title: Vascular Reactivity Profile of Novel KCa 3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed.
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.
authors.affiliation: Aragon Institute of Health Sciences & IIS, Zaragoza, Spain.
authors.forename: Aida
authors.initials: A
authors.lastname: Oliván-Viguera
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain.
authors.forename: Marta Sofía
authors.initials: MS
authors.lastname: Valero
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
authors.forename: Estéfano
authors.initials: E
authors.lastname: Pinilla
authors.affiliation: Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Amor
authors.affiliation: Department of Physiology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ángel Luis
authors.initials: ÁL
authors.lastname: García-Villalón
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.
authors.forename: Nichole
authors.initials: N
authors.lastname: Coleman
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Laría
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Calvín-Tienza
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Spain.
authors.forename: Ángel-Luis
authors.initials: ÁL
authors.lastname: García-Otín
authors.affiliation: Laboratori de Fisiologia Molecular i Canalopaties, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Fernández-Fernández
authors.affiliation: Department of Pharmacology and Physiology, Veterinary Faculty, University of Zaragoza, Zaragoza, Spain.
authors.forename: M Divina
authors.initials: MD
authors.lastname: Murillo
authors.affiliation: Departamento de Catálisis y Procesos Catalíticos, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC - Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Gálvez
authors.affiliation: Departamento de Catálisis y Procesos Catalíticos, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC - Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: María D
authors.initials: MD
authors.lastname: Díaz-de-Villegas
authors.affiliation: Departamento de Catálisis y Procesos Catalíticos, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC - Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Badorrey
authors.affiliation: Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rivera
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Aragon Institute of Health Sciences & IIS, Zaragoza, Spain.|Aragon Agency for Research and Development (ARAID), Zaragoza, Spain.
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000502:physiology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000502:physiology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C000591919:5-methylnaphtho(2,1-d)oxazol-2-amine; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D010080:Oxazoles; D011720:Pyrazoles; D012333:RNA, Messenger; C411671:TRAM 34; D014665:Vasodilator Agents; D052250:Nitric Oxide Synthase Type III; D001920:Bradykinin
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