Endothelium-derived hyperpolarizing factor(s): Species and tissue heterogeneity

1. Endothelium-derived relaxing factor is almost universally considered to be synonymous with nitric oxide (NO): however, it is now vi ell established that at least two other chemically distinct species (prostacyclin (PGI(2)) and a hyperpolarizing factor) may also contribute to endothelium-dependent relaxation, 2. Only relatively few studies have provided definitive evidence that an endothelium-derived hyperpolarizing factor (EDHF). which is neither NO nor PGI(2), exists as a chemical mediator. 3. There is a lack of agreement as to the likely chemical identity of this putative factor. Some evidence suggests that EDHF may be a cytochrome P-450-derived arachidonic acid product, possibly an epoxyeicosatrienoic acid (EET); conflicting evidence supports an endogenous cannabinoid as the mediator and still other studies infer an unknown mediator that is neither a cytochrome P-450 nor a cannabinoid. 4. Data from our laboratory with a rabbit carotid artery 'sandwich' preparation have provided evidence that a mediator that meets the pharmacological expectations of a cytochrome P-450 product is an EDHF. 5. Data from guinea-pig mesenteric arterioles suggest that EDHF is not a cytochrome P-450 product, whereas in guinea-pig middle cerebral arteries, relaxation mediated by the NO/PGI(2)-independent mediator(s) is sensitive to cytochrome P-450 inhibitors. In addition, in the rabbit middle cerebral artery, it is likely that endothelium-dependent hyperpolarization is mediated by both NO and PGI(2). 6. In conclusion, these data indicate that EDHF is unlikely to be a single factor and that considerable tissue and species differences exist for the nature and cellular targets of the hyperpolarizing factors.