Inhibition of delayed rectifier potassium channels and induction of arrhythmia

A novel effect of celecoxib and the mechanism underlying it

Roman V. Frolov, Ilya Berim, Satpal Singh

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1518-1524
Number of pages7
JournalJournal of Biological Chemistry
Volume283
Issue number3
DOIs
StatePublished - Jan 18 2008
Externally publishedYes

Fingerprint

Celecoxib
Delayed Rectifier Potassium Channels
Drosophila
Cardiac Arrhythmias
Rats
Cyclooxygenase 2
Aspirin
Shab Potassium Channels
Thromboxane A2
Cyclooxygenase 2 Inhibitors
Epoprostenol
Prostaglandin-Endoperoxide Synthases
Pharmaceutical Preparations
Arthritis
Stomach
Cell Culture Techniques
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Inhibition of delayed rectifier potassium channels and induction of arrhythmia : A novel effect of celecoxib and the mechanism underlying it. / Frolov, Roman V.; Berim, Ilya; Singh, Satpal.

In: Journal of Biological Chemistry, Vol. 283, No. 3, 18.01.2008, p. 1518-1524.

Research output: Contribution to journalArticle

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