Characterization of a novel Kv1.5 channel blocker in Xenopus oocytes, CHO cells, human and rat cardiomyocytes

Abstract.

The inhibitory effects of the novel Kv1.5 channel blocker, S9947 (2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide), on cloned human Kv1.5 (hKv1.5), expressed in both Xenopus oocytes and Chinese hamster ovary (CHO) cells, and on native cardiac ultrarapid delayed rectifier potassium currents (I _Kur) in rat (ventricle myocytes) and human (atrial myocytes) were investigated. The influence of S9947 on the action potential was examined in rat ventricular myocytes.

Using the two-electrode voltage-clamp technique in Xenopus oocytes and the patch-clamp technique (whole cell configuration) in CHO cells, hKv1.5 was inhibited by S9947 with IC₅₀ values of 0.65 µM and 0.42 µM, respectively. In addition, inhibition of human Kv4.3 (hKv4.3) and HERG by 10 µM S9947 was low (~20%) and absent, respectively. Using the patch-clamp technique in the whole cell configuration, I _Kur currents in rat ventricular (rI _Kur) cardiomyocytes and human atrial (hI _Kur) cardiomyocytes were inhibited by S9947 with IC₅₀ values of 0.96 µM and 0.07 µM, respectively. In contrast, rat cardiac inward rectifier current (rI _K1) and rat (rI _to) and human (hI _to) cardiac transient outward currents were only inhibited by ~20% with 10 µM S9947. In rat cardiomyocytes, using the patch-clamp technique, action potential duration was increased by S9947 in a concentration-dependent (0.3–10 µM) and rate-independent manner.

The data show that S9947 suppresses both cloned (Kv1.5) and native (I _Kur) cardiac potassium currents. Furthermore, S9947 prolongs rat action potential in a rate-independent manner.