Activation of K_v7 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_v1.5 and K_v7 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_v7 channel inhibitors and by the GC inhibitor ODQ but preserved when K_v1.5 channels were inhibited. Additionally, DEA‐NO enhanced K_v7.5 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_v7 inhibition. Likewise, PA relaxation induced by NO donors and riociguat was attenuated by K_v7 inhibitors.

Conclusions and Implications

NO donors and riociguat enhance K_v7 currents, leading to PASMC hyperpolarization. This mechanism contributes to NO/cGMP‐induced PA vasodilation. Our study identifies K_v7 channels as a novel mechanism of action of vasodilator drugs used in the treatment of pulmonary arterial hypertension.

DOI: 10.1111/bph.14662

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