Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention

Mackie, Alexander R; Byron, Kenneth L.

doi:10.1124/mol.108.049825

Cited by 101 publications

(110 citation statements)

References 79 publications

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“…There is no single drug that opens all five known K V 7 channels, but flupirtine is an agonist of K V 7.2, K V 7.3, K V 7.4, and K V 7.5 (27). Thus flupirtine was chosen to determine the effects of a K V 7 channel opener on coronary vascular tone.…”

Section: Resultsmentioning

confidence: 99%

K_V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

Goodwill

Noblet

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Goodwill AG, Fu L, Noblet JN, Casalini ED, Sassoon D, Berwick ZC, Kassab GS, Tune JD, Dick GM. K V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine. Am J Physiol Heart Circ Physiol 310: H693-H704, 2016. First published January 29, 2016 doi:10.1152 doi:10. /ajpheart.00688.2015 and voltage-dependent K ϩ (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The K V channels responsible have not been identified, but K V7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that K V7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and K V7.4 protein (Western blot). Immunostaining demonstrated K V7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a K V7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a K V7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H 2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that K V7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular K V7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli. (3,14). Recent evidence suggests that myocardial production of hydrogen peroxide (H 2 O 2 ) may be a signal responsible for the near lockstep increases of coronary blood flow that accompany intensified metabolic demand (21,40,47). H 2 O 2 is generated in a variety of cellular processes and may be the primary transmitter of physiological redox signals (9, 45). For example, in coronary microvessels, H 2 O 2 is an endogenous hyperpolarizing factor released by mechanical and paracrine stimulation of the endothelium (31, 46). The specific redox-sensitive targets mediating H 2 O 2 -induced vasodilation of coronary vascular smooth have not been firmly established. Our previous findings suggest that voltage-dependent K ϩ (K V ) channels may play an important role, but the identities of individual K V channels involved remain elusive (4,5,12,38,39). K V 7 channels are expressed in a variety of vascular smooth muscle ...

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Section: Resultsmentioning

confidence: 99%

K_V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

Goodwill

Noblet

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…4,6,7,11,14,15 Moreover, evidence is accumulating that activation of K V 7 channels contributes to the vasodilatory response of various endogenous molecules, including β-adrenoceptor agonists 3 and H 2 S. 16 In addition, mesenteric and renal arteries from hypertensive animals exhibit considerable attenuated response to K V 7 activators and marked reduction in K V 7.4 abundance. 6,14 The present study now reveals that coronary arteries express KCNQ1, 4, and 5 transcripts, as well as all members of the KCNE gene family except KCNE1.…”

Section: Discussionmentioning

confidence: 99%

“…Voltage-gated potassium channels (K V ) have been implicated in the control of the coronary circulation and reactive hyperemia, 1,2 but little is known about the specific molecular components. Kv channels encoded by KCNQ1-5 (K V 7.1-K V 7.5) are important regulators of the smooth muscle resting membrane potential and contractility in several different rodent and human arteries, [3][4][5][6][7][8][9][10][11] which are known to be compromised in animal models of primary and secondary hypertension. 3,6 These channels, in particular K V 7.4, are also functional end points in β-adrenoceptor-mediated relaxations.…”

