Review
EDHF: bringing the concepts together

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Abstract

Endothelial cells synthesize and release vasoactive mediators in response to various neurohumoural substances (e.g. bradykinin or acetylcholine) and physical stimuli (e.g. cyclic stretch or fluid shear stress). The best-characterized endothelium-derived relaxing factors are nitric oxide and prostacyclin. However, an additional relaxant pathway associated with smooth muscle hyperpolarization also exists. This hyperpolarization was originally attributed to the release of an endothelium-derived hyperpolarizing factor (EDHF) that diffuses to and activates smooth muscle K+ channels. More recent evidence suggests that endothelial cell receptor activation by these neurohumoural substances opens endothelial cell K+ channels. Several mechanisms have been proposed to link this pivotal step to the subsequent smooth muscle hyperpolarization. The main concepts are considered in detail in this review.

Section snippets

Pivotal role of Ca2+ and endothelial Ca2+-activated K+ channels in the EDHF pathway

EDHF-mediated responses, in response to agonists that stimulate G-protein-coupled receptors, are associated with an increase in [Ca2+]i in the endothelial cell (Fig. 1) 17., 18. and are also generated by substances that increase endothelial [Ca2+]i in a receptor-independent manner (e.g. Ca2+ ionophores, and the sarcoplasmic reticulum Ca2+-ATPase inhibitors thapsigargin and cyclopiazonic acid) 19., 20.. Conversely, a decrease in the extracellular Ca2+ concentration attenuates EDHF responses [21]

Identification of the K+ channels involved in the EDHF pathway

Endothelium-dependent hyperpolarizations (in the presence of inhibitors of NO synthases and cyclooxygenases) are not prevented by glibenclamide [an inhibitor of ATP-dependent K+ (KATP) channels] but are blocked by specific toxins that inhibit Ca2+-sensitive (KCa) K+ channels. Indeed, a hallmark of the EDHF-mediated response, first observed by Garland’s group, is its abolition by the combination of apamin [a specific inhibitor of KCa channels of small conductance (SKCa channels)] plus

Beyond endothelial hyperpolarization

Why have so many vastly different hypotheses been proposed concerning the mechanism of EDHF-mediated responses? Increasing the [Ca2+]i in endothelial cells opens not only SKCa and IKCa channels, which results in the efflux and accumulation of K+ in the myo-endothelial space, but also leads to the activation of various enzymes including phospholipases and the subsequent metabolism of arachidonic acid by cytochrome P450 epoxygenases. Currently, experimental evidence favours three explanations for

Conclusion: bringing the concepts together

There is now good evidence that EDHF-mediated responses are initiated by an increase in the endothelial [Ca2+]i and the consequent activation of endothelial SKCa and IKCa channels, which elicits the hyperpolarization of the endothelial cells (Fig. 2). In some tissues, the hyperpolarization of the endothelial cells might be regulated by the activation of cytochrome P450 and the resulting generation of EETs. The endothelial hyperpolarization could then spread to the adjacent smooth muscle cells

Note added in proof

Recently, a specific antagonist of EETs was synthesized and was shown to further substantiate, in bovine coronary artery, the involvement of cytochrome P450 epoxygenase metabolites in EDHF-mediated responses [81]. However, it is not yet known whether this antagonist targets the endothelial cells or the smooth muscle cells. A transient increase in the level of cAMP might play a permissive role in the EDHF-mediated responses by enhancing the electrotonic spread of endothelial hyperpolarization

References (82)

  • J. Quilley

    Hyperpolarizing factors

    Biochem. Pharmacol.

    (1997)
  • J. Quilley et al.

    Is EDHF an epoxyeicosatrienoic acid?

    Trends Pharmacol. Sci.

    (2000)
  • D. Harris

    Role of gap junctions in endothelium-derived hyperpolarizing factor responses and mechanisms of K+-relaxation

    Eur. J. Pharmacol.

    (2000)
  • T.B. Bolton

    Mechanism of action of noradrenaline and carbachol on smooth muscle of guinea-pig anterior mesenteric artery

    J. Physiol.

    (1984)
  • M. Félétou et al.

    Endothelium-dependent hyperpolarisation of canine coronary smooth muscle

    Br. J. Pharmacol.

    (1988)
  • S.G. Taylor

    Endothelium-dependent effects of acetylcholine in rat aorta: a comparison with sodium nitroprusside and cromakalim

    Br. J. Pharmacol.

    (1988)
  • G. Chen

    Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels

    Br. J. Pharmacol.

    (1988)
  • A.H. Huang

    Endothelium-dependent hyperpolarization of smooth muscle cells in rabbit femoral arteries is not mediated by EDRF (nitric oxide)

    Naunyn-Schmiedebergs Arch. Pharmacol.

    (1988)
  • T. Nagao et al.

    Hyperpolarisation as a mechanism for endothelium-dependent relaxations in the porcine coronary artery

    J. Physiol.

    (1992)
  • C.J. Garland et al.

    Evidence that nitric oxide does not mediate the hyperpolarisation and relaxation to acetylcholine in the rat small mesentery artery

    Br. J. Pharmacol.

    (1992)
  • C.L. Cowan et al.

    Two mechanisms mediate relaxation by bradykinin of pig coronary artery: NO-dependent and independent responses

    Am. J. Physiol.

