Endothelium‐derived Hyperpolarizing Factor(s): Species and Tissue Heterogeneity

Abstract

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.

Determinants of renal microvascular response to ACh: afferent and efferent arteriolar actions of EDHF

“…As predicted, we found that the efferent arteriole response to ACh does not exhibit this EDHFlike component. A number of studies have demonstrated regional differences in regard to the role of EDHF (39). This study is the first to demonstrate that, within the renal microcirculation, EDHF contributes to the regulation of preglomerular tone but does not affect the postglomerular efferent arteriole.…”

“…Furthermore, it has been suggested that in resistance vessels endothelium-dependent hyperpolarization may not involve a released factor but rather may be mediated via myoendothelial gap junctional communication (4,23,35). Differing regions of the circulation exhibit considerable heterogeneity in regard to the nature of EDHF, its contribution to endothelium-dependent vasodilation, and the underlying ionic mechanisms (28,39). Since its discovery, the role of NO in the regulation of renal hemodynamics has received considerable attention.…”

An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice

“…Indeed, EDHF-like dilations could be demonstrated only in perfused vascular preparations in the present study. This may simply reflect the fact that EDHF responses observed in different vascular beds from the same species or between species are highly variable (18). Alternatively, fluid shear stress may facilitate agonist-induced EDHF production in mice.…”

Mediation of Arachidonic Acid Metabolite(s) Produced by Endothelial Cytochrome P-450 3A4 in Monkey Arterial Relaxation.

“…Cytochrome P-450 (CYP)-derived arachidonic acid metabolites are postulated to (12), and hydrogen peroxide has been reported as an EDHF in mouse (13) and human mesenteric arteries (14). Therefore, the identity of EDHF appears to differ among vascular beds and animal species (15)(16)(17). Recently, it has been postulated that the myoendothelial gap junction is important for spreading membrane hyperpolarization from endothelial cells to smooth muscle cells (18,19).…”