The novel KV7 channel activator URO-K10 exerts enhanced pulmonary vascular effects independent of the KCNE4 regulatory subunit

Abstract

KV7 channels exert a pivotal role regulating vascular tone in several vascular beds. In this context, KV7 channel agonists represent an attractive strategy for the treatment of pulmonary arterial hypertension (PAH). Therefore, in this study, we have explored the pulmonary vascular effects of the novel KV7 channel agonist URO-K10. Consequently, the vasodilator and electrophysiological effects of URO-K10 were tested in rat and human pulmonary arteries (PA) and PA smooth muscle cells (PASMC) using myography and patch-clamp techniques. Protein expression was also determined by Western blot. Morpholino-induced knockdown of KCNE4 was assessed in isolated PA. PASMC proliferation was measured by BrdU incorporation assay. In summary, our data show that URO-K10 is a more effective relaxant of PA than the classical KV7 activators retigabine and flupirtine. URO-K10 enhanced KV currents in PASMC and its electrophysiological and relaxant effects were inhibited by the KV7 channel blocker XE991. The effects of URO-K10 were confirmed in human PA. URO-K10 also exhibited antiproliferative effects in human PASMC. Unlike retigabine and flupirtine, URO-K10-induced pulmonary vasodilation was not affected by morpholino-induced knockdown of the KCNE4 regulatory subunit. Noteworthy, the pulmonary vasodilator efficacy of this compound was considerably increased under conditions mimicking the ionic remodelling (as an in vitro model of PAH) and in PA from monocrotaline-induced pulmonary hypertensive rats. Taking all together, URO-K10 behaves as a KCNE4-independent KV7 channel activator with much increased pulmonary vascular effects compared to classical KV7 channel activators. Our study identifies a promising new drug in the context of PAH.