© 2001 American Heart Association, Inc.
Integrative Physiology |
Functional Roles of Cardiac and Vascular ATP-Sensitive Potassium Channels Clarified by Kir6.2-Knockout Mice
From the Department of Pharmacology (M.S., H.U., N.S., Y.O.-S., M.T., T.O., H.N.), Chiba University School of Medicine, and Department of Molecular Medicine (T.M., S.S.), Chiba University Graduate School of Medicine, Chiba, Japan, and Institute of Molecular Cardiobiology (R.A.L., E.M.), The Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Haruaki Nakaya, M.D., Ph.D., Department of Pharmacology, Chiba University School of Medicine, Inohana 1-8-1, Chuo-Ku, Chiba 260-8670, Japan. E-mail nakaya{at}med.m.chiba-u.ac.jp
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Abstract |
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Abstract—ATP-sensitive potassium (KATP) channels were discovered in ventricular cells, but their roles in the heart remain mysterious. KATP channels have also been found in numerous other tissues, including vascular smooth muscle. Two pore-forming subunits, Kir6.1 and Kir6.2, contribute to the diversity of KATP channels. To determine which subunits are operative in the cardiovascular system and their functional roles, we characterized the effects of pharmacological K+ channel openers (KCOs, ie, pinacidil, P-1075, and diazoxide) in Kir6.2-deficient mice. Sarcolemmal KATP channels could be recorded electrophysiologically in ventricular cells from Kir6.2+/+ (wild-type [WT]) but not from Kir6.2-/- (knockout [KO]) mice. In WT ventricular cells, pinacidil induced an outward current and action potential shortening, effects that were blocked by glibenclamide, a KATP channel blocker. KO ventricular cells exhibited no response to KCOs, but gene transfer of Kir6.2 into neonatal ventricular cells rescued the electrophysiological response to P-1075. In terms of contractile function, pinacidil decreased force generation in WT but not KO hearts. Pinacidil and diazoxide produced concentration-dependent relaxation in both WT and KO aortas precontracted with norepinephrine. In addition, pinacidil induced a glibenclamide-sensitive current of similar magnitude in WT and KO aortic smooth muscle cells and comparable levels of hypotension in anesthetized WT and KO mice. In both WT and KO aortas, only Kir6.1 mRNA was expressed. These findings indicate that the Kir6.2 subunit mediates the depression of cardiac excitability and contractility induced by KCOs; in contrast, Kir6.2 plays no discernible role in the arterial tree.
Key Words: gene targeting • heart • vascular smooth muscle • ATP-sensitive K+ current • action potential
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Introduction |
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ATP-sensitive K+ (KATP) channels, originally discovered in cardiac myocytes,1 have been described in many other tissues including pancreatic ß cells, skeletal and smooth muscle cells, and neurons.2 3 4 5 They play important roles in the physiology and pathophysiology of various tissues by coupling the metabolic state of the cell to its electrical activity.6 Recent progress in molecular biology and electrophysiology resulted in cloning of KATP channel genes and elucidation of their subunit composition.7 8 KATP channels are assembled with a hetero-octameric stoichiometry from the following 2 structurally distinct subunits: an inwardly rectifying potassium channel subunit forming the pore (Kir6.X) and a regulatory subunit, a sulfonylurea receptor (SUR) belonging to the ATP binding cassette superfamily.9 10 11 The pancreatic ß-cell KATP channels have been shown to consist of SUR1 and Kir6.2.10 In fact, our previous report indicated that insulin secretion in response to glucose or sulfonylurea was absent in pancreatic ß cells from KATP channel–deficient mice generated by genetic disruption of Kir6.2.12 Cardiac KATP channels are thought to be formed by SUR2A and Kir6.2, because coexpression of these clones in a cell line reconstitutes the basic electrophysiological and pharmacological properties of the native cardiac channel.11 In terms of vascular KATP channels, Isomoto et al13 showed that coexpression of Kir6.2 and SUR2B, a splice variant of SUR2A, reconstituted the pharmacological and electrophysiological properties of KATP channels described in some smooth muscle cells. Indeed, it has been suggested that KATP channels of smooth muscle cells of murine colon14 and guinea pig bladder15 comprise SUR2B and Kir6.2. However, Yamada et al16 have suggested that K+ channel composed of SUR2B and Kir6.1 closely resembles the NDP-dependent K+ (KNDP) channel observed in vascular smooth muscle cells. To clarify the functional role(s) of a defined KATP-channel subunit in cardiac and vascular tissues, we studied KATP channel-deficient mice (Kir6.2-/-) produced by knockout (KO) of the Kir6.2 gene. We find that Kir6.2 is essential for the depression of cardiac excitation and contraction, but not for vasodilation, in response to K+ channel openers (KCOs), highlighting major functional and genetic distinctions between cardiac and vascular KATP channels.
