4-Aminopyridine: a Pan Voltage-gated Potassium Channel Inhibitor That Enhances K 7.4 Currents and Inhibits Noradrenaline-mediated Contraction of Rat Mesenteric Small Arteries

Background And Purpose: K 7.4 and K 7.5 channels are regulators of vascular tone. 4-Aminopyridine (4-AP) is considered a broad inhibitor of voltage-gated potassium (K ) channels, with little inhibitory effect on K 7 family members at mmol concentrations. However, the effect of 4-AP on K 7 channels has not been systematically studied. The aim of this study was to investigate the pharmacological activity of 4-AP on K 7.4 and K 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 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 7.4-mediated current in oocytes and HEK cells but did not affect K 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 ] and caused concentration-dependent relaxations that were independent of 4-AP-mediated changes in intracellular pH. Application of the K 7 channel blocker XE991 and BK 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 7.4 and BK channels and attenuating NA-mediated signalling.