Activation of K_v7 channels as a novel mechanism for NO/cGMP‐induced pulmonary vasodilation

Abstract

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. Kv channels expressed in PA smooth muscle cells (PASMCs) are key determinants of vascular tone. We aimed to analyse the contribution of Kv1.5 and Kv7 channels in the electrophysiological and vasodilating effects evoked by NO donors and the GC stimulator riociguat in PA. Experimental Approach Kv 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 Kv 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 Kv7 channel inhibitors and by the GC inhibitor ODQ but preserved when Kv1.5 channels were inhibited. Additionally, DEA‐NO enhanced Kv7.5 currents in COS7 cells expressing the KCNQ5 gene. Riociguat increased Kv currents at all potentials ≥−40 mV and induced membrane hyperpolarization. Both effects were prevented by Kv7 inhibition. Likewise, PA relaxation induced by NO donors and riociguat was attenuated by Kv7 inhibitors. Conclusions and Implications NO donors and riociguat enhance Kv7 currents, leading to PASMC hyperpolarization. This mechanism contributes to NO/cGMP‐induced PA vasodilation. Our study identifies Kv7 channels as a novel mechanism of action of vasodilator drugs used in the treatment of pulmonary arterial hypertension.

Kv7 Channels in Lung Diseases

“…The NO/cGMP pathway represents a key physiological signaling controlling tone in PAs, and drugs stimulating this pathway are used to treat PAH (Barnes and Liu, 1995), and drugs activating this pathway are used to treat pulmonary arterial hypertension. Recently, we have found that NO donors and riociguat, a stimulator of sGC used for the treatment of pulmonary arterial hypertension, enhance Kv7 current and induce membrane hyperpolarization in fresh isolated PASMCs contributing to pulmonary vasodilation (Mondejar-Parreño et al, 2019). Further, we identified Kv7.5 channels as a potential member of the Kv7 family targeted by these drugs.…”

“…As detailed above, different studies have provided evidence that treatment with Kv7 channel activators such as flupirtine, retigabine, or fasudil is beneficial in different pulmonary hypertension models (Morecroft et al, 2009;Duong-Quy et al, 2013;Sedivy et al, 2015;Zhang and Wu, 2017). In addition, Kv7 channel activation has been shown to contribute to the pulmonary vasodilating effect induced by drugs approved for the pulmonary hypertension treatment such as nitric oxide or riociguat (Mondejar-Parreño et al, 2019).…”

“…Although, in other types of arteries, the expression of Kv7 channels has been located also in endothelial cells ( Goodwill et al, 2016 ), whether this is also the case for pulmonary artery endothelial cells (PAECs) remains unknown. The main function of these channels is to regulate pulmonary vascular tone, due to their contribution to maintain the membrane potential (Em) of PASMC ( Joshi et al, 2009 ; Sedivy et al, 2015 ; Mondejar-Parreño et al, 2018 , 2019 ).…”

“…Likewise, a markedly diminished KCNQ5 expression was found in the pulmonary vasculature of congenital diaphragmatic hernia fetuses. Since Kv7.5 channels have shown to contribute to NO donors-induced pulmonary vasodilation ( Mondejar-Parreño et al, 2019 ), its reduced availability in congenital diaphragmatic hernia could partly explain the poor therapeutic response to inhaled NO in these patients ( Group (NINOS), 1997 ; Putnam et al, 2016 ).…”

“…The mechanism may involve increased membrane expression of Kv7 channels mediated by colchicine-sensitive microtubule disruption (Lindman et al, 2018). Kv7 channels are also regulated by GPCR-independent mediators activating soluble guanylate cyclase (sGC) such as nitric oxide (NO) (Mondejar-Parreño et al, 2019) and natriuretic peptide (Stott et al, 2015). The implications in respiratory diseases and drug therapy are discussed below.…”