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Circulation Research. 2001;88:132-133

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(Circulation Research. 2001;88:132.)
© 2001 American Heart Association, Inc.

Editorials

Potassium Ions as Vasodilators: Role of Inward Rectifier Potassium Channels

Delrae M. Eckman, Mark T. Nelson

From the Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vt.

Correspondence to Mark T. Nelson, PhD, Department of Pharmacology, Given Building, B326, University of Vermont College of Medicine, Burlington, VT 05405. E-mail nelson{at}salus.med.uvm.edu


Key Words: kidney • afferent arteriole • potassium channels • renal arterioles


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
External potassium ions have long been known as mediators of vasodilation of several vascular beds, including the coronary and cerebral circulations.1 2 3 4 5 6 Indeed, potassium ions have been viewed as communicators of the metabolic state of the cells that surround blood vessels. For example, release of potassium ions from neurons is communicated through glial cells to regulate cerebral artery diameter.7 Recently, it has been suggested that the potassium ions from endothelial cells may signal smooth muscle to relax and, as such, may constitute an endothelial-derived hyperpolarizing factor.8

Two targets of external potassium ions have been proposed: the Na+/K+ ATPase and the inward rectifier potassium channel.1 5 9 An elevation of external potassium causes very different responses of these two molecular targets. The electrogenic Na+/K+ ATPase is activated by external potassium with a half-activation constant of about 1 to 2 mmol/L10 and saturation above 5 mmol/L.11 12 Activation of the Na+/K+ ATPase by elevating external potassium from nominally 0 to 5 mmol/L causes transient hyperpolarization and dilation5 ; the transient nature presumably reflects the extrusion of sodium until a new steady state is reached. In contrast, elevation of external potassium causes a graded shift in the apparent voltage-dependence of the inward rectifier potassium channel conductance,13 which can lead to a maintained hyperpolarization and dilation.14 Unfortunately, the dissection of these pathways until recently has relied on two imperfect pharmacological probes: cardiotonic steroids, such as ouabain, and barium ions. Inhibition of the Na+/K+ ATPase with ouabain leads to a membrane potential depolarization, an elevation in intracellular sodium and calcium, and several other changes downstream from these events. This complicates the interpretation of ouabain effects, unless it has no effect on potassium-induced hyperpolarization and dilations.14 Barium ions block inward rectifier potassium channels with a relatively high affinity of {approx}10 µmol/L at physiological membrane potentials.13 Nonetheless, barium ions block other ion channels at higher concentrations. These problems have been obviated by the use of inward rectifier knockout mice, which have been shown to lack potassium-induced dilations.15

Much of the research on potassium-induced dilations has focused on the cerebral and coronary circulation. Small increases in circulating potassium ions in vivo dilate and increase cerebral flow.4 16 17 Recently, Chrissabolis et al17 demonstrated that cerebral artery dilations in vivo to elevated K+ in cerebral spinal fluid were Ba2+-sensitive and insensitive to ouabain, strongly supporting a role for inward rectifier potassium channels. In the cerebral vasculature, elevations in K+ ions increase with neuronal activity and during stresses such as cerebral hypoxia, ischemia, and hypoglycemia.7 16 18 K+-induced dilations have also been reported in coronary arteries.1 K+ ions are normally released from cardiac cells during increased workload and particularly under ischemia.19 20 21 In the kidney, elevated potassium ({approx}10 mmol/L) or acute hyperkalemia have been shown to increase renal blood flow and glomerular filtration rate.22 23

In a study in this issue of Circulation Research, Chilton and Loutzenhiser24 have explored the role of inward rectifier potassium channels in K+-induced dilations of rat renal afferent arterioles, using the hydronephrotic kidney model. This model permits visualization of the renal microvasculature under normal flow and pressure conditions. Loutzenhiser et al25 have taken this model one step further and developed a method for measuring stable membrane potentials while simultaneously measuring diameter of intact afferent arterioles in the intact kidney. In pressurized afferent arterioles, increasing [K+]o from 5 to 15 mmol/L resulted in Ba2+-sensitive dilations. In the presence of the {alpha}-adrenoceptor blockers, K+-induced dilations were also abolished by chloroethylclonidine (CEC). CEC has been shown to inhibit native inwardly rectifying potassium channels (Kir) in skeletal muscle (rat flexor digitorium brevis) as well as Kir2.1 channels expressed in the MEL cell line.26 Neither the KATP channel inhibitor glibenclamide nor ouabain inhibited K+-induced dilations in the afferent arteriole. Ba2+ depolarized and constricted afferent arterioles at low pressures, suggesting a role for Kir channels in regulating membrane potential. The Chilton and Loutzenhiser24 study, along with studies on the cerebral and coronary circulations,14 15 17 27 strongly supports the idea that the inward rectifier potassium channel, in particular the Kir2.1 subtype,28 is a molecular target for external potassium-induced vasodilation.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
up arrowTop
 up arrowIntroduction
 *References
 

