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J. Biol. Chem., Vol. 283, Issue 3, 1518-1524, January 18, 2008

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Inhibition of Delayed Rectifier Potassium Channels and Induction of Arrhythmia

A NOVEL EFFECT OF CELECOXIB AND THE MECHANISM UNDERLYING IT^*

Roman V. Frolov, Ilya G. Berim, and Satpal Singh¹

From the Departments of Pharmacology and Toxicology and Medicine, State University of New York, Buffalo, New York 14214

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.

Received for publication, September 28, 2007

^* This work was supported by Grants MCB-0094477 and MCB-0322461 from the National Science Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedures," supplemental Fig. 1, and supplemental Table 1.

¹ To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, 102 Farber Hall, State University of New York at Buffalo, Buffalo, NY 14214. Tel.: 716-829-2453; Fax: 716-829-2801; E-mail: singhs{at}buffalo.edu.

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