Hyperpolarizing Factors

Abstract

There is now overwhelming evidence for factors, other than nitric oxide (NO), that mediate endothelium-dependent vasodilation by hyperpolarizing the underlying smooth muscle via activation of Ca2+-activated K+ channels. Although the identity of endothelium-derived hyperpolarizing factor (EDHF) remains to be established, cytochrome P450 (CYP)-dependent metabolites of arachidonic acid (AA), namely, the epoxides, fulfill several of the criteria required for consideration as putative mediators of endothelium-dependent hyperpolarization. They are produced by the endothelium, released in response to vasoactive hormones, and elicit vasorelaxation via stimulation of Ca2+-activated K+ channels. Our studies in the rat indicate that, of the epoxides, 5,6-epoxyeicosatrienoic acid (5,6-EET) is the most likely mediator of NO-independent, but CYP-dependent coronary vasodilation in response to bradykinin. Studies in the rat kidney, however, support the existence of additional EDHFs as acetylcholine also exhibits NO-independent vasodilation that is unaffected by CYP inhibitors in concentrations that attenuate responses to bradykinin. In some blood vessels, NO may tonically suppress the expression of CYP-dependent EDHF. In the event of impaired NO synthesis, therefore, a CYP-dependent vasodilator mechanism may serve as a backup to a primary NO-dependent mechanism, although they may act in concert. In other vessels, particularly microvessels, an EDHF may constitute the major vasodilator mechanism for hormones and other physiological stimuli. EDHFs appear to be important regulators of vascular tone; alterations in this system can be demonstrated in hypertension and diabetes, conditions associated with altered endothelium-dependent vasodilator responsiveness.

Combined aerobic and resistance exercise training decreases peripheral but not central artery wall thickness in subjects with type 2 diabetes

“…Studies, largely performed in animals, found that such stimuli are associated with remodelling and antiatherogenic effects (e.g. eNOS-expression/activity (Awolesi et al 1995), EDHF-synthase expression (Quilley et al 1997)). Alternative systemic mechanisms may relate to novel markers, such as endothelial progenitor cells (EPCs) and miRNA .…”

Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B 2 Receptor–Dependent, NO Synthase–Independent, and Cyclooxygenase-Independent Pathway

“…EDHF causes endothelium-dependent NOS/COX inhibitor-insensitive hyperpolarization and relaxation of vascular smooth muscle that is blocked by inhibitors of calcium-activated potassium channels such as charbydotoxin and apamin but not by inhibitors of ATP-sensitive potassium channels. 34 Although the identity of EDHF may vary among vascular beds and species, mounting evidence suggests that EDHF is a cytochrome P 450 epoxygenase-derived product of arachidonic acid. 35 The contribution of EDHF to BKstimulated vasodilation in human arteries in vitro has been demonstrated, 30,36 and recent work by Taddei et al 37 indicates that prevention of hyperpolarization by ouabain attenuates the forearm vasodilator response to BK in hypertensive patients.…”

Inhibition of the production of endothelium‐derived hyperpolarizing factor by cannabinoid receptor agonists

“…Current opinion is that the synthesis of EDHF is secondary to the activation of phospholipase A 2 (PLA 2 ), and the liberation of arachidonic acid (Quilley et al, 1997). Indeed, the synthesis of EDHF is thought to be Ca 2+ -dependent by virtue of the reported Ca 2+ -dependency of PLA 2 .…”

“…Indeed, the synthesis of EDHF is thought to be Ca 2+ -dependent by virtue of the reported Ca 2+ -dependency of PLA 2 . Thereafter, the signalling pathway is obscure and although EDHF may be generated from arachidonic acid by CYP enzymes in some vascular beds this is almost certainly not the case in others (Mombouli & Vanhoutte, 1997;Quilley et al, 1997). Since the EDHF produced in all of the arteries under investigation has been pharmacologically characterized as a CYP-dependent metabolite of arachidonic acid, it seemed plausible to suggest that the CB1 agonists attenuated EDHF production by decreasing the activity of the`EDHF synthase'.…”