TY - JOUR

T1 - 4-Aminopyridine: a pan voltage-gated potassium channel inhibitor that enhances K7.4 currents and inhibits noradrenaline-mediated contraction of rat mesenteric small arteries

AU - Khammy, Makhala M

AU - Kim, Sukhan

AU - Bentzen, Bo H

AU - Lee, Soojung

AU - Choi, Inyeong

AU - Aalkjaer, Christian

AU - Jepps, Thomas A

N1 - © 2017 The British Pharmacological Society.

PY - 2018/2

Y1 - 2018/2

N2 - BACKGROUND AND PURPOSE: Kv7.4 and Kv7.5 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 Kv7 family members at mmol concentrations. However, the effect of 4-AP on Kv7 channels has not been systematically studied. The aim of this study was to investigate the pharmacological activity of 4-AP on Kv7.4 and Kv7.5 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 Kv7.4 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 Kv7.4-mediated current in oocytes and HEK cells but did not affect Kv7.5 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+]iand caused concentration-dependent relaxations that were independent of 4-AP-mediated changes in intracellular pH. Application of the Kv7 channel blocker XE991 and BKCachannel 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 Kv7.4 and BKCachannels and attenuating NA-mediated signalling.

AB - BACKGROUND AND PURPOSE: Kv7.4 and Kv7.5 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 Kv7 family members at mmol concentrations. However, the effect of 4-AP on Kv7 channels has not been systematically studied. The aim of this study was to investigate the pharmacological activity of 4-AP on Kv7.4 and Kv7.5 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 Kv7.4 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 Kv7.4-mediated current in oocytes and HEK cells but did not affect Kv7.5 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+]iand caused concentration-dependent relaxations that were independent of 4-AP-mediated changes in intracellular pH. Application of the Kv7 channel blocker XE991 and BKCachannel 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 Kv7.4 and BKCachannels and attenuating NA-mediated signalling.

U2 - 10.1111/bph.14097

DO - 10.1111/bph.14097

M3 - Journal article

C2 - 29156097

VL - 175

SP - 501

EP - 516

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

ER -