo. Am J Physiol 279(6): H2704-H2712.
37. Eckman D, Nelson M (2001) Potassium ions as vasodilators: role of inward rectifier potassium channel. Circ Res 88(2): 132-133.
38. Forsyth S, Hoger A, Hoger J (1997) Molecular cloning and expression of a bovine endothelial inward rectifier potassium channel. FEBS Lett 409(2): 277-282.
39. Wallner M, Meera P, Toro L (1996) Determinant for β-subunit regulation in high-conductance voltage-activated and Ca2+-sensitive K+ channels: an additional transmembrane region at the N terminus. Proc Natl Acad Sci USA 93(25): 14922-14927.
40. Wallner M, Meera P, Ottolia M, Kaczorowski G, Latorre R, et al. (1995) Characterization of and modulation by a beta-subunit of a human maxi KCa channel cloned from myometrium. Recept Channels 3(3): 185-199.
41. Waldron G, Cole W (1996) Activation of vascular smooth muscle K+ channels by endothelium derived relaxing factors. Clin Exp Pharmacol Physiol 26(2): 180-184.
42. Tanaka Y, Meera P, Song M, Knaus H, Toro L (1997) Molecular constituents of maxi KCa channels in human coronary smooth muscle: predominant α + β subunit complexes. J Physiol Lond 502(pt 3): 545-557.
43. Felipe A, Vicente R, Villalonga N, Roura-Ferrer M, Martinez M, et al. (2006) Potassium channels: new targets in cancer therapy. Cancer Detect Prev 30(4): 375-385.
44. Park W, Son Y, Kim N, Youm J, Warda M, et al. (2007) Direct modulation of Ca(2+)-activated K(+) current by H-89 in rabbit coronary arterial smooth muscle cells. Vascul Pharmacol 46(2): 105-113.
45. Minami K, Fukuzawa K, Nakaya Y, Zeng X, Inoue I (1993) Mechanism of activation of the Ca(2+)-activated K+ channel by cyclic AMP in cultured porcine coronary artery smooth muscle cells. Life Sci 53(14): 1129-1135.
46. Zhou X, Arntz C, Kamm S, Motejlek K, Sausbier U, et al. (2001) A molecular switch for specific stimulation of the BKCa channel by cGMP and cAMP kinase. J Biol Chem 276(46): 43239-43245.
47. Archer S, Huang J, Hampl V, Nelson D, Shultz P, et al. (1994) Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci USA 91(16): 7583-7587.
48. Langton P, Nelson M, Huang Y, Standen N (1991) Block of calcium-activated potassium channels in mammalian arterial myocytes by tetraethylammonium ions. Am J Physiol 260(3): H927-H934.
49. Giangiacomo K, Garcia M, McManus O (1992) Mechanism of iberiotoxin block of large conductance calcium-activated potassium channel from bovine aortic smooth muscle. Biochemistry 31(29): 6719-6727.
50. Park W, Kang S, Son Y, Kim N, Ko J, et al. (2007) The mitochondrial Ca2+-activated K+ channel activator, NS 1619 inhibits L-type Ca2+ channels in rat ventricular myocytes. Biochem Biophys Res Commun 362(1): 31-36.
51. Jackson W, Blair K (1998) Characterization and function of Ca(2+)-activated K(+) channels in arteriolar muscle cells. Am J Physiol Heart Circ Physiol 274(1): H27-H34.
52. Berkefeld H, Sailer C, Bildl W, Rohde V, Thumfart J, et al. (2006) BKCa-Cav channel complexes mediate rapid and localized Ca2+-activated K+signaling. Science 314(5799): 615-620.
53. Brayden J, Nelson M (1992) Regulation of arterial tone by activation of calcium-dependent potassium channels. Science 256(5056): 532-535.
54. Lange A, Gebremedhin D, Narayanan J, Harder D (1997) 20-Hydroxyeicosatetraenoic acid-induced vasoconstriction and inhibition of potassium current in cerebral vascular smooth muscle is dependent on activation of protein kinase C. J Biol Chem 272(43): 27345-27352.
55. Asano M, Nomura Y, Ito K, Uyama Y, Imaizumi Y, et al. (1995) Increased function of voltage-dependent Ca++ channels and Ca(++)-activated K+ channels in resting state of femoral arteries from spontaneously hypertensive rats at prehypertensive stage. J Pharmacol Exp Ther 275(2): 775-783.
56. Rusch N, De Lucena R, Wooldridge T, England S, Cowley A (1992) A Ca2+-dependent K+ current is enhanced in arterial membranes of hypertensive rats. Hypertension 19(4): 301-307.
57. Rusch N, Runnells A (1994) Remission of high blood pressure reverses arterial potassium channel alterations. Hypertension 23(6): 941-945.
58. England S, Wooldridge T, Stekiel W, Rusch N (1993) Enhanced single-channel K+ current in arterial membranes from genetically hypertensive rats. Am J Physiol 264(5): H1337-H1345.
59. Rusch N, Liu Y, Pleyte K (1996) Mechanisms for regulation of arterial tone by Ca2+-dependent K+ channels in hypertension. Clin Exp Pharmacol Physiol 23(12): 1077-1081.
60. Martens J, Gelband C (1996) Alterations in rat interlobar artery membrane potential and K+ channels in genetic and nongenetic hypertension. Circ Res 79(2): 295-301.
61. Harder D, Smeda J, Lombard J (1985) Enhanced myogenic depolarization in hypertensive cerebral arterial muscle. Circ Res 57(2): 319-322.
62. Falcone J, Granger H, Meininger G (1993) Enhanced myogenic activation in skeletal muscle arterioles from spontaneously hypertensive rats. Am J Physiol 265(6): H1847-H1855.
63. Shan J, Benishin C, Lewanczuk R, Pang P (1994) Mechanism of the vascular action of parathyroid hypertensive factor. J Cardiovasc Pharmacol 23(suppl 2): S1-S8.
64. Lewanczuk R, Pang P (1989) In vivo potentiation of vasopressors by spontaneously hypertensive rat plasma: correlation with blood pressure and calcium uptake. Clin Exp Hyper Theory Pract 11(8): 1471-1485.
65. Sobey C, Faraci F (1999) Inhibitory effect of 4-aminopyridine on responses of the basilar artery to nitric oxide. Br J Pharmacol 126(6): 1437-1443.
66. Toyoda K, Fujii K, Ibayashi S, Kitazono T, Nagao T, et al. (1997) Role of ATP-sensitive potassium channels in brainstem circulation during hypotension. Am J Physiol 273(3): H1342-H1346.
67. Toyoda K, Fujii K, Ibayashi S, Kitazono T, Nagao T, et al. (1998) Attenuation and recovery of brain stem autoregulation in spontaneously hypertensive rats. J Cereb Blood Flow Metab 18(3): 305-310.
68. Kitazono T, Heistad D, FaraciFM (1993) ATP-sensitive potassium channels in the basilar artery during chronic hypertension. Hypertension 22(5): 677-681.
69. Kalliovalkama J, Jolma P, Tolvanen J, Kahonen M, Hutri-Kahonen N, et al. (1999) Arterial function in nitric oxide-deficient hypertension: influence of long-term angiotensin II receptor antagonism. Cardiovasc Res 42(3): 773-782.
70. McCarron J, Halpern W (1990) Impaired potassium-induced dilation in hypertensive rat cerebral arteries does not reflect altered Na+,- K(+)- ATPase dilation. Circ Res 67(4): 1035-1039.