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Materials and Methods |
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Kir6.2-/- Mice
All procedures complied with the standards for the care and use of animal subjects as stated in the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23, revised 1996). A mouse line deficient in KATP channel was generated by targeted disruption of the gene coding for Kir6.2, as described previously.12 C57BL/6 mice were used as control because they had been backcrossed to a C57BL/6 strain for 5 generations.
Electrophysiology
Adult Ventricular Cells
Single ventricular cells of the adult
mouse heart were isolated by conventional enzymatic digestion.
Single-channel and whole-cell membrane currents were recorded by
the patch-clamp method as previously
described.17 18
For single-channel recordings from the open cell-attached
patches, symmetrical high-K+ pipette
solution (solution A) and internal solution (solution B) were used.
After the gigaohm seal formation, part of the surface membrane of a
rod-shaped cell was disrupted by penetrating the membrane with a glass
pipette (1 to 2 µm in tip diameter) and the ruptured cell was exposed
to the solution containing only a trace amount of ATP (solution B). The
single-channel currents were recorded at room temperature and
analyzed with pClamp software (version 5.5, Axon
Instruments).
Whole-cell current recordings were performed at 36.0°C using glass patch pipettes filled with solution C (pCa 8.0). The external solution used was HEPES-Tyrode solution (solution D). A liquid junction potential between the internal solution and the bath solution of -8 mV was corrected. A ramp pulse protocol was used to record the quasi–steady-state membrane current as previously described.18 Current-clamp experiments were also performed in the whole-cell recording mode at 36.0°C.
Isolation of Neonatal Ventricular
Myocytes and Viral Gene Transfer
Neonatal (1- to 2-day-old)
ventricular myocytes were prepared by trypsin digestion as
previously described.19
Briefly, ventricles of a single litter of mouse pups (
10, 1 to 2
days old) were aseptically removed immediately after decapitation.
Isolated hearts were pooled, minced, and digested at room temperature
with trypsin. After digestion, cells were centrifuged, plated
at low density (2x105 cells
mL-1), and
incubated at 37°C in a humidified atmosphere of
95%O2/5%CO2.
The ecdysone-inducible recombinant adenovirus (AdKir6.2) carrying the wild-type (WT) Kir6.2 channel and the reporter (enhanced green fluorescent protein) genes were generated by Cre-lox recombination.20 21 22 Neonatal myocytes were coinfected with the channel virus AdKir6.2 and the hormone receptor virus AdVgRXR (ratio=1:10) at a final concentration of 10 000 particles mL-1. Protein expression was induced by adding 1 mmol/L ponasterone A (Invitrogen) to the culture medium.
Electrical recordings were performed at room temperature after 72 hours in culture using the whole-cell patch clamp technique with a pipette solution (solution E) and a bath solution (solution F). Only successfully infected cells, as identified by their green fluorescence using epifluorescent microscopy, were selected for experiments.
Vascular Smooth Muscle Cells
Single smooth muscle cells were enzymatically
isolated from the adult mouse aorta, and the membrane currents were
recorded at room temperature using the whole-cell patch clamp
technique with high-K+ HEPES-buffered bath
solution (solution G) and pipette solution (solution
H).
