ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR

1. Not all endothelium-dependent relaxations can be fully explained by the release of either nitric oxide (NO) and/or prostacyclin. Another unidentified substance(s) that hyperpolarizes the underlying vascular smooth muscle cells (endothelium-derived hyperpolarizing factor; EDHF) contributes to endothelium-dependent relaxations. 2. In blood vessels from various species these hyperpolarizations are resistant to inhibi tors of NO synthase (NOS) and cyclo-oxygenase. In canine, porcine and human blood vessels the hyperpolarization cannot be mimicked by nitrov asodilators or exogeneous NO. However, in other species (rat, guinea-p ig, rabbit) endothelium-dependent hyperpolarizations resistant to inhi bitors of NOS and cyclo-oxygenase and hyperpolarizations to endotheliu m-derived or exogeneous NO can be observed in the same vascular smooth muscle cells. 3. In blood vessels where NO causes hyperpolarization, the response is blocked by glibenclamide, suggesting the involvement o f ATP-dependent potassium channels. Hyperpolarizations caused by EDHF are insensitive to glibenclamide but, depending on the tissue, are inh ibited by relatively small concentrations of tetraethylammonium (TEA) or by apamin or the combination of charybdotoxin plus apamin, indicati ng that calcium-dependent potassium channels are likely to be involved . 4. Metabolites of arachidonic acid, through the cytochrome P450 mono -oxygenase pathway (epoxyeicosatrienoic acids), are produced by the en dothelial cells, increase the open-state probability of calcium-activa ted potassium channels sensitive to TEA or charybdotoxin, and induce t he hyperpolarization of arterial smooth muscle cells, indicating that epoxyeicosatrienoic acids could be EDHF. However, in blood vessels fro m various species, cytochrome P450 inhibitors do not affect endotheliu m-dependent hyperpolarizations, indicating that EDHF is not yet identi fied with certainty. 5. Endothelium-derived hyperpolarizing factor rel eased from cultured endothelial cells reduces the intracellular calciu m concentration in vascular smooth muscle cells and the EDHF component of the relaxation is proportionally more important in smaller than la rger arteries. In aging animals and in various models of diseases, end othelium-dependent hyperpolarizations are diminished. 6. The identific ation of EDHF and/or the discovery of specific inhibitors of its synth esis and its action may allow a better understanding of its physiologi cal and pathophysiological role(s).