Activation of Kv7 contributes to the relaxant effects of the NO/cGMP pathway in the pulmonary circulation

[Speaker] Angel Cogolludo:1,2,3
[Co-author] Gema Mondejar-Parreno:1,2,3, Bianca Barreira:1,2,3, Maria Callejo:1,2,3, Daniel Morales-Cano:1,2,3, Sergio Esquivel:1,2,3, Alicia De La Cruz:4, Laura Moreno:1,2,3, Carmen Valenzuela:4, Francisco Perez-Vizcaino:1,2,3
1:Department of Pharmacology, Universidad Complutense de Madrid, Spain, 2:Ciber Enfermedades Respiratorias (CIBERES), Spain, 3:Instituto de Investigacion Sanitaria Gregorio Maranon (IiSGM), Spain, 4:Instituto de Investigaciones BiomedicasAlberto Sols CSIC-Universidad Autonoma de Madrid, Spain

Background. The nitric oxide-NO/cGMP pathway plays a key role in the control of pulmonary arterial (PA) tone and drugs activating this pathway (phosphodiesterase V inhibitors and soluble guanylate cyclase-sGC stimulators) are important therapeutic options to treat pulmonary arterial hypertension. Recent studies indicate that Kv7 channels are main regulators of vascular tone in several blood vessels, including the pulmonary circulation. However, their possible modulation by the NO/cGMP pathway remains unknown. We aimed to analyze the possible contribution of Kv7 channels to the pulmonary vasodilatation induced by NO donors and the sGC stimulator riociguat.
Methods. Membrane potential and K currents were recorded using the whole cell configuration of the patch-clamp technique in male Wistar rat or human PA smooth muscle cells (PASMC). Currents were evoked by application of voltage ramps. PA were mounted on a wire myograph for vascular reactivity studies. The effects induced by NO donors (DEA-NO and sodium nitroprusside-SNP) and riociguat were analyzed. The role of Kv7 channels was characterized by using selective Kv7 blockers (XE991 or linopirdine). In some experiments Kv1.5 channels were inhibited by the application of long (4s) depolarizing steps or using a selective inhibitor (DPO-1).
Results. In PASMC, DEA-NO and SNP hyperpolarized the membrane potential and induced a bimodal effect on K currents (augmenting the current between -40 to -10 mV and decreasing it at more depolarized potentials) when a 1s ramp was applied. The hyperpolarization and the enhancement of the current were suppressed in the presence of Kv7 channel inhibitors but preserved by DPO-1 or after 4s depolarizing pulses. The increase of the current and the hyperpolarization were also prevented by the sGC inhibitor ODQ and mimicked by Riociguat. Likewise, the electrophysiological effects induced by riociguat were prevented by XE991. In line with these data, PA relaxation induced by DEA-NO or riociguat was attenuated by Kv7 inhibitors.
Conclusions. Our study provides the first evidence that Kv7 channels contribute to the pulmonary vasodilation induced by the NO/cGMP pathway. Our data may be of great interest since it identifies a new mechanism of action of drugs used in the treatment of pulmonary arterial hypertension. Supported by SAF2016-77222-R.

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