title: Celecoxib blocks cardiac Kv1.5, Kv4.3 and Kv7.1 (KCNQ1) channels: effects on cardiac action potentials.
abstract: Celecoxib is a COX-2 inhibitor that has been related to an increased cardiovascular risk and that exerts several actions on different targets. The aim of this study was to analyze the effects of this drug on human cardiac voltage-gated potassium channels (Kv) involved on cardiac repolarization Kv1.5 (I(Kur)), Kv4.3+KChIP2 (I(to1)) and Kv7.1+KCNE1 (I(Ks)) and to compare with another COX-2 inhibitor, rofecoxib. Currents were recorded in transfected mammalian cells by whole-cell patch-clamp. Celecoxib blocked all the Kv channels analyzed and rofecoxib was always less potent, except on Kv4.3+KChIP2 channels. Kv1.5 block increased in the voltage range of channel activation, decreasing at potentials positive to 0 mV. The drug modified the activation curve of the channels that became biphasic. Block was frequency-dependent, increasing at fastest frequencies. Celecoxib effects were not altered by TEA(out) in R487Y mutant Kv1.5 channels but the kinetics of block were slower and the degree of block was smaller with TEA(in), indicating that celecoxib acts from the cytosolic side. We confirmed the blocking properties of celecoxib on native Kv currents from rat vascular cells, where Kv1.5 are the main contributors (IC(50)≈ 7 μM). Finally, we demonstrate that celecoxib prolongs the action potential duration in mouse cardiac myocytes and shortens it in guinea pig cardiac myocytes, suggesting that Kv block induced by celecoxib may be of clinical relevance.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols CSIC/UAM, Madrid, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Macías
authors.forename: Cristina
authors.initials: C
authors.lastname: Moreno
authors.forename: Javier
authors.initials: J
authors.lastname: Moral-Sanz
authors.forename: Angel
authors.initials: A
authors.lastname: Cogolludo
authors.forename: Miren
authors.initials: M
authors.lastname: David
authors.forename: Matteo
authors.initials: M
authors.lastname: Alemanni
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
authors.forename: Carmen
authors.initials: C
authors.lastname: Valenzuela
authors.forename: Teresa
authors.initials: T
authors.lastname: González
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000068579:Celecoxib; D006168:Guinea Pigs; D015640:Ion Channel Gating / Q000187:drug effects*; D051657:KCNQ1 Potassium Channel / Q000378:metabolism*; D051666:Kv1.5 Potassium Channel / Q000378:metabolism*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D051672:Shal Potassium Channels / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D051657:KCNQ1 Potassium Channel; D051666:Kv1.5 Potassium Channel; D011720:Pyrazoles; D051672:Shal Potassium Channels; D013449:Sulfonamides; D000068579:Celecoxib