Novel Actions of Nonsteroidal Anti-Inflammatory Drugs on Vascular Ion Channels: Accounting for Cardiovascular Side Effects and Identifying New Therapeutic Applications.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications for the treatment of both acute and chronic pain. Selective cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex(®)), rofecoxib (Vioxx(®)), and diclofenac, have been among the most widely prescribed NSAIDs because they prevent the generation of prostaglandins involved in inflammation and pain, but avoid some of the gastrointestinal complications associated with less selective COX-1/COX-2 inhibitors. In 2004, rofecoxib (Vioxx(®)) was voluntarily withdrawn from the market because of adverse cardiovascular side effects. This led to an explosion of research into the cardiovascular effects of the 'coxibs', which revealed differential cardiovascular risk profiles among the members of this drug class. The differential risk profiles may relate to the tendency of some of the drugs to elevate blood pressure (BP). An important component of BP regulation is dependent on the contractile state of vascular smooth muscle cells (VSMCs), which is controlled to a large extent by the activities of KCNQ (Kv7 family) potassium channels and L-type calcium channels. Our recently published data indicate that celecoxib, but not rofecoxib or diclofenac, at therapeutically relevant concentrations, acts as a Kv7 potassium channel activator and a calcium channel blocker, causing relaxation of VSMCs and decreasing vascular tone. These vasorelaxant ion channel effects may account for the differential cardiovascular risk profiles among the different COX-2 inhibitors. We further speculate that these properties may be exploited for therapeutic benefit in the treatment of cardiovascular diseases or other medical conditions.