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
  • 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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