Contribution of K+ channels to endothelium-derived hypolarization-induced renal vasodilation in rats in vivo and in vitro

  • Kasper Moller Boje Rasmussen
  • Thomas Hartig Braunstein
  • Max Salomonsson
  • Jens Christian Brasen
  • Charlotte Mehlin Sorensen
Integrative physiology

Abstract

We investigated the mechanisms behind the endothelial-derived hyperpolarization (EDH)-induced renal vasodilation in vivo and in vitro in rats. We assessed the role of Ca2+-activated K+ channels and whether K+ released from the endothelial cells activates inward rectifier K+ (Kir) channels and/or the Na+/K+-ATPase. Also, involvement of renal myoendothelial gap junctions was evaluated in vitro. Isometric tension in rat renal interlobar arteries was measured using a wire myograph. Renal blood flow was measured in isoflurane anesthetized rats. The EDH response was defined as the ACh-induced vasodilation assessed after inhibition of nitric oxide synthase and cyclooxygenase using L-NAME and indomethacin, respectively. After inhibition of small conductance Ca2+-activated K+ channels (SKCa) and intermediate conductance Ca2+-activated K+ channels (IKCa) (by apamin and TRAM-34, respectively), the EDH response in vitro was strongly attenuated whereas the EDH response in vivo was not significantly reduced. Inhibition of Kir channels and Na+/K+-ATPases (by ouabain and Ba2+, respectively) significantly attenuated renal vasorelaxation in vitro but did not affect the response in vivo. Inhibition of gap junctions in vitro using carbenoxolone or 18α-glycyrrhetinic acid significantly reduced the endothelial-derived hyperpolarization-induced vasorelaxation. We conclude that SKCa and IKCa channels are important for EDH-induced renal vasorelaxation in vitro. Activation of Kir channels and Na+/K+-ATPases plays a significant role in the renal vascular EDH response in vitro but not in vivo. The renal EDH response in vivo is complex and may consist of several overlapping mechanisms some of which remain obscure.

Keywords

Calcium activated K+ channels Endothelial-derived hyperpolarization Renal Vasodilation 

Notes

Acknowledgments

The skillful technical assistance of Ms. Cecilia Vallin, Ms. Nadia Soori, and Mr. Kristoffer Racz is gratefully acknowledged. We acknowledge the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen. This study was supported by the Danish National Research Foundation, the Danish Heart Foundation, and the A.P Møller Foundation for the Advancement of Medical Sciences.

