Inhibition of delayed rectifier potassium channels and induction of arrhythmia: a novel effect of celecoxib and the mechanism underlying it.
Selective inhibitors of cyclooxygenase-2 (COX-2), such as rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra), have been developed for treating arthritis and other musculoskeletal complaints. Selective inhibition of COX-2 over COX-1 results in preferential decrease in prostacyclin production over thromboxane A2 production, thus leading to less gastric effects than those seen with nonselective COX inhibitors such as acetylsalicylic acid (aspirin). Here we show a novel effect of celecoxib via a mechanism that is independent of COX-2 inhibition. The drug inhibited the delayed rectifier (Kv2) potassium channels from Drosophila, rats, and humans and led to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture. These effects occurred despite the genomic absence of cyclooxygenases in Drosophila and the failure of acetylsalicylic acid, a potent inhibitor of both COX-1 and COX-2, to inhibit rat Kv2.1 channels. A genetically null mutant of Drosophila Shab (Kv2) channels reproduced the cardiac effect of celecoxib, and the drug was unable to further enhance the effect of the mutation. These observations reveal an unanticipated effect of celecoxib on Drosophila hearts and on heart cells from rats, implicating the inhibition of Kv2 channels as the mechanism underlying this effect.
Frolov
Roman V
RV
Department of Pharmacology and Toxicology, State University of New York, Buffalo, New York 14214.
Berim
Ilya G
IG
Department of Medicine, State University of New York, Buffalo, New York 14214.
Singh
Satpal
S
Department of Pharmacology and Toxicology, State University of New York, Buffalo, New York 14214. Electronic address: singhs@buffalo.edu.
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D000068579:Celecoxib; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D051669:Shab Potassium Channels / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D051668:Delayed Rectifier Potassium Channels; D011720:Pyrazoles; D051669:Shab Potassium Channels; D013449:Sulfonamides; D000068579:Celecoxib