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confidence: 99%

Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

et al. 2013

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F ailure of the coronary circulation to meet the constant demands of the cardiomyocytes results in ischemic heart disease or infarction. Determining the factors that regulate coronary blood flow is, therefore, crucial for understanding pathophysiological manifestations and for the development of new therapeutic strategies. Voltage-gated potassium channels (K V ) have been implicated in the control of the coronary circulation and reactive hyperemia, 1,2 but little is known about the specific molecular components. Kv channels encoded by KCNQ1-5 (K V 7.1-K V 7.5) are important regulators of the smooth muscle resting membrane potential and contractility in several different rodent and human arteries, [3][4][5][6][7][8][9][10][11] which are known to be compromised in animal models of primary and secondary hypertension. 3,6 These channels, in particular K V 7.4, are also functional end points in β-adrenoceptor-mediated relaxations.3 These combined observations provide a mechanism by which arteries become relatively resistant to endogenous vasorelaxants. However, little is known about K V 7 expression levels or the functional importance of these channels in coronary arteries.Consequently, we determined the expression profiles of KCNQ genes and the functional impact of K V 7 channel modulators in left anterior descending (LAD) coronary arteries. We also ascertained whether K V 7 channels contribute to relaxations produced by adenosine, which is released rapidly after myocardial ischemia in vivo and acts as a local metabolic regulator of coronary flow. 12,13 This study demonstrates that K V 7 channels are key regulators of coronary flow at rest, and they also contribute to adenosine-mediated dilatations and the active response to ischemia. MethodsFor more complete descriptions, see the online-only Data Supplement. AnimalsThe study complies with the European Community Guidelines for the Care and Use of Experimental Animals and was approved by the Animal Ethics Screening Committee in Denmark (license number: 2010/561-1799) and by the UK Animal (Scientific Procedures) Act 1986. Male, normotensive Wistar Hannover rats and spontaneously hypertensive rats (SHRs), aged 11 to 16 weeks, were purchased from Abstract-The goal of the present study was to determine the role of KCNQ-encoded K V channels (K V 7 channels) in the passive and active regulation of coronary flow in normotensive and hypertensive rats. In left anterior descending coronary arteries from normotensive rats, structurally different K V 7.2 to 7.5 activators produced relaxations, which were considerably less in arteries from hypertensive rats and were not mimicked by the K V 7.1-specific activator R-L3. In isolated, perfused heart preparations, coronary flow rate increased in response to the K V 7.2 to 7.5 activator (S)-1 and was diminished in the presence of a K V 7 inhibitor. The expression levels of KCNQ1-5 and their known accessory KCNE1-5 subunits in coronary arteries were similar in normotensive and hypertensive rats as measured by quantitative polymerase cha...

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“…They have been successfully used to identify specific roles of KCNQ channels in the circulatory system. 30,37 Of note, XE991 has been reported to reduce currents carried by heteromeric K v 1.2/K v 1.5 channels in HEK293 cells, 38 which have been suggested to be predominantly expressed in rat cerebral artery smooth muscle cells. 39 In contrast, our real-time PCR analysis of rat Gracilis muscle arteries 39,40 In addition, the anticontractile effect of perivascular fat was also not influenced by blockers targeting other non-K v -type K + channels expressed in vascular smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Role of KCNQ Channels in Skeletal Muscle Arteries and Periadventitial Vascular Dysfunction

et al. 2013

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KCNQ channels have been identified in arterial smooth muscle. However, their role in vasoregulation and chronic vascular diseases remains elusive. We tested the hypothesis that KCNQ channels contribute to periadventitial vasoregulation in peripheral skeletal muscle arteries by perivascular adipose tissue and that they represent novel targets to rescue periadventitial vascular dysfunction. Two models, spontaneously hypertensive rats and New Zealand obese mice, were studied using quantitative polymerase chain reaction, the patch-clamp technique, membrane potential measurements, myography of isolated vessels, and blood pressure telemetry. In rat Gracilis muscle arteries, anticontractile effects of perivascular fat were inhibited by the KCNQ channel blockers XE991 and linopirdine but not by other selective K + channel inhibitors. Accordingly, XE991 and linopirdine blocked noninactivating K + currents in freshly isolated Gracilis artery smooth muscle cells. mRNAs of several KCNQ channel subtypes were detected in those arteries, with KCNQ4 channels being dominant. In spontaneously hypertensive rats, the anticontractile effect of perivascular fat in Gracilis muscle arteries was largely reduced compared with Wistar rats. However, the vasodilator effects of KCNQ channel openers and mRNA expression of KCNQ channels were normal. Furthermore, KCNQ channel openers restored the diminished anticontractile effects of perivascular fat in spontaneously hypertensive rats. Moreover, KCNQ channel openers reduced arterial blood pressure in both models of hypertension independent of ganglionic blockade. Thus, our data suggest that KCNQ channels play a pivotal role in periadventitial vasoregulation of peripheral skeletal muscle arteries, and KCNQ channel opening may be an effective mechanism to improve impaired periadventitial vasoregulation and associated hypertension.

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Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention

Cited by 101 publications

References 79 publications

K_V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

K_V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

Role of KCNQ Channels in Skeletal Muscle Arteries and Periadventitial Vascular Dysfunction

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Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention

Cited by 101 publications

References 79 publications

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

Contribution of K v 7 Channels to Basal Coronary Flow and Active Response to Ischemia

Role of KCNQ Channels in Skeletal Muscle Arteries and Periadventitial Vascular Dysfunction

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K_V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

K_V7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

Contribution of K _v 7 Channels to Basal Coronary Flow and Active Response to Ischemia