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 journalArticle

3 Citations (Scopus)

Abstract

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
Volume119
Issue number2
DOIs
StatePublished - Aug 1 2016

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Bradykinin
Modulators
Blood Vessels
Endothelium
Coronary Vessels
Swine
Membranes
Rats
Endothelial cells
Intermediate-Conductance Calcium-Activated Potassium Channels
Endothelial Cells
Coronary Circulation
Vascular Endothelium
Clamping devices
Vasodilation
Membrane Potentials
Blood
Cardiovascular Diseases
Modulation
5-methylnaphtho(2,1-d)oxazol-2-amine

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Oliván-Viguera, A., Valero, M. S., Pinilla, E., Amor, S., García-Villalón, Á. L., Coleman, N., ... Köhler, R. (2016). Vascular Reactivity Profile of Novel KCa3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed. Basic and Clinical Pharmacology and Toxicology, 119(2), 184-192. https://doi.org/10.1111/bcpt.12560

Vascular Reactivity Profile of Novel KCa3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed. / Oliván-Viguera, Aida; Valero, Marta Sofía; Pinilla, Estéfano; Amor, Sara; García-Villalón, Ángel Luis; Coleman, Nichole; Laría, Celia; Calvín-Tienza, Víctor; García-Otín, Ángel Luis; Fernández-Fernández, José M.; Murillo, Mª Divina; Gálvez, José A.; Díaz-de-Villegas, María D.; Badorrey, Ramón; Simonsen, Ulf; Rivera, Luis; Wulff, Heike; Köhler, Ralf.

In: Basic and Clinical Pharmacology and Toxicology, Vol. 119, No. 2, 01.08.2016, p. 184-192.

Research output: Contribution to journalArticle

Oliván-Viguera, A, Valero, MS, Pinilla, E, Amor, S, García-Villalón, ÁL, Coleman, N, Laría, C, Calvín-Tienza, V, García-Otín, ÁL, Fernández-Fernández, JM, Murillo, MD, Gálvez, JA, Díaz-de-Villegas, MD, Badorrey, R, Simonsen, U, Rivera, L, Wulff, H & Köhler, R 2016, 'Vascular Reactivity Profile of Novel KCa3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed', Basic and Clinical Pharmacology and Toxicology, vol. 119, no. 2, pp. 184-192. https://doi.org/10.1111/bcpt.12560
Oliván-Viguera, Aida ; Valero, Marta Sofía ; Pinilla, Estéfano ; Amor, Sara ; García-Villalón, Ángel Luis ; Coleman, Nichole ; Laría, Celia ; Calvín-Tienza, Víctor ; García-Otín, Ángel Luis ; Fernández-Fernández, José M. ; Murillo, Mª Divina ; Gálvez, José A. ; Díaz-de-Villegas, María D. ; Badorrey, Ramón ; Simonsen, Ulf ; Rivera, Luis ; Wulff, Heike ; Köhler, Ralf. / Vascular Reactivity Profile of Novel KCa3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed. In: Basic and Clinical Pharmacology and Toxicology. 2016 ; Vol. 119, No. 2. pp. 184-192.
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AU - Pinilla, Estéfano

AU - Amor, Sara

AU - García-Villalón, Ángel Luis

AU - Coleman, Nichole

AU - Laría, Celia

AU - Calvín-Tienza, Víctor

AU - García-Otín, Ángel Luis

AU - Fernández-Fernández, José M.

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AU - Gálvez, José A.

AU - Díaz-de-Villegas, María D.

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