References

  1. 1.
    Akata T, Nakashima M, Kodama K, Boyle WA III, Takahashi S (1995) Effects of volatile anesthetics on acetylcholine-induced relaxation in the rabbit mesenteric resistance artery. Anesthesiology 82:188–204CrossRefPubMedGoogle Scholar
  2. 2.
    Boedtkjer E, Kim S, Aalkjaer C (2013) Endothelial alkalinisation inhibits gap junction communication and endothelium-derived hyperpolarisations in mouse mesenteric arteries. J Physiol 591:1447–1461CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Boettcher M, de Wit C (2011) Distinct endothelium-derived hyperpolarizing factors emerge in vitro and in vivo and are mediated in part via connexin 40-dependent myoendothelial coupling. Hypertension 57:802–808CrossRefPubMedGoogle Scholar
  4. 4.
    Brahler S, Kaistha A, Schmidt VJ, Wolfle SE, Busch C, Kaistha BP, Kacik M, Hasenau AL, Grgic I, Si H, Bond CT et al (2009) Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension. Circulation 119:2323–2332CrossRefPubMedGoogle Scholar
  5. 5.
    Brasen JC, Jacobsen JC, Holstein-Rathlou NH (2012) The nanostructure of myoendothelial junctions contributes to signal rectification between endothelial and vascular smooth muscle cells. PLoS One 7:e33632CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bussemaker E, Popp R, Binder J, Busse R, Fleming I (2003) Characterization of the endothelium-derived hyperpolarizing factor (EDHF) response in the human interlobar artery. Kidney Int 63:1749–1755CrossRefPubMedGoogle Scholar
  7. 7.
    Bussemaker E, Wallner C, Fisslthaler B, Fleming I (2002) The Na-K-ATPase is a target for an EDHF displaying characteristics similar to potassium ions in the porcine renal interlobar artery. Br J Pharmacol 137:647–654CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Chaytor AT, Evans WH, Griffith TM (1998) Central role of heterocellular gap junctional communication in endothelium-dependent relaxations of rabbit arteries. J Physiol 508(Pt 2):561–573CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Chilton L, Loutzenhiser R (2001) Functional evidence for an inward rectifier potassium current in rat renal afferent arterioles. Circ Res 88:152–158CrossRefPubMedGoogle Scholar
  10. 10.
    Chilton L, Loutzenhiser K, Morales E, Breaks J, Kargacin GJ, Loutzenhiser R (2008) Inward rectifier K+ currents and Kir2.1 expression in renal afferent and efferent arterioles. J Am Soc Nephrol 19:69–76CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Crane GJ, Gallagher N, Dora KA, Garland CJ (2003) Small- and intermediate-conductance calcium-activated K+ channels provide different facets of endothelium-dependent hyperpolarization in rat mesenteric artery. J Physiol 553:183–189CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    De Vriese AS, Van DV, Lameire NH (2002) Effects of connexin-mimetic peptides on nitric oxide synthase- and cyclooxygenase-independent renal vasodilation. Kidney Int 61:177–185CrossRefPubMedGoogle Scholar
  13. 13.
    de Wit C, Roos F, Bolz SS, Kirchhoff S, Kruger O, Willecke K, Pohl U (2000) Impaired conduction of vasodilation along arterioles in connexin40-deficient mice. Circ Res 86:649–655CrossRefPubMedGoogle Scholar
  14. 14.
    de Wit C, Wolfle SE (2007) EDHF and gap junctions: important regulators of vascular tone within the microcirculation. Curr Pharm Biotechnol 8:11–25CrossRefPubMedGoogle Scholar
  15. 15.
    DeFelice AF, Brousseau A (1988) Natriuretic and vasodilating activities of intrarenally administered atriopeptin II, substance P and bradykinin in the dog. J Pharmacol Exp Ther 246:183–188PubMedGoogle Scholar
  16. 16.
    Dora KA, Martin PE, Chaytor AT, Evans WH, Garland CJ, Griffith TM (1999) Role of heterocellular Gap junctional communication in endothelium-dependent smooth muscle hyperpolarization: inhibition by a connexin-mimetic peptide. Biochem Biophys Res Commun 254:27–31CrossRefPubMedGoogle Scholar
  17. 17.
    Edgley AJ, Tare M, Evans RG, Skordilis C, Parkington HC (2008) In vivo regulation of endothelium-dependent vasodilation in the rat renal circulation and the effect of streptozotocin-induced diabetes. Am J Physiol Regul Integr Comp Physiol 295:R829–R839CrossRefPubMedGoogle Scholar
  18. 18.
    Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH (1998) K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396:269–272CrossRefPubMedGoogle Scholar
  19. 19.
    Edwards G, Feletou M, Weston AH (2010) Endothelium-derived hyperpolarising factors and associated pathways: a synopsis. Pflugers Arch 459:863–879CrossRefPubMedGoogle Scholar
