Third pathway: Endothelium‐dependent hyperpolarization

The mechanism of endothelium‐dependent hyperpolarizations, once attributed to an elusive endothelium‐derived hyperpolarizing factor (EDHF), is better understood. The first steps involve an increase in the intracellular calcium concentration of the endothelial cells followed by the opening of endothelial calcium‐activated potassium channels and the hyperpolarization of the endothelial cells. In certain arteries, these endothelial events are under the control of the endothelial cytochrome P450 monooxygenase. Then, the endothelium‐dependent hyperpolarization of the smooth muscle cells can be evoked by direct electrical coupling through myo‐endothelial junctions, accumulation of potassium ions in the intracellular space between the endothelial and the smooth muscle cells, and in rare occasions the release of a metabolite(s) of arachidonic acid via the cytochrome P450 pathway. These various mechanisms are not necessarily exclusive and can occur simultaneously and even in synergy. Drug Dev. Res. 58:18–22, 2003.