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4‐Aminopyridine: a pan voltage‐gated potassium channel inhibitor that enhances K v 7.4 currents and inhibits noradrenaline‐mediated contraction of rat mesenteric small arteries
Author(s) -
Khammy Makhala M,
Kim Sukhan,
Bentzen Bo H,
Lee Soojung,
Choi Inyeong,
Aalkjær Christian,
Jepps Thomas A
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14097
Subject(s) - iberiotoxin , mesenteric arteries , potassium channel , biophysics , chemistry , patch clamp , membrane potential , channel blocker , 4 aminopyridine , inward rectifier potassium ion channel , vascular smooth muscle , medicine , endocrinology , ion channel , electrophysiology , biochemistry , artery , calcium , biology , receptor , smooth muscle
Background and Purpose K v 7.4 and K v 7.5 channels are regulators of vascular tone. 4‐Aminopyridine (4‐AP) is considered a broad inhibitor of voltage‐gated potassium (K V ) channels, with little inhibitory effect on K v 7 family members at mmol concentrations. However, the effect of 4‐AP on K v 7 channels has not been systematically studied. The aim of this study was to investigate the pharmacological activity of 4‐AP on K v 7.4 and K v 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 K v 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 K v 7.4‐mediated current in oocytes and HEK cells but did not affect K v 7.5 current. 4‐AP also enhanced native mesenteric artery myocyte K + current at sub‐mmol concentrations. When applied to NA‐preconstricted mesenteric artery segments, 4‐AP hyperpolarized the membrane, decreased [Ca 2+ ] i and caused concentration‐dependent relaxations that were independent of 4‐AP‐mediated changes in intracellular pH. Application of the K v 7 channel blocker XE991 and BK Ca 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 K v 7.4 and BK Ca channels and attenuating NA‐mediated signalling.