2. Academic Validation
  3. Vascular Reactivity Profile of Novel KCa 3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed

Vascular Reactivity Profile of Novel KCa 3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed

  • Basic Clin Pharmacol Toxicol. 2016 Aug;119(2):184-92. doi: 10.1111/bcpt.12560.
Aida Oliván-Viguera 1,  Marta Sofía Valero 2,  Estéfano Pinilla 3,  Sara Amor 4,  Ángel Luis García-Villalón 4,  Nichole Coleman 5,  Celia Laría 2,  Víctor Calvín-Tienza 2,  Ángel-Luis García-Otín 2,  José M Fernández-Fernández 6,  M Divina Murillo 7,  José A Gálvez 8,  María D Díaz-de-Villegas 8,  Ramón Badorrey 8,  Ulf Simonsen 3,  Luis Rivera 9,  Heike Wulff 5,  Ralf Köhler 1 10
Affiliations

Affiliations

  • 1 Aragon Institute of Health Sciences & IIS, Zaragoza, Spain.
  • 2 Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain.
  • 3 Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
  • 4 Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
  • 5 Department of Pharmacology, University of California, Davis, CA, USA.
  • 6 Laboratori de Fisiologia Molecular i Canalopaties, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
  • 7 Department of Pharmacology and Physiology, Veterinary Faculty, University of Zaragoza, Zaragoza, Spain.
  • 8 Departamento de Catálisis y Procesos Catalíticos, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC - Universidad de Zaragoza, Zaragoza, Spain.
  • 9 Department of Physiology, Faculty of Pharmacy, Universidad Complutense de Madrid, Madrid, Spain.
  • 10 Aragon Agency for Research and Development (ARAID), Zaragoza, Spain.
PMID: 26821335 DOI: 10.1111/bcpt.12560
Abstract

Opening of intermediate-conductance calcium-activated potassium channels (KC a 3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new KC a 3.1-selective positive-gating modulators, SKA-111 and SKA-121, to (1) evoke porcine endothelial cell KC a 3.1 membrane hyperpolarization, (2) induce endothelium-dependent and, particularly, endothelium-derived hyperpolarization (EDH)-type relaxation in porcine coronary arteries (PCA) and (3) influence coronary artery tone in isolated rat hearts. In whole-cell patch-clamp experiments on endothelial cells of PCA (PCAEC), KC a currents evoked by bradykinin (BK) were potentiated ≈7-fold by either SKA-111 or SKA-121 (both at 1 μM) and were blocked by a KC a 3.1 blocker, TRAM-34. In membrane potential measurements, SKA-111 and SKA-121 augmented bradykinin-induced hyperpolarization. Isometric tension measurements in large- and small-calibre PCA showed that SKA-111 and SKA-121 potentiated endothelium-dependent relaxation with intact NO synthesis and EDH-type relaxation to BK by ≈2-fold. Potentiation of the BK response was prevented by KC a 3.1 inhibition. In Langendorff-perfused rat hearts, SKA-111 potentiated coronary vasodilation elicited by BK. In conclusion, our data show that positive-gating modulation of KC a 3.1 channels improves BK-induced membrane hyperpolarization and endothelium-dependent relaxation in small and large PCA as well as in the coronary circulation of rats. Positive-gating modulators of KC a 3.1 could be therapeutically useful to improve coronary blood flow and counteract impaired coronary endothelial dysfunction in Cardiovascular Disease.

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