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

Nature volume 396, pages 269–272 (1998)Cite this article

Abstract

In arteries, muscarinic agonists such as acetylcholine release an unidentified, endothelium-derived hyperpolarizing factor (EDHF) which is neither prostacyclin nor nitric oxide1,2,3. Here we show that EDHF-induced hyperpolarization of smooth muscle and relaxation of small resistance arteries are inhibited by ouabain plus Ba2+; ouabain is a blocker of Na+/K+ ATPase4 and Ba2+ blocks inwardly rectifying K+ channels5. Small increases in the amount of extracellular K+ mimic these effects of EDHF in a ouabain- and Ba2+-sensitive, but endothelium-independent, manner. Acetylcholine hyperpolarizes endothelial cells and increases the K+ concentration in the myoendothelial space; these effects are abolished by charbdotoxin plus apamin. Hyperpolarization of smooth muscle by EDHF is also abolished by this toxin combination, but these toxins do not affect the hyperpolarizaiton of smooth muscle by added K+. These data show that EDHF is K+ that effluxes through charybdotoxin- and apamin-sensitive K+ channels on endothelial cells. The resulting increase in myoendothelial K+ concentration hyperpolarizes and relaxes adjacent smooth-muscle cells by activating Ba2+-sensitive K+ channels and Na+/K+ ATPase. These results show that fluctuations in K+ levels originating within the blood vessel itself are important in regulating mammalian blood pressure and flow.

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Figure 1: Profiles of EDHF- and K+-induced hyperpolarizations in hepatic artery.
Figure 2: Determination of the myoendothelial K+ concentration in endothelium-intact hepatic arteries using a K+-sensitive microelectrode.
Figure 3: Comparison of EDHF- and K+-induced relaxations and identification of inwardly rectifying K+ currents (I K(IR)) in hepatic artery.
Figure 4: Comparison of the effects of EDHF and K+ in small mesenteric arteries with an intact endothelium (+E).

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Acknowledgements

We thank D. Beech, J.-L. Bény, M. Félétou, S. Greenwood, N. Standen, A. Wareham and A. Schwab for advice. This work was supported by the British Heart Foundation, the MRC and the Wellcome Trust.

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Authors and Affiliations

  1. Division of Physiology, Pharmacology and Toxicology, School of Biological Sciences, G38 Stopford Building, University of Manchester, Manchester, M13 9PT, UK

    G. Edwards, M. J. Gardener & A. H. Weston

  2. Department of Pharmacology, University of Bristol, Bristol, BS8 1TD, UK

    K. A. Dora & C. J. Garland

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  1. G. Edwards
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Correspondence to A. H. Weston.

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Edwards, G., Dora, K., Gardener, M. et al. K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396, 269–272 (1998). https://doi.org/10.1038/24388

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