1. Academic Validation
  2. Activation of Kv 7 channels as a novel mechanism for NO/cGMP-induced pulmonary vasodilation

Activation of Kv 7 channels as a novel mechanism for NO/cGMP-induced pulmonary vasodilation

  • Br J Pharmacol. 2019 Jul;176(13):2131-2145. doi: 10.1111/bph.14662.
Gema Mondéjar-Parreño 1 2 Javier Moral-Sanz 3 Bianca Barreira 1 2 Alicia De la Cruz 4 5 Teresa Gonzalez 4 5 6 Maria Callejo 1 2 Sergio Esquivel-Ruiz 1 2 Daniel Morales-Cano 1 2 Laura Moreno 1 2 Carmen Valenzuela 4 5 Francisco Perez-Vizcaino 1 2 Angel Cogolludo 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
  • 2 Ciber Enfermedades Respiratorias (CIBERES), Madrid, Spain.
  • 3 Centres for Discovery Brain Sciences and Cardiovascular Science, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
  • 4 Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain.
  • 5 CIBER Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
  • 6 Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
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 Kv 1.5 and Kv 7 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 Kv 7 channel inhibitors and by the GC inhibitor ODQ but preserved when Kv 1.5 channels were inhibited. Additionally, DEA-NO enhanced Kv 7.5 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 Kv 7 inhibition. Likewise, PA relaxation induced by NO donors and riociguat was attenuated by Kv 7 inhibitors.

Conclusions and implications: NO donors and riociguat enhance Kv 7 currents, leading to PASMC hyperpolarization. This mechanism contributes to NO/cGMP-induced PA vasodilation. Our study identifies Kv 7 channels as a novel mechanism of action of vasodilator drugs used in the treatment of pulmonary arterial hypertension.

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