    (1991)
  • J.V. Mombouli

    The potentiation of bradykinin-induced relaxations by perindoprilat in canine coronary arteries involves both nitric oxide and endothelium-derived hyperpolarizing factor

    Circ. Res.

    (1992)
  • J.J. McGuire

    Endothelium-derived relaxing factors: a focus on endothelium-derived hyperpolarizing factor(s)

    Can. J. Physiol. Pharmacol.

    (2001)
  • M.T. Nelson

    Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone

    Am. J. Physiol.

    (1990)
  • H. Shimokawa

    The importance of the hyperpolarizing mechanism increases as the vessel size decrease in endothelium-dependent relaxations in rat mesenteric circulation

    J. Cardiovasc. Pharmacol.

    (1996)
  • M. Félétou et al.

    Endothelium-derived hyperpolarizing factor

    Drug News Perspect.

    (1999)
  • G.J. Waldron

    Acetylcholine-induced relaxation of peripheral arteries isolated from mice lacking endothelial nitric oxide synthase

    Br. J. Pharmacol.

    (1999)
  • R.P. Brandes

    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 knock-out mice

    Proc. Natl. Acad. Sci. U. S. A.

    (2000)
  • A. Luckhoff

    Differential role of extra- and intracellular calcium in the release of EDRF and prostacyclin from cultured endothelial cells

    Br. J. Pharmacol.

    (1988)
  • A. Johns

    Role of calcium in the activation of endothelial cells

    J. Cardiovasc. Pharmacol.

    (1988)
  • S.C. Illiano

    Calmidazolium, a calmodulin inhibitor, inhibits endothelium-dependent relaxations resistant to nitro-l-arginine in the canine coronary artery

    Br. J. Pharmacol.

    (1992)
  • M. Fukao

    Thapsigargin- and cyclopiazonic acid-induced endothelium-dependent hyperpolarization in rat mesenteric artery

    Br. J. Pharmacol.

    (1995)
  • G. Chen et al.

    Calcium dependency of the endothelium-dependent hyperpolarisation in smooth muscle cells of the rabbit carotid artery

    J. Physiol.

    (1990)
  • B. Nilius et al.

    Ion channels and their functional role in vascular endothelium

    Physiol. Rev.

    (2001)
  • G. Chen et al.

    Some electrical properties of the endothelium-dependent hyperpolarisation recorded from rat arterial smooth muscle cells

    J. Physiol.

    (1989)
  • C.J. Garland et al.

    Relative importance of endothelium-derived hyperpolarizing factor for the relaxation of vascular smooth muscle in different arterial beds

  • P.M. Zygmunt et al.

    Role of potassium channels in endothelium-dependent relaxation resistant to nitroarginine in the rat hepatic artery

    Br. J. Pharmacol.

    (1996)
  • C. Corriu

    Endothelium-derived factors and hyperpolarisations of the isolated carotid artery of the guinea-pig

    Br. J. Pharmacol.

    (1996)
  • M.E. Murphy et al.

    Apamin-sensitive K+ channels mediate an endothelium-dependent hyperpolarization in rabbit mesenteric arteries

    J. Physiol.

    (1995)
  • H. Miura

    Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: contribution of nitric oxide and Ca2+-activated potassium channels

    Circulation

    (1999)
  • Y. Nishikawa

    In vivo location and mechanism of EDHF-mediated vasodilation in canine coronary microcirculation

    Am. J. Physiol.

    (1999)
  • A. Huang

    In eNOS knockout mice skeletal muscle arteriolar dilation to acetylcholine is mediated by EDHF

    Am. J. Physiol.

    (2000)
  • T. Chataigneau

    Epoxyeicosatrienoic acids, potassium channel blockers and endothelium-dependent hyperpolarisation in the guinea-pig carotid artery

    Br. J. Pharmacol.

    (1998)
  • S.M. Marchenko et al.

    Calcium-activated potassium channels in the endothelium of intact rat aorta

    J. Physiol.

    (1996)
  • S. Cai

    Single channel characterization of the pharmacological properties of the K(Ca2+) channel of intermediate conductance in bovine aortic endothelial cells

    J. Membr. Biol.

    (1998)
  • M.P. Burnham

    Characterization of an apamin-sensitive small conductance Ca2+-activated K+ channel in porcine coronary artery endothelium: relevance to EDHF

    Br. J. Pharmacol.

    (2002)
  • R. Busse

    Hyperpolarisation and increased free calcium in acetylcholine-stimulated endothelial cells

    Am. J. Physiol.

    (1988)
  • G. Edwards

    K+ is an endothelium-derived hyperpolarizing factor in rat arteries

    Nature

    (1998)
  • G. Edwards

    Role of gap junctions and EETs in endothelium-dependent hyperpolarization of porcine coronary artery

    Br. J. Pharmacol.

    (2000)
  • J.M. Doughty

    Charybdotoxin and apamin block EDHF in rat mesenteric artery if selectively applied to the endothelium

    Am. J. Physiol.

    (1999)
  • G. Edwards

    Further investigation of endothelium-derived hyperpolarizing factor (EDHF) in rat hepatic artery: studies using 1-EBIO and ouabain

    Br. J. Pharmacol.

    (1999)
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