Activation of Kv7 channels as a novel mechanism for NO/cGMP‐induced pulmonary vasodilation

Background and Purpose The NO/cGMP pathway represents a major physiological signalling controlling tone in pulmonary arteries (PA), and drugs activating this pathway are used to treat pulmonary arterial hypertension. K v channels expressed in PA smooth muscle cells (PASMCs) are key determinants of vascular tone. We aimed to analyse the contribution of K v 1.5 and K v 7 channels in the electrophysiological and vasodilating effects evoked by NO donors and the GC stimulator riociguat in PA. Experimental Approach K v currents were recorded in isolated rat PASMCs using the patch‐clamp technique. Vascular reactivity was assessed in a wire myograph. Key Results The NO donors diethylamine NONOate diethylammonium (DEA‐NO) and sodium nitroprusside hyperpolarized the membrane potential and induced a bimodal effect on K v currents (augmenting the current between −40 and −10 mV and decreasing it at more depolarized potentials). The hyperpolarization and the enhancement of the current were suppressed by K v 7 channel inhibitors and by the GC inhibitor ODQ but preserved when K v 1.5 channels were inhibited. Additionally, DEA‐NO enhanced K v 7.5 currents in COS7 cells expressing the KCNQ5 gene. Riociguat increased K v currents at all potentials ≥−40 mV and induced membrane hyperpolarization. Both effects were prevented by K v 7 inhibition. Likewise, PA relaxation induced by NO donors and riociguat was attenuated by K v 7 inhibitors. Conclusions and Implications NO donors and riociguat enhance K v 7 currents, leading to PASMC hyperpolarization. This mechanism contributes to NO/cGMP‐induced PA vasodilation. Our study identifies K v 7 channels as a novel mechanism of action of vasodilator drugs used in the treatment of pulmonary arterial hypertension.