Vascular KCNQ Potassium Channels as Novel Targets for the Control of Mesenteric Artery Constriction by Vasopressin, Based on Studies in Single Cells, Pressurized Arteries, and in Vivo Measurements of Mesenteric Vascular Resistance (original) (raw)
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Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective
Fundamental & Clinical Pharmacology, 2019
Potassium (K +) ion channel activity is an important determinant of vascular tone by regulating cell membrane potential (MP). Activation of K + channels leads to membrane hyperpolarization and subsequently vasodilatation, while inhibition of the channels causes membrane depolarization and then vasoconstriction. So far five distinct types of K + channels have been identified in vascular smooth muscle cells (VSMCs); Ca +2-activated K + channels (BK Ca), voltage-dependent K + channels Accepted Article This article is protected by copyright. All rights reserved. (K V), ATP-sensitive K + channels (K ATP), inward rectifier K + channels (K ir), and tandem-two pore K + channels (K 2 P). The activity and expression of vascular K + channels are changed during major vascular diseases such as hypertension, pulmonary hypertension, hypercholesterolemia, atherosclerosis, and diabetes mellitus. The defective function of K + channels is commonly associated with impaired vascular responses and is likely to become as a result of changes in K + channels during vascular diseases. Increased K + channel function and expression may also help to compensate for increased abnormal vascular tone. There are many pharmacological and genotypic studies which were carried out on the subtypes of K + channels expressed in variable amounts in different vascular beds. Modulation of K + channel activity by molecular approaches and selective drug development may be a novel treatment modality for vascular dysfunction in the future. This review presents the basic properties, physiological functions, pathophysiological and pharmacological roles of the five major classes of K + channels that have been determined in VSMCs.
Vascular KCNQ channels in humans: the sub-threshold brake that regulates vascular tone?
British Journal of Pharmacology, 2011
Contraction of arterial smooth muscle cells results in vasoconstriction, which in turn reduces blood flow and increases blood pressure. There has been a great deal of interest in understanding the ionic mechanisms that regulate smooth muscle contraction, in part because ion channels represent potential pharmacological targets for therapies directed towards cardiovascular diseases and other conditions. Potassium channels have been recognized for their roles in maintaining or stabilizing negative membrane voltages. Activation of potassium channels opposes opening of voltage-sensitive calcium channels which conduct calcium ions into the smooth muscle cells to stimulate contraction. KCNQ potassium channels were recently discovered in arterial smooth muscle cells from rats and mice. These channels have distinctive pharmacological and biophysical characteristics that have led them to be implicated as important regulators of membrane voltage and as novel pharmacological targets for modulation of vascular contractility. In this issue of British Journal of Pharmacology, Ng et al., extend the findings from rodent models to the human vasculature and establish that KCNQ channels also regulate constriction of human arteries. The findings have important implications for the use of pharmacological KCNQ channel modulators to treat human diseases.
Biomedical Journal of Scientific and Technical Research, 2023
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.
BKCa and KV channels limit conducted vasomotor responses in rat mesenteric terminal arterioles
Pflügers Archiv - European Journal of Physiology, 2012
Intracellular Ca 2+ signals underlying conducted vasoconstriction to local application of a brief depolarizing KCl stimulus was investigated in rat mesenteric terminal arterioles (<40 μm). Using a computer model of an arteriole segment comprised of coupled endothelial cells (EC) and vascular smooth muscle cells (VSMC) simulations of both membrane potential and intracellular [Ca 2+ ] were performed. The "characteristic" length constant, λ, was approximated using a modified cable equation in both experiments and simulations. We hypothesized that K + conductance in the arteriolar wall limit the electrotonic spread of a local depolarization along arterioles by current dissipation across the VSMC plasma membrane. Thus, we anticipated an increased λ by inhibition of voltage-activated K + channels. Application of the BK Ca channel blocker iberiotoxin (100 nM) onto mesenteric arterioles in vitro and inhibition of BK Ca channel current in silico increased λ by 34% and 32%, respectively. Similarly, inhibition of K V channels in vitro (4-aminopyridine, 1 mM) or in silico increased λ by 41% and 21%, respectively. Immunofluorescence microscopy demonstrated expression of BK Ca , Kv1.5, Kv2.1, but not Kv1.2, in VSMCs of rat mesenteric terminal arterioles. Our results demonstrate that inhibition of voltage-activated K + channels enhance vascular-conducted responses to local depolarization in terminal arterioles by increasing the membrane resistance of VSMCs. These data contribute to our understanding of how differential expression patterns of voltage-activated K + channels may influence conducted vasoconstriction in small arteriolar networks. This finding is potentially relevant to understanding the compromised microcirculatory blood flow in systemic vascular diseases such as diabetes mellitus and hypertension. Keywords Calcium. Terminal arteriole. Conducted vasoconstriction. Intercellular communication. Electrotonic conduction. K V channel. BK Ca channel. Computer model. Simulation ABBREVIATIONS 4-AP 4-Aminopyridine IbTx Iberiotoxin EC Endothelial cell VCR Vascular-conducted response VSMC Vascular smooth muscle cell Electronic supplementary material The online version of this article
