Cycloxygenase-2 Inhibitor Celecoxib Is A Potent Activator Of Vascular KCNQ K+ Channels And An Inhibitor Of L-type Ca2+ Channels

Abstract

Cyclooxygenase-2 (COX-2) inhibitors are important members of the family of non-steroidal anti-inflammatory drugs (NSAIDs). Celebrex® (celecoxib) and Vioxx® (rofecoxib) were introduced in 1999 and rapidly became the most frequently prescribed new drugs in the United States. Vioxx® was voluntarily withdrawn from the market because of a reported increased risk of myocardial infarction and stroke in patients taking the drug for prolonged periods of time. Celecoxib has been reported to inhibit several classes of ion channels, but its effects on vascular smooth muscle ion channels have not been described. Using whole-cell perforated patch clamp techniques we examined effects of celecoxib on K+ and Ca2+ currents in A7r5 rat aortic smooth muscle cells. Application of 10μM celecoxib enhanced K+ current by 2-3 fold and substantially inhibited Ca2+ currents with an apparent positive shift in the voltage-dependence of activation. Both effects were reversible on washout. Nether rofecoxib (10μM), another selective COX-2 inhibitor, nor diclofenac (10μM), a nonselective COX inhibitor, affected Ca2+ or K+ currents in A7r5 cells. We previously reported that KCNQ5 channels are the predominant K+ channels determining outward potassium current at negative membrane potentials in A7r5 cells. We estimated cumulative dose-response curve of celecoxib on isolated KCNQ5 currents. Celecoxib enhances KCNQ5 current in 3.5 fold with an EC50 of 6.9 ± 1.5 μM, without shifting the activation curve. Celecoxib (10μM) was unable to restore KCNQ current inhibited by 100 pM vasopressin (AVP, vasoconstrictor hormone) or 1nM PMA (PKC activator) but inhibition of L-type Ca2+ currents (with a positive shift of activation) persisted. The effects of celecoxib, but not rofecoxib, on vascular Ca2+ and K+ channels may explain the differential risks of cardiovascular diseases in patients treated with Celebrex® or Vioxx®.