  20. 20.
    Ellinsworth DC, Earley S, Murphy TV, Sandow SL (2014) Endothelial control of vasodilation: integration of myoendothelial microdomain signalling and modulation by epoxyeicosatrienoic acids. Pflugers Arch 466:389–405CrossRefPubMedGoogle Scholar
  21. 21.
    Falcone JC, Kuo L, Meininger GA (1993) Endothelial cell calcium increases during flow-induced dilation in isolated arterioles. Am J Physiol 264:H653–H659PubMedGoogle Scholar
  22. 22.
    Feletou M, Kohler R, Vanhoutte PM (2012) Nitric oxide: orchestrator of endothelium-dependent responses. Ann Med 44:694–716CrossRefPubMedGoogle Scholar
  23. 23.
    Gauthier KM, Spitzbarth N, Edwards EM, Campbell WB (2004) Apamin-sensitive K+ currents mediate arachidonic acid-induced relaxations of rabbit aorta. Hypertension 43:413–419CrossRefPubMedGoogle Scholar
  24. 24.
    Gebremedhin D, Kaldunski M, Jacobs ER, Harder DR, Roman RJ (1996) Coexistence of two types of Ca(2+)-activated K+ channels in rat renal arterioles. Am J Physiol 270:F69–F81PubMedGoogle Scholar
  25. 25.
    Iranami H, Hatano Y, Tsukiyama Y, Yamamoto M, Maeda H, Mizumoto K (1997) Halothane inhibition of acetylcholine-induced relaxation in rat mesenteric artery and aorta. Can J Anaesth 44:1196–1203CrossRefPubMedGoogle Scholar
  26. 26.
    Jackson WF (2005) Potassium channels in the peripheral microcirculation. Microcirculation 12:113–127CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Jiang F, Dusting GJ (2001) Endothelium-dependent vasorelaxation independent of nitric oxide and K(+) release in isolated renal arteries of rats. Br J Pharmacol 132:1558–1564CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jiang F, Li CG, Rand MJ (2000) Mechanisms of nitric oxide-independent relaxations induced by carbachol and acetylcholine in rat isolated renal arteries. Br J Pharmacol 130:1191–1200CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Knight DS, Beal JA, Yuan ZP, Fournet TS (1987) Substance P-immunoreactive nerves in the rat kidney. J Auton Nerv Syst 21:145–155CrossRefPubMedGoogle Scholar
  30. 30.
    Knight DS, Beal JA, Yuan ZP, Fournet TS (1987) Vasoactive intestinal peptide-immunoreactive nerves in the rat kidney. Anat Rec 219:193–203CrossRefPubMedGoogle Scholar
  31. 31.
    Knight DS, Cicero S, Beal JA (1991) Calcitonin gene-related peptide-immunoreactive nerves in the rat kidney. Am J Anat 190:31–40CrossRefPubMedGoogle Scholar
  32. 32.
    Ledoux J, Taylor MS, Bonev AD, Hannah RM, Solodushko V, Shui B, Tallini Y, Kotlikoff MI, Nelson MT (2008) Functional architecture of inositol 1,4,5-trisphosphate signaling in restricted spaces of myoendothelial projections. Proc Natl Acad Sci U S A 105:9627–9632CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lischke V, Busse R, Hecker M (1995) Inhalation anesthetics inhibit the release of endothelium-derived hyperpolarizing factor in the rabbit carotid artery. Anesthesiology 83:574–582CrossRefPubMedGoogle Scholar
  34. 34.
    Loeb AL, Godeny I, Longnecker DE (1997) Anesthetics alter relative contributions of NO and EDHF in rat cremaster muscle microcirculation. Am J Physiol 273:H618–H627PubMedGoogle Scholar
  35. 35.
    Magnusson L, Sorensen CM, Braunstein TH, Holstein-Rathlou NH, Salomonsson M (2011) Mechanisms of K(+) induced renal vasodilation in normo- and hypertensive rats in vivo. Acta Physiol (Oxf) 202:703–712CrossRefGoogle Scholar
  36. 36.
    Mink D, Schiller A, Kriz W, Taugner R (1984) Interendothelial junctions in kidney vessels. Cell Tissue Res 236:567–576CrossRefPubMedGoogle Scholar
  37. 37.
    Mishra RC, Tripathy S, Desai KM, Quest D, Lu Y, Akhtar J, Gopalakrishnan V (2008) Nitric oxide synthase inhibition promotes endothelium-dependent vasodilatation and the antihypertensive effect of L-serine. Hypertension 51:791–796CrossRefPubMedGoogle Scholar
  38. 38.
    Mulvany MJ, Halpern W (1977) Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 41:19–26CrossRefPubMedGoogle Scholar
  39. 39.
    Mustafa AK, Sikka G, Gazi SK, Steppan J, Jung SM, Bhunia AK, Barodka VM, Gazi FK, Barrow RK, Wang R, Amzel LM et al (2011) Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. Circ Res 109:1259–1268CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Nilius B, Droogmans G, Wondergem R (2003) Transient receptor potential channels in endothelium: solving the calcium entry puzzle? Endothelium 10:5–15CrossRefPubMedGoogle Scholar
