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Endothelium-derived hyperpolarising factors and associated pathways: a synopsis

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Abstract

The term endothelium-derived hyperpolarising factor (EDHF) was introduced in 1987 to describe the hypothetical factor responsible for myocyte hyperpolarisations not associated with nitric oxide (EDRF) or prostacyclin. Two broad categories of EDHF response exist. The classical EDHF pathway is blocked by apamin plus TRAM-34 but not by apamin plus iberiotoxin and is associated with endothelial cell hyperpolarisation. This follows an increase in intracellular [Ca2+] and the opening of endothelial SKCa and IKCa channels preferentially located in caveolae and in endothelial cell projections through the internal elastic lamina, respectively. In some vessels, endothelial hyperpolarisations are transmitted to myocytes through myoendothelial gap junctions without involving any EDHF. In others, the K+ that effluxes through SKCa activates myocytic and endothelial Ba2+-sensitive KIR channels leading to myocyte hyperpolarisation. K+ effluxing through IKCa activates ouabain-sensitive Na+/K+-ATPases generating further myocyte hyperpolarisation. For the classical pathway, the hyperpolarising “factor” involved is the K+ that effluxes through endothelial KCa channels. During vessel contraction, K+ efflux through activated myocyte BKCa channels generates intravascular K+ clouds. These compromise activation of Na+/K+-ATPases and KIR channels by endothelium-derived K+ and increase the importance of gap junctional electrical coupling in myocyte hyperpolarisations. The second category of EDHF pathway does not require endothelial hyperpolarisation. It involves the endothelial release of factors that include NO, HNO, H2O2 and vasoactive peptides as well as prostacyclin and epoxyeicosatrienoic acids. These hyperpolarise myocytes by opening various populations of myocyte potassium channels, but predominantly BKCa and/or KATP, which are sensitive to blockade by iberiotoxin or glibenclamide, respectively.

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Acknowledgements

GE and AHW acknowledge the generous support of the British Heart Foundation in their studies over many years.

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  1. Faculty of Life Sciences, University of Manchester, CTF Building, 46 Grafton St, Manchester, M13 9NT, UK

    Gillian Edwards & Arthur H. Weston

  2. Département Angiologie, Institut de Recherches Servier, 11 rue des Moulineaux, 92150, Suresnes, France

    Michel Félétou

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  1. Gillian Edwards
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Correspondence to Arthur H. Weston.

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Edwards, G., Félétou, M. & Weston, A.H. Endothelium-derived hyperpolarising factors and associated pathways: a synopsis. Pflugers Arch - Eur J Physiol 459, 863–879 (2010). https://doi.org/10.1007/s00424-010-0817-1

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