  1. Buenger R, Haddy FJ, Querengasser A, Eckehart G. Studies on potassium induced coronary dilation in the isolated guinea pig heart. Pflügers Arch. 1976;363:27–31.
  2. Kuschinsky W, Wahl M, Bosse O, Thurau K. Perivascular potassium and pH as determinants of local pial arterial diameter in cats. Circ Res. 1972;31:240–247.[Abstract/Free Full Text]
  3. Edwards FR, Hirst GDS, Silverberg GD. Inward rectification in rat cerebral arterioles; involvement of potassium ions in autoregulation. J Physiol (Lond). 1988;404:455–466.[Abstract/Free Full Text]
  4. Fujii K, Heistad DD, Faraci FM. Ionic mechanisms in spontaneous vasomotion of the rat basilar artery in vivo. J Physiol (Lond). 1990;430:389–398.[Abstract/Free Full Text]
  5. McCarron JG, Halpern W. Potassium dilates rat cerebral arteries by two independent mechanisms. Am J Physiol. 1990;259:H902–H908.[Abstract/Free Full Text]
  6. Haddy FJ, Scott JB. Metabolically linked vasoactive chemicals in local regulation of blood flow. Physiol Rev. 1968;48:688–707.[Free Full Text]
  7. Paulson OB, Newman EA. Does the release of potasium from astrocyte endfeet regulate cerebral blood flow? Science. 1987;237:896–898.[Abstract/Free Full Text]
  8. Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH. K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature. 1998;396:269–272.[Medline] [Order article via Infotrieve]
  9. Chen WT, Brace RA, Scott JB, Anderson DK, Haddy FJ. The mechanism of the vasodilator mechanism of potassium. Proc Soc Exp Biol Med. 1972;140:820–824.[Medline] [Order article via Infotrieve]
  10. Nakamura Y, Ohya Y, Abe I, Fujishima M. Sodium-potassium pump current in smooth muscle cells from mesenteric resistance arteries of the guinea-pig. J Physiol (Lond). 1999;519:203–212.[Abstract/Free Full Text]
  11. Hexum TD. Characterization of the Na+/K+ ATPase from vascular smooth muscle. Gen Pharmacol. 1981;12:393–396.[Medline] [Order article via Infotrieve]
  12. Nakao M, Gadsby DC. [Na] and [K] dependence of the Na/K pump current-voltage relationship in guinea pig ventricular myocytes. J Gen Physiol. 1989;94:539–566.[Abstract/Free Full Text]
  13. Quayle JM, Nelson MT, Standen NB. ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev. 1997;77:1165–1232.[Abstract/Free Full Text]
  14. Knot HJ, Zimmerman PA, Nelson MT. Extracellular K+-induced hyperpolarizations and dilatations of rat coronary and cerebral arteries involve inward rectifier K+ channels. J Physiol (Lond). 1996;492:419–430.[Medline] [Order article via Infotrieve]
  15. Zaritsky JJ, Eckman DM, Wellman GC, Nelson MT, Schwarz TL. Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K+ current in K+-mediated vasodilation. Circ Res. 2000;87:160–166.[Abstract/Free Full Text]
  16. Sieber FE, Wilson DA, Hanley DE, Traystman RJ. Extracellular potassium activity and cerebral blood flow during moderate hypoglycemia in anesthetized dogs. Am J Physiol. 1993;264:H1774–H1780.[Abstract/Free Full Text]
  17. Chrissobolis S, Ziogas J, Chu Y, Faraci FM, Sobey CG. Role of inwardly rectifying K+ channels in K+-induced cerebral vasodilation in vivo. Am J Physiol. 2000;279:H2704–H2712.[Abstract/Free Full Text]
  18. Somjen GG. Extracellular potassium in the mammalian central nervous system. Annu Rev Physiol. 1979;41:159–177.[Medline] [Order article via Infotrieve]
  19. Kléber A. Resting membrane potential, extracellular potassium activity, and intracellular sodium activity during acute global ischemia in isolated perfused guinea pig heart. Circ Res. 1983;52:442–450.[Abstract/Free Full Text]
  20. Weiss JN, Lamp ST, Shine KI. Cellular K+ loss and anion efflux during myocardial ischemia and metabolic inhibition. Am J Physiol. 1989;256:H1165–H1175.[Abstract/Free Full Text]
  21. Warner MR, Kroeker TS, Zipes DP. Sympathetic stimulation and norepinephrine infusion modulate extracellular potassium concentration during acute myocardial ischemia. Circ Res. 1992;71:1078–1087.[Abstract/Free Full Text]
  22. Scott J, Emanuel D, Haddy F. Effect of potassium on renal vascular resistance and urine flow rate. Am J Physiol. 1959;197:305–308.
  23. Budtz-Olsen OE, Clark RC, Cross RB, French TJ. Changes in renal haemodynamics and electrolyte excretion during acute hyperkalemia in conscious adrenectomized sheep. Quarterly J Exp Physiol Cogn Med Sci. 1975;60:207–221.
  24. Chilton L, Loutzenhiser R. Functional evidence for an inward rectifier potassium current in rat renal afferent arterioles. Circ Res. 2001;88:152–158.[Abstract/Free Full Text]
  25. Loutzenhiser R, Chilton L, Trottier G. Membrane potential measurements in renal afferent and efferent arterioles: actions of angiotensin II. Am J Physiol. 1997;273:F307–F308.[Abstract/Free Full Text]
  26. Barrett-Jolley R, Dart C, Standen NB. Direct block of native and cloned (Kir2.1) inward rectifier K+ channels by chloroethylclonidine. Br J Pharmacol. 1999;128:760–766.[Medline] [Order article via Infotrieve]
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  28. Bradley KK, Jaggar JH, Bonev AD, Heppner TJ, Flynn ERM, Nelson MT, Horowitz B. Kir2.1 encodes the inward rectifier potassium channel in rat arterial smooth muscle cells. J Physiol (Lond). 1999;515:639–651.[Abstract/Free Full Text]



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*BARIUM COMPOUNDS
*BARIUM, ELEMENTAL
*POTASSIUM
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Right arrow Ion channels/membrane transport

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