An ion channel hypothesis to explain divergent cardiovascular safety of cyclooxygenase-2 inhibitors: The answer to a hotly debated puzzle?

Cyclooxygenase inhibitors represented extremely promising novel anti-inflammatory drugs until one of them, rofecoxib (Vioxx), was found to be associated with increased cardiovascular morbidity; however, another such drug, celecoxib (Celebrex), suffers far less from this side effect for unknown reasons and is still widely used. In this issue, Brueggemann et al. (page p. 1053) suggest a hypothesis. Celecoxib, but not rofecoxib, is shown to act as an "opener" of voltage-gated KCNQ5 K⁺ channels and a blocker of "L-type" Ca²⁺ channels, causing a reduction in the excitability and contractility of vascular smooth-muscle cells (VSMCs). Furthermore, VSMC tone is shown to be selectively reduced by celecoxib, resulting in dilation of blood vessels and reduction in systemic blood pressure, suggesting that the reduced work load on the heart may counteract any other deleterious effects of this class of drugs. Here, these findings are discussed in light of the role of KCNQ K⁺ channels in control of excitability in general, the "lipid imbalance theory" of cyclooxygenase-2 risks, and the potential for novel therapeutic modalities for cardiovascular disease focused on ion channels in vascular smooth muscle.