Novel effects of Celebrex: Inhibition of ion channels, induction of heart arrhythmia, and suppression of neuronal firing
Frolov, Roman V.
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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. Despite their strong beneficial therapeutic effects, the coxibs are now associated with a number of deaths from cardiac arrest, acute myocardial infarction (AMI) and stroke, which are thought to arise from the prothrombotic effects of the drugs due to a selective inhibition of prostacyclin production over thromboxane A 2 synthesis. We observed unexpected and novel effects of two coxibs, celecoxib and SC-791, on the ion channels and function of cardiomyocytes and neurons. Application of celecoxib caused inhibition of heart rate and pronounced arrhythmia in Drosophila. A similar effect was observed in rat cardiomyocytes in culture in which the drug reduced the beating rate in clusters of cells and made the beating arrhythmic. SC-791 reduced the heart rate in flies, caused a moderate arrhythmia, and dramatically increased the duration of heart contraction. Both drugs exerted their effects by inhibiting calcium and potassium currents as revealed during voltage-clamp experiments in Drosophila body-wall muscles. To examine possible effects of celecoxib on central nervous system, we tested effects of the drug on ionic currents and neuronal activity in isolated rat retinal neurons. We found that celecoxib suppressed voltage-gated potassium currents in retinal bipolar cells with an EC 50 of 5.5 μM. In retinal amacrine and ganglion cells, celecoxib inhibited voltage-dependent sodium channels with an EC 50 of 5.2 μM, and voltage-dependent transient and sustained potassium currents with EC 50 s of 16.3 and 9.1 μM, respectively. Notably, the rate of spontaneous spike activity was dramatically suppressed in ganglion and amacrine cells with an EC 50 of 0.76 μM. All actions of celecoxib on ionic currents and action potentials occurred from the extracellular side and were completely reversible. These findings indicate that inhibition of ion channels by celecoxib in the central nervous system may affect neuronal function at clinically relevant concentrations. Our previous results pointed out that the drugs can inhibit a number of different ion channels. It was, therefore, important to examine effects of celecoxib and SC-791 on isolated ionic currents. We used HEK-293 cell line to transiently express rat and human Kv2.1, KCNQ1 and KCNE1 channels, and HEK-293 cell line stably expressing hERG channels. Celecoxib and SC-791 inhibited human KCNQ1 channels, KCNQ1 channels coexpressed with a KCNE1 auxillary channel subunit, rat and human Kv2.1 channels, and hERG channels. These effects occurred in spite of genomic absence of cyclooxygenases in Drosophila and a lack of effect of acetylsalicylic acid on ion 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 on the regularity of fly heart beat. The detailed analyses of mechanisms of inhibition, by which celecoxib and SC-791 exerted their effects on potassium channels, revealed that the drugs at relatively low concentrations (≤ 10 μM) acted, through modification of channel gating but not open-channel blockade. The mechanism of drug action on the delayed rectifier K + channels was similar for hERG, KCNQ, and Kv2.1 channels and was unique with respect to the striking acceleration of different aspects of channel kinetics. These observations suggest novel mechanisms, independent of cyclooxygenase inhibition, by which celecoxib may affect cardiac and neuronal functions in Drosophila, rats, and humans.