  41. 41.
    Porter JP, Reid IA, Said SI, Ganong WF (1982) Stimulation of renin secretion by vasoactive intestinal peptide. Am J Physiol 243:F306–F310PubMedGoogle Scholar
  42. 42.
    Prysyazhna O, Rudyk O, Eaton P (2012) Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension. Nat Med 18:286–290CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Sandow SL, Neylon CB, Chen MX, Garland CJ (2006) Spatial separation of endothelial small- and intermediate-conductance calcium-activated potassium channels (K(Ca)) and connexins: possible relationship to vasodilator function? J Anat 209:689–698CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Shimokawa H (2014) 2014 Williams Harvey Lecture: importance of coronary vasomotion abnormalities—from bench to bedside. Eur Heart J 35:3180–3193CrossRefPubMedGoogle Scholar
  45. 45.
    Si H, Heyken WT, Wolfle SE, Tysiac M, Schubert R, Grgic I, Vilianovich L, Giebing G, Maier T, Gross V, Bader M et al (2006) Impaired endothelium-derived hyperpolarizing factor-mediated dilations and increased blood pressure in mice deficient of the intermediate-conductance Ca2+-activated K+ channel. Circ Res 99:537–544CrossRefPubMedGoogle Scholar
  46. 46.
    Simonet S, Isabelle M, Bousquenaud M, Clavreul N, Feletou M, Vayssettes-Courchay C, Verbeuren TJ (2012) KCa 3.1 channels maintain endothelium-dependent vasodilatation in isolated perfused kidneys of spontaneously hypertensive rats after chronic inhibition of NOS. Br J Pharmacol 167:854–867CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Siren AL, Feuerstein G (1988) Cardiovascular effects of rat calcitonin gene-related peptide in the conscious rat. J Pharmacol Exp Ther 247:69–78PubMedGoogle Scholar
  48. 48.
    Sorensen CM, Braunstein TH, Holstein-Rathlou NH, Salomonsson M (2012) Role of vascular potassium channels in the regulation of renal hemodynamics. Am J Physiol Renal Physiol 302:F505–F518CrossRefPubMedGoogle Scholar
  49. 49.
    Steendahl J, Holstein-Rathlou NH, Sorensen CM, Salomonsson M (2004) Effects of chloride channel blockers on rat renal vascular responses to angiotensin II and norepinephrine. Am J Physiol Renal Physiol 286:F323–F330CrossRefPubMedGoogle Scholar
  50. 50.
    Taugner R, Kirchheim H, Forssmann WG (1984) Myoendothelial contacts in glomerular arterioles and in renal interlobular arteries of rat, mouse and Tupaia belangeri. Cell Tissue Res 235:319–325CrossRefPubMedGoogle Scholar
  51. 51.
    Waeckel L, Bertin F, Clavreul N, Damery T, Kohler R, Paysant J, Sansilvestri-Morel P, Simonet S, Vayssettes-Courchay C, Wulff H, Verbeuren TJ et al (2015) Preserved regulation of renal perfusion pressure by small and intermediate conductance KCa channels in hypertensive mice with or without renal failure. Pflugers Arch 467:817–831CrossRefPubMedGoogle Scholar
  52. 52.
    Wang D, Borrego-Conde LJ, Falck JR, Sharma KK, Wilcox CS, Umans JG (2003) Contributions of nitric oxide, EDHF, and EETs to endothelium-dependent relaxation in renal afferent arterioles. Kidney Int 63:2187–2193CrossRefPubMedGoogle Scholar
  53. 53.
    Wang X, Loutzenhiser R (2002) Determinants of renal microvascular response to ACh: afferent and efferent arteriolar actions of EDHF. Am J Physiol Renal Physiol 282:F124–F132CrossRefPubMedGoogle Scholar
  54. 54.
    Wang X, Trottier G, Loutzenhiser R (2003) Determinants of renal afferent arteriolar actions of bradykinin: evidence that multiple pathways mediate responses attributed to EDHF. Am J Physiol Renal Physiol 285:F540–F549CrossRefPubMedGoogle Scholar
  55. 55.
    Wolfle SE, Schmidt VJ, Hoyer J, Kohler R, de Wit C (2009) Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo. Cardiovasc Res 82:476–483CrossRefPubMedGoogle Scholar
  56. 56.
    Yamamoto Y, Imaeda K, Suzuki H (1999) Endothelium-dependent hyperpolarization and intercellular electrical coupling in guinea-pig mesenteric arterioles. J Physiol 514(Pt 2):505–513CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yi L, Morgan JT, Ragsdale SW (2010) Identification of a thiol/disulfide redox switch in the human BK channel that controls its affinity for heme and CO. J Biol Chem 285:20117–20127CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Institute of Biomedical Sciences, Division of Renal and Vascular PhysiologyUniversity of CopenhagenCopenhagenDenmark
  2. 2.Department of Electrical EngineeringTechnical University of DenmarkKgs. LyngbyDenmark

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