Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2018 Feb 01;1753:501-516. doi: 10.1111/bph.14097.
Show Gene links
Show Anatomy links
4-Aminopyridine: a pan voltage-gated potassium channel inhibitor that enhances Kv 7.4 currents and inhibits noradrenaline-mediated contraction of rat mesenteric small arteries.
Khammy MM
,
Kim S
,
Bentzen BH
,
Lee S
,
Choi I
,
Aalkjaer C
,
Jepps TA
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: Kv 7.4 and Kv 7.5 channels are regulators of vascular tone. 4-Aminopyridine (4-AP) is considered a broad inhibitor of voltage-gated potassium (KV ) channels, with little inhibitory effect on Kv 7 family members at mmol concentrations. However, the effect of 4-AP on Kv 7 channels has not been systematically studied. The aim of this study was to investigate the pharmacological activity of 4-AP on Kv 7.4 and Kv 7.5 channels and characterize the effect of 4-AP on rat resistance arteries.
EXPERIMENTAL APPROACH: Voltage clamp experiments were performed on Xenopus laevis oocytes injected with cRNA encoding KCNQ4 or KCNQ5, HEK cells expressing Kv 7.4 channels and on rat, freshly isolated mesenteric artery smooth muscle cells. The effect of 4-AP on tension, membrane potential, intracellular calcium and pH was assessed in rat mesenteric artery segments.
KEY RESULTS: 4-AP increased the Kv 7.4-mediated current in oocytes and HEK cells but did not affect Kv 7.5 current. 4-AP also enhanced native mesenteric arterymyocyte K+ current at sub-mmol concentrations. When applied to NA-preconstricted mesenteric artery segments, 4-AP hyperpolarized the membrane, decreased [Ca2+ ]i and caused concentration-dependent relaxations that were independent of 4-AP-mediated changes in intracellular pH. Application of the Kv 7 channel blocker XE991 and BKCa channel blocker iberiotoxin attenuated 4-AP-mediated relaxation. 4-AP also inhibited the NA-mediated signal transduction to elicit a relaxation.
CONCLUSIONS AND IMPLICATIONS: These data show that 4-AP is able to relax NA-preconstricted rat mesenteric arteries by enhancing the activity of Kv 7.4 and BKCa channels and attenuating NA-mediated signalling.
Aalkjaer,
Intracellular pH regulation in resting and contracting segments of rat mesenteric resistance vessels.
1988, Pubmed
Aalkjaer,
Intracellular pH regulation in resting and contracting segments of rat mesenteric resistance vessels.
1988,
Pubmed
Abbott,
Kcne4 Deletion Sex-Dependently Alters Vascular Reactivity.
2016,
Pubmed
Albarwani,
Voltage-gated K+ channels in rat small cerebral arteries: molecular identity of the functional channels.
2003,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Voltage-gated ion channels.
2017,
Pubmed
Brueggemann,
Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels.
2014,
Pubmed
Chadha,
Pharmacological dissection of K(v)7.1 channels in systemic and pulmonary arteries.
2012,
Pubmed
,
Xenbase
Chadha,
Contribution of kv7.4/kv7.5 heteromers to intrinsic and calcitonin gene-related peptide-induced cerebral reactivity.
2014,
Pubmed
Choquet,
Mechanism of 4-aminopyridine action on voltage-gated potassium channels in lymphocytes.
1992,
Pubmed
Coetzee,
Molecular diversity of K+ channels.
1999,
Pubmed
,
Xenbase
Coleman,
Nonlinear effects of potassium channel blockers on endothelium-dependent hyperpolarization.
2017,
Pubmed
Cox,
Voltage gated K+ channel expression in arteries of Wistar-Kyoto and spontaneously hypertensive rats.
2008,
Pubmed
Curtis,
Experimental design and analysis and their reporting: new guidance for publication in BJP.
2015,
Pubmed
Fergus,
Kv channel subunits that contribute to voltage-gated K+ current in renal vascular smooth muscle.
2003,
Pubmed
Fujihara,
The effects of 4-aminopyridine on motor evoked potentials in multiple sclerosis.
1998,
Pubmed
Grissmer,
Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines.
1994,
Pubmed
Hedegaard,
KV 7 channels are involved in hypoxia-induced vasodilatation of porcine coronary arteries.
2014,
Pubmed
Jensen,
4-Aminopyridine for symptomatic treatment of multiple sclerosis: a systematic review.
2014,
Pubmed
Jepps,
Fundamental role for the KCNE4 ancillary subunit in Kv7.4 regulation of arterial tone.
2015,
Pubmed
Jepps,
Vasorelaxant effects of novel Kv 7.4 channel enhancers ML213 and NS15370.
2014,
Pubmed
Khammy,
4-Aminopyridine: a pan voltage-gated potassium channel inhibitor that enhances Kv 7.4 currents and inhibits noradrenaline-mediated contraction of rat mesenteric small arteries.
2018,
Pubmed
,
Xenbase
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Kimitsuki,
Property of I(K,)(n) in inner hair cells isolated from guinea-pig cochlea.
2010,
Pubmed
Laskowski,
Potassium-Channel-Independent Relaxing Influence of Adipose Tissue on Mouse Carotid Artery.
2017,
Pubmed
Lee,
Systematic family-wide analysis of sodium bicarbonate cotransporter NBCn1/SLC4A7 interactions with PDZ scaffold proteins.
2014,
Pubmed
,
Xenbase
Lee,
Sodium-bicarbonate cotransporter NBCn1/Slc4a7 inhibits NH4Cl-mediated inward current in Xenopus oocytes.
2011,
Pubmed
,
Xenbase
Mackie,
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.
2008,
Pubmed
Mani,
Vascular KCNQ (Kv7) potassium channels as common signaling intermediates and therapeutic targets in cerebral vasospasm.
2013,
Pubmed
McGrath,
Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP.
2015,
Pubmed
Mulvany,
Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats.
1977,
Pubmed
Mulvany,
Role of membrane potential in the response of rat small mesenteric arteries to exogenous noradrenaline stimulation.
1982,
Pubmed
Ng,
Expression and function of the K+ channel KCNQ genes in human arteries.
2011,
Pubmed
Ohya,
Molecular variants of KCNQ channels expressed in murine portal vein myocytes: a role in delayed rectifier current.
2003,
Pubmed
Oliver,
Resting potential and submembrane calcium concentration of inner hair cells in the isolated mouse cochlea are set by KCNQ-type potassium channels.
2003,
Pubmed
Petkova-Kirova,
4-aminopyridine affects rat arterial smooth muscle BK(Ca) currents by changing intracellular pH.
2000,
Pubmed
Robbins,
KCNQ potassium channels: physiology, pathophysiology, and pharmacology.
2001,
Pubmed
Schubert,
Protons inhibit the BK(Ca) channel of rat small artery smooth muscle cells.
2001,
Pubmed
Southan,
The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands.
2016,
Pubmed
Stott,
K(V)7 potassium channels: a new therapeutic target in smooth muscle disorders.
2014,
Pubmed
Stühmer,
Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain.
1989,
Pubmed
,
Xenbase
Thomas,
Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ.
1979,
Pubmed
Wulff,
Voltage-gated potassium channels as therapeutic targets.
2009,
Pubmed
Yeung,
Molecular expression and pharmacological identification of a role for K(v)7 channels in murine vascular reactivity.
2007,
Pubmed
Yeung,
Electrophysiological and functional effects of the KCNQ channel blocker XE991 on murine portal vein smooth muscle cells.
2005,
Pubmed
