Activation of Kv 7 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.