Hyperpolarizing factors

John Quilley, David Fulton, John C. McGiff

Research output: Contribution to journalArticlepeer-review

152 Scopus citations


There is now overwhelming evidence for factors, other than nitric oxide (NO), chat 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 eposides, 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 he important regulators of vascular tone; alterations in this system can be demonstrated in hypertension and diabetes, conditions associated with altered endothelium dependent vasodilator responsiveness.

Original languageEnglish (US)
Pages (from-to)1059-1070
Number of pages12
JournalBiochemical Pharmacology
Issue number10
StatePublished - Nov 15 1997
Externally publishedYes


  • Arachidonic acid
  • Bradykinin
  • Cytochrome P450-AA
  • Endothelium
  • Endothelium-derived hyperpolarizing factor
  • Nitric oxide

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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