Editorials |
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 |
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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
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 (
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
-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 |
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| References |
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2.
Kuschinsky W, Wahl
M, Bosse O, Thurau K. Perivascular potassium and pH as determinants of
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3.
Edwards FR, Hirst
GDS, Silverberg GD. Inward rectification in rat cerebral arterioles;
involvement of potassium ions in autoregulation.
J Physiol (Lond). 1988;404:455466.
4.
Fujii K, Heistad
DD, Faraci FM. Ionic mechanisms in spontaneous vasomotion of the rat
basilar artery in vivo. J Physiol
(Lond). 1990;430:389398.
5.
McCarron JG,
Halpern W. Potassium dilates rat cerebral arteries by two independent
mechanisms. Am J Physiol. 1990;259:H902H908.
6.
Haddy FJ, Scott JB.
Metabolically linked vasoactive chemicals in local regulation of blood
flow. Physiol Rev. 1968;48:688707.
7.
Paulson OB, Newman
EA. Does the release of potasium from astrocyte endfeet regulate
cerebral blood flow? Science. 1987;237:896898.
8. Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH. K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature. 1998;396:269272.[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;140:820824.[Medline] [Order article via Infotrieve]
10.
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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;519:203212.
11. Hexum TD. Characterization of the Na+/K+ ATPase from vascular smooth muscle. Gen Pharmacol. 1981;12:393396.[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;94:539566.
13.
Quayle JM, Nelson
MT, Standen NB. ATP-sensitive and inwardly rectifying potassium
channels in smooth muscle. Physiol
Rev. 1997;77:11651232.
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;492:419430.
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;87:160166.
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:H1774H1780.
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:H2704H2712.
18. Somjen GG. Extracellular potassium in the mammalian central nervous system. Annu Rev Physiol. 1979;41:159177.[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;52:442450.
20.
Weiss JN, Lamp
ST, Shine KI. Cellular K+ loss and anion
efflux during myocardial ischemia and metabolic inhibition.
Am J Physiol. 1989;256:H1165H1175.
21.
Warner MR,
Kroeker TS, Zipes DP. Sympathetic stimulation and norepinephrine
infusion modulate extracellular potassium concentration during acute
myocardial ischemia. Circ Res. 1992;71:10781087.
22. Scott J, Emanuel D, Haddy F. Effect of potassium on renal vascular resistance and urine flow rate. Am J Physiol. 1959;197:305308.
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;60:207221.
24.
Chilton L,
Loutzenhiser R. Functional evidence for an inward rectifier potassium
current in rat renal afferent arterioles.
Circ Res. 2001;88:152158.
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:F307F308.
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;128:760766.[Medline] [Order article via Infotrieve]
27. Golding EM, Steenberg ML, Johnson TD, Bryan RM. The effects of potassium on the rat middle cerebral artery. Brain Res. 2000;880:159166.[Medline] [Order article via Infotrieve]
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;515:639651.
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