Contribution of EDHF and the role of potassium channels in the regulation of vascular tone

Potassium channels in both endothelial and vascular smooth muscle play an important role in the regulation of vascular tone and are therefore potential targets for new drug development. Endothelial cell potassium channels, notably small conductance and intermediate conductance calcium‐activated K channels (SKCa and IKCa, respectively), are of critical importance for the regulation of synthesis and, possibly, release of nitric oxide (NO) and prostacyclin (PGI2) as well as the elusive endothelium‐derived hyperpolarizing factor (EDHF). EDHF may represent the “third” pathway for endothelium‐dependent relaxation and, if a chemical mediator is involved, EDHF may represent a new class of K‐channel openers. Of interest also is that endothelial cell dysfunction is a common feature of cardiovascular disease and this dysfunction is often associated with a decreased availability of endothelium‐derived NO and, sometimes, an enhanced contribution of EDHF. This raises the question of the possibility that EDHF may play a pathophysiological function. A high degree of heterogeneity exists with respect to the pharmacological properties of EDHF and this may indicate that multiple EDHFs exist with some degree of vessel selectivity. Despite the heterogeneity in the properties of EDHF, a common feature is that a combination of two K‐channel toxins, apamin and charybdotoxin, which target the SKCa and IKCa channels, respectively (charybdotoxin also inhibits large‐conductance KCa, BKCa, and voltage‐gated, KV channels). The requirement for both toxins for inhibiting EDHF is suggestive that a novel K channel may exist in the vasculature; however, to date the discovery of such a channel has remained elusive. Drug Dev. Res. 58:81–89, 2003.