The Journal of Membrane Biology, 1994
We describe the activation of a K + current and inhibition of a C1-current by a cyanoguanidine activator of ATP-sensitive K + channels (KATP) in the smooth muscle cell line A10. The efficacy of U83757, an analogue of pinacidil, as an activator of KAT P was confirmed in single channel experiments on isolated ventricular myocytes. The effects of U83757 were examined in the clonal smooth muscle cell line A10 using voltage-sensitive dyes and digital fluorescent imaging techniques. Exposure of A10 cells to U83757 (10 nM to 1 ~tM) produced a rapid membrane hyperpolarization as monitored by the membrane potential-sensitive dye bis-oxonol ([diBAC4(3)], 5 ~tM). The U83757induced hyperpolarization was antagonized by glyburide and tetrapropylammonium (TPrA) but not by tetraethlylammonium (TEA) or charybdotoxin (ChTX). The molecular basis of the observed hyperpolarization was studied in whole-cell, voltage-clamp experiments. Exposure of voltage-clamped cells to U83757 (300 nM to 300 ~tM) produced a hyperpolarizing shift in the zero current potential; however, the hyperpolarizing shift in reversal potential was associated with either an increase or decrease in membrane conductance. In solutions where E K =-82 mV and Ecl = 0 mV, the reversal potential of the U83757-sensitive current was approximately-70 mV in those experiments where an increase in membrane conductance was observed. In experiments in which a decrease in conductance was observed, the reversal potential of the U83757-sensitive current was approximately 0 mV, suggesting that U83757 might be acting as a C1-channel blocker as well as a K +chan-Correspondence to: DJ. Nelson nel opener. In experiments in which C1-current activation was specifically brought about by cellular swelling and performed in solutions where C1-was the major permeant ion, U83757 (300 nM tO 300 gM) produced a dose-dependent current inhibition. Taken together these results (i) demonstrate the presence of a K+-selective current which is sensitive to KAy P channel openers in A10 cells and (ii) indicate that the hyperpolarizing effects of K + channel openers in vascular smooth muscle may be due to both the inhibition of C1currents as well as the activation of a K+-selective current.
Molecular pharmacology, 2015
Kv7 (KCNQ) channels, formed as homo- or hetero-tetramers of Kv7.4 and Kv7.5 α-subunits, are important regulators of vascular smooth muscle cell (VSMC) membrane voltage. Recent studies demonstrate that direct pharmacological modulation of VSMC Kv7 channel activity can influence blood vessel contractility and diameter. The physiological regulation of Kv7 channel activity, however, is still poorly understood. Here, we study the effect of cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) activation on whole cell K(+) currents through endogenous Kv7.5 channels in A7r5 rat aortic smooth muscle cells, or through Kv7.4/Kv7.5 heteromeric channels natively expressed in rat mesenteric artery smooth muscle cells. The contributions of specific α-subunits are further dissected using exogenously expressed human Kv7.4 and Kv7.5 homo- or hetero-tetrameric channels in A7r5 cells. Stimulation of Gαs-coupled β-adrenergic receptors with isoproterenol induced PKA-dependent activation of endogeno...
AJP: Heart and Circulatory Physiology, 2006
Byron KL. Vasopressin stimulates action potential firing by protein kinase C-dependent inhibition of KCNQ5 in A7r5 rat aortic smooth muscle cells. [Arg 8 ]-vasopressin (AVP), at low concentrations (10 -500 pM), stimulates oscillations in intracellular Ca 2ϩ concentration (Ca 2ϩ spikes) in A7r5 rat aortic smooth muscle cells. Our previous studies provided biochemical evidence that protein kinase C (PKC) activation and phosphorylation of voltage-sensitive K ϩ (Kv) channels are crucial steps in this process. In the present study, K v currents (IKv) and membrane potential were measured using patch clamp techniques. Treatment of A7r5 cells with 100 pM AVP resulted in significant inhibition of I Kv. This effect was associated with gradual membrane depolarization, increased membrane resistance, and action potential (AP) generation in the same cells. The AVP-sensitive I Kv was resistant to 4-aminopyridine, iberiotoxin, and glibenclamide but was fully inhibited by the selective KCNQ channel blockers linopirdine (10 M) and XE-991 (10 M) and enhanced by the KCNQ channel activator flupirtine (10 M). BaCl 2 (100 M) or linopirdine (5 M) mimicked the effects of AVP on K ϩ currents, AP generation, and Ca 2ϩ spiking. Expression of KCNQ5 was detected by RT-PCR in A7r5 cells and freshly isolated rat aortic smooth muscle. RNA interference directed toward KCNQ5 reduced KCNQ5 protein expression and resulted in a significant decrease in I Kv in A7r5 cells. IKv was also inhibited in response to the PKC activator 4-phorbol 12myristate 13-acetate (10 nM), and the inhibition of I Kv by AVP was prevented by the PKC inhibitor calphostin C (250 nM). These results suggest that the stimulation of Ca 2ϩ spiking by physiological concentrations of AVP involves PKC-dependent inhibition of KCNQ5 channels and increased AP firing in A7r5 cells.