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Vascular Reactivity Profile of Novel K Ca 3.1‐Selective Positive‐Gating Modulators in the Coronary Vascular Bed
Author(s) -
OlivánViguera Aida,
Valero Marta Sofía,
Pinilla Estéfano,
Amor Sara,
GarcíaVillalón Ángel Luis,
Coleman Nichole,
Laría Celia,
CalvínTienza Víctor,
GarcíaOtín ÁngelLuis,
FernándezFernández José M.,
Murillo Mª Divina,
Gálvez José A.,
DíazdeVillegas María D.,
Badorrey Ramón,
Simonsen Ulf,
Rivera Luis,
Wulff Heike,
Köhler Ralf
Publication year - 2016
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12560
Subject(s) - hyperpolarization (physics) , bradykinin , gating , chemistry , biophysics , membrane potential , bk channel , vasodilation , apamin , endothelium , potassium channel , vascular smooth muscle , endothelium derived hyperpolarizing factor , medicine , endocrinology , charybdotoxin , biochemistry , biology , stereochemistry , smooth muscle , nuclear magnetic resonance spectroscopy , receptor
Opening of intermediate‐conductance calcium‐activated potassium channels ( K C a 3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new K C a 3.1‐selective positive‐gating modulators, SKA ‐111 and SKA ‐121, to (1) evoke porcine endothelial cell K C 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 ), K C 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 K C 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 K C 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 K C 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 K C a 3.1 could be therapeutically useful to improve coronary blood flow and counteract impaired coronary endothelial dysfunction in cardiovascular disease.