TY - JOUR
T1 - Vascular Reactivity Profile of Novel KCa3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed
AU - Oliván-Viguera, Aida
AU - Valero, Marta Sofía
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.
AU - Murillo, Mª Divina
AU - Gálvez, José A.
AU - Díaz-de-Villegas, María D.
AU - Badorrey, Ramón
AU - Simonsen, Ulf
AU - Rivera, Luis
AU - Wulff, Heike
AU - Köhler, Ralf
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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.
AB - 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.
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U2 - 10.1111/bcpt.12560
DO - 10.1111/bcpt.12560
M3 - Article
C2 - 26821335
AN - SCOPUS:84978805161
VL - 119
SP - 184
EP - 192
JO - Basic and Clinical Pharmacology and Toxicology
JF - Basic and Clinical Pharmacology and Toxicology
SN - 1742-7835
IS - 2
ER -