Mechanical Function Study
Langendorff-Perfused Heart Preparation
The heart was quickly removed from the mouse
anesthetized with urethane (1.5 mg/g, IP). The heart was
retrogradely perfused at a constant flow (3 mL/min) with the
Krebs-Henseleit solution (solution I, 37°C) gassed with 95%
O2/5% CO2. A
polyethylene film balloon was inserted into the cavity of the left
ventricle through the left atrium. The balloon was filled with saline
to adjust the baseline end-diastolic pressure to 5 to
10 mm Hg. Left ventricular pressure and its dp/dt
were measured continuously.
Isolated Aortic Preparation
The aorta was carefully removed and cut into rings
(4 mm in length). The endothelium was removed
carefully by rubbing with a small steel pin, and the rings were mounted
in a thermostatic organ bath for isometric tension recording
under a resting tension of 0.5 grams. The bath was
continuously perfused with the Krebs-Henseleit solution (solution H)
gassed with 95% O2/5%
CO2 at 37°C.
Hemodynamic Measurement
Blood pressure and heart rate (HR) were measured in
mice anesthetized with urethane. Subcutaneous needle electrodes
were inserted in the limbs for ECG recording. Femoral artery
and vein were cannulated with small polyethylene catheters for the
measurement of blood pressure and the injection of saline or drugs,
respectively. Body temperature was monitored with a rectal probe and
maintained at 37°C using a heating lamp.
Northern Blot Analysis
Total cellular RNA was isolated using the RNeasy Mini
kit (QIAGEN). Total RNA (10 µg) from the hearts and
aortas of the mice were denatured with formaldehyde, subjected to
electrophoresis on a 1% agarose gel, and transferred to nylon
membranes. Hybridization was carried out under high-stringency
conditions with a 32P-labeled full-length
cDNA of Kir6.1 or Kir6.2. For autoradiography, the
nylon membranes were exposed to x-ray film with an intensifying screen
at -80°C for 1 day. Results from these analyses were
quantified through densitometry.
Drugs
The following drugs were used: pinacidil (Research
Biochemicals International), diazoxide and glibenclamide
(Sigma), norepinephrine (Wako), P-1075 (Leo Pharmaceutical
Products), and HMR1098 (Aventis Pharmaceuticals). Pinacidil was
dissolved in 0.1N HCl+saline. Diazoxide and P-1075 were dissolved in
DMSO (final concentration of solvent, <0.1%).
L-Ascorbic acid (0.1
mmol/L) was added to the Krebs-Henseleit solutions to prevent the
oxidation of norepinephrine.
Statistics
All data are presented as mean±SE.
Statistical analyses of the data were performed using the
Student t test or ANOVA.
Probability values <0.05 were considered significant.
EC50 values were obtained by use of Delta Graph
Professional (Delta Point).
A table listing the composition of the various solutions can be found in an online data supplement available at http://www.circresaha.org.
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Results |
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Electrophysiology in Cardiomyocytes
The open cell-attached patches of ventricular cells were held at -40 mV and exposed to a solution containing only a trace amount of ATP (1 µmol/L). Single KATP channel activity could be recorded from 32 of 32 patches of 6 WT mice (Figure 1a
). The channel openings were inhibited by addition
of 1 mmol/L ATP or 10 µmol/L glibenclamide to the solution. The
linear slope conductance obtained from the current-voltage
relationship from -80 to 0 mV for the single-channel current of WT
ventricular cells was 79±1 pS (6 cells from 3 animals)
(Figures 1c and 1d). In contrast, openings of
KATP channels could not be recorded from any
open cell-attached patches of KO mouse (22 cells from 4 animals)
(Figure 1b). The channel activity could not be
activated even by addition of Mg-UDP, Mg-ATP, and/or
pinacidil.
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Whole-cell membrane currents were recorded using a
ramp-pulse protocol. The reversal potential was close to the potassium
equilibrium potential in ventricular cells of both WT and
KO mice
(Figures 2a and 2b). There was no significant difference in
the density of the outward current at 0 mV between
ventricular cells isolated from WT (2.67±0.83 pA/pF) and
KO (3.47±0.91 pA/pF) mice under control conditions. Pinacidil produced
concentration-dependent increases of an outward current, which, by
virtue of its blockade by 1 µmol/L glibenclamide, was confirmed as
the ATP-sensitive K+ current
(IK,ATP);
such a current was observed in WT ventricular cells but not
in KO cells
(Figure 2c). There were no significant differences in the
basal parameter values of the action potentials
recorded from the ventricular cells stimulated at 0.2
Hz. Exposure to pinacidil revealed dramatic differences. The action
potential duration (APD) was shortened by pinacidil in WT but not in KO
ventricular cells
(Figures 2d and 2e). APD at 90% repolarization level
(APD90) of WT cells was significantly decreased
from 34.0±1.5 to 10.8±3.1 ms by 100 µmol/L pinacidil and reversed
to 37.9±2.5 ms after the addition of 1 µmol/L glibenclamide
(Figure 2f). However, the APD90 of the
KO ventricular cells was not significantly changed from
35.6±2.4 ms after exposure to pinacidil
(Figure 2f).
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Restoration of
IK,ATP
by Adenoviral Gene Transfer of Kir6.2
As anticipated from our data in adult mouse cells,
application of 100 µmol/L P-1075, a pinacidil derivative and a potent
specific opener of surface
IK,ATP,23
induced sarcolemmal
IK,ATP
only in neonatal myocytes isolated from WT but not from KO mice
(Figure 3a). If this absence of the surface current in KO is
solely due to the absence of functional Kir6.2 channels, we should be
able to restore the missing current by expressing Kir6.2. Therefore, we
attempted to rescue the KO phenotype by delivering Kir6.2 to
cells via adenoviral gene transfer. Indeed,
IK,ATP
was observed in KO cells infected with AdKir6.2 on addition of 100
µmol/L P-1075
(Figures 3a and 3b). The identity of this virally induced and
P-1075–induced current as
IK,ATP
was confirmed by its complete suppression by coapplication with 100
µmol/L P-1075 of the specific surface channel blocker
HMR1098.23
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Electrophysiology in Aortic Smooth Muscle
Cells
Effects of pinacidil on the whole-cell membrane current
were examined in aortic smooth muscle cells held at -40 mV in the
high-K+ solution. Pinacidil
activated a glibenclamide-sensitive inward current in smooth
muscle cells from both WT and KO mice in a concentration-dependent
manner
(Figures 4a and 4b). The concentration-response curves for the
stimulatory effects of pinacidil in WT and KO smooth muscle cells were
almost superimposable
(Figure 4c). The calculated EC50
values of pinacidil for activating the
IK,ATP
were 0.21 and 0.16 µmol/L in aortic smooth muscle cells of WT and KO
mice, respectively.
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) and Kir6.2-/- mice (
). Data are mean±SE of WT (5 to 11 cells from 22 mice) and KO cells (7 to 13 cells from 24 mice).
Functional Experiments in Isolated Cardiac and
Vascular Tissues
Cardiac function of the hearts isolated from WT and KO
mice was evaluated by measuring the left ventricular
developed pressure (LVDP) and its derivative. In WT hearts, pinacidil
at a concentration of 100 µmol/L significantly decreased LVDP and
maximal dp/dt to 70.7±2.0% (n=10,
P<0.05) and 71.5±2.1% (n=10,
P<0.05) of the control,
respectively
(Figure 5a). In WT hearts, the addition of 1 µmol/L
glibenclamide reversed the pinacidil-induced decreases in LVDP and
maximal dp/dt to 93.4±2.4% and 92.4±2.6% of the control,
respectively. In contrast, the LVDP and maximal dp/dt of KO hearts were
99.1±3.2% (n=10, NS) and 98.4±3.1% (n=10, NS) of the control after
100 µmol/L pinacidil in KO hearts
(Figure 5b). To assess vascular reactivity, effects of KCOs
on aortic preparations precontracted with 0.1 µmol/L
norepinephrