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      Inward rectifier potassium (Kir2.1) channels as end‐stage boosters of endothelium‐dependent vasodilators

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          Abstract

          Key points

          • Increase in endothelial cell (EC) calcium activates calcium‐sensitive intermediate and small conductance potassium (IK and SK) channels, thereby causing hyperpolarization and endothelium‐dependent vasodilatation.

          • Endothelial cells express inward rectifier potassium (Kir) channels, but their role in endothelium‐dependent vasodilatation is not clear.

          • In the mesenteric arteries, only ECs, but not smooth muscle cells, displayed Kir currents that were predominantly mediated by the Kir2.1 isoform.

          • Endothelium‐dependent vasodilatations in response to muscarinic receptor, TRPV4 (transient receptor potential vanilloid 4) channel and IK/SK channel agonists were highly attenuated by Kir channel inhibitors and by Kir2.1 channel knockdown.

          • These results point to EC Kir channels as amplifiers of vasodilatation in response to increases in EC calcium and IK/SK channel activation and suggest that EC Kir channels could be targeted to treat endothelial dysfunction, which is a hallmark of vascular disorders.

          Abstract

          Endothelium‐dependent vasodilators, such as acetylcholine, increase intracellular Ca 2+ through activation of transient receptor potential vanilloid 4 (TRPV4) channels in the plasma membrane and inositol trisphosphate receptors in the endoplasmic reticulum, leading to stimulation of Ca 2+‐sensitive intermediate and small conductance K + (IK and SK, respectively) channels. Although strong inward rectifier K + (Kir) channels have been reported in the native endothelial cells (ECs) their role in EC‐dependent vasodilatation is not clear. Here, we test the idea that Kir channels boost the EC‐dependent vasodilatation of resistance‐sized arteries. We show that ECs, but not smooth muscle cells, of small mesenteric arteries have Kir currents, which are substantially reduced in EC‐specific Kir2.1 knockdown (EC‐ Kir2.1 −/−) mice. Elevation of extracellular K + to 14 m m caused vasodilatation of pressurized arteries, which was prevented by endothelial denudation and Kir channel inhibitors (Ba 2+, ML‐133) or in the arteries from EC‐ Kir2.1 −/− mice. Potassium‐induced dilatations were unaffected by inhibitors of TRPV4, IK and SK channels. The Kir channel blocker, Ba 2+, did not affect currents through TRPV4, IK or SK channels. Endothelial cell‐dependent vasodilatations in response to activation of muscarinic receptors, TRPV4 channels or IK/SK channels were reduced, but not eliminated, by Kir channel inhibitors or EC‐ Kir2.1 −/−. In angiotensin II‐induced hypertension, the Kir channel function was not altered, although the endothelium‐dependent vasodilatation was severely impaired. Our results support the concept that EC Kir2 channels boost vasodilatory signals that are generated by Ca 2+‐dependent activation of IK and SK channels.

          Key points

          • Increase in endothelial cell (EC) calcium activates calcium‐sensitive intermediate and small conductance potassium (IK and SK) channels, thereby causing hyperpolarization and endothelium‐dependent vasodilatation.

          • Endothelial cells express inward rectifier potassium (Kir) channels, but their role in endothelium‐dependent vasodilatation is not clear.

          • In the mesenteric arteries, only ECs, but not smooth muscle cells, displayed Kir currents that were predominantly mediated by the Kir2.1 isoform.

          • Endothelium‐dependent vasodilatations in response to muscarinic receptor, TRPV4 (transient receptor potential vanilloid 4) channel and IK/SK channel agonists were highly attenuated by Kir channel inhibitors and by Kir2.1 channel knockdown.

          • These results point to EC Kir channels as amplifiers of vasodilatation in response to increases in EC calcium and IK/SK channel activation and suggest that EC Kir channels could be targeted to treat endothelial dysfunction, which is a hallmark of vascular disorders.

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          Author and article information

          Journal
          J Physiol
          J. Physiol. (Lond.)
          10.1111/(ISSN)1469-7793
          TJP
          jphysiol
          The Journal of Physiology
          John Wiley and Sons Inc. (Hoboken )
          0022-3751
          1469-7793
          04 March 2016
          15 June 2016
          : 594
          : 12 ( doiID: 10.1113/tjp.2016.594.issue-12 )
          : 3271-3285
          Affiliations
          [ 1 ] Department of Pharmacology University of Vermont VT USA
          [ 2 ] Department of Molecular Physiology and Biological Physics University of Virginia VA USA
          [ 3 ] Robert M. Berne Cardiovascular Research Center University of Virginia VA USA
          [ 4 ] Institute of Cardiovascular Sciences University of Manchester Manchester UK
          Author notes
          [*] [* ] Corresponding author S. K. Sonkusare: 409 Lane Road, Room 6051A, Medical Research Building 4 (MR4), Charlottesville, VA 22908, USA. Email: sks2n@ 123456virginia.edu
          Article
          PMC4908010 PMC4908010 4908010 TJP7105
          10.1113/JP271652
          4908010
          26840527
          4c81db03-074d-4742-9ae5-b9d6ed0a214b
          © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society
          History
          : 29 September 2015
          : 20 January 2016
          Page count
          Pages: 15
          Categories
          Cardiovascular Physiology
          Vasculature
          Research Paper
          Cardiovascular
          Custom metadata
          2.0
          tjp7105
          15 June 2016
          Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:14.06.2016

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