Vascular Reactivity Profile of Novel KCa3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed

Aida Oliván-Viguera, Marta Sofía Valero, Estéfano Pinilla, Sara Amor, Ángel Luis García-Villalón, Nichole Coleman, Celia Laría, Víctor Calvín-Tienza, Ángel Luis García-Otín, José M. Fernández-Fernández, Mª Divina Murillo, José A. Gálvez, María D. Díaz-de-Villegas, Ramón Badorrey, Ulf Simonsen, Luis Rivera, Heike Wulff, Ralf Köhler

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Opening of intermediate-conductance calcium-activated potassium channels (KC a3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new KC a3.1-selective positive-gating modulators, SKA-111 and SKA-121, to (1) evoke porcine endothelial cell KC a3.1 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 a3.1 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 a3.1 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 a3.1 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 a3.1 could be therapeutically useful to improve coronary blood flow and counteract impaired coronary endothelial dysfunction in cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)184-192
Number of pages9
JournalBasic and Clinical Pharmacology and Toxicology
Issue number2
StatePublished - Aug 1 2016

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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