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4-Aminopyridine: a pan voltage-gated potassium channel inhibitor that enhances Kv7.4 currents and inhibits noradrenaline-mediated contraction of rat mesenteric small arteries

Authors :
Soojung Lee
Makhala M. Khammy
Christian Aalkjaer
Thomas A. Jepps
Bo Hjorth Bentzen
Sukhan Kim
Inyeong Choi
Source :
British Journal of Pharmacology. 175:501-516
Publication Year :
2018
Publisher :
Wiley, 2018.

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 artery myocyte 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.

Details

ISSN :
00071188
Volume :
175
Database :
OpenAIRE
Journal :
British Journal of Pharmacology
Accession number :
edsair.doi...........be70f68a4b053f07d9d87ec735aeea4d
Full Text :
https://doi.org/10.1111/bph.14097