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 well established that at least two other chemically distinct species (prostacyclin (PGI2) 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 PGI2, 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 P450‐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 P450 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 P450 product is an EDHF. 5. Data from guinea‐pig mesenteric arterioles suggest that EDHF is not a cytochrome P450 product, whereas in guinea‐pig middle cerebral arteries, relaxation mediated by the NO/PGI2‐independent mediator(s) is sensitive to cytochrome P450 inhibitors. In addition, in the rabbit middle cerebral artery, it is likely that endothelium‐dependent hyperpolarization is mediated by both NO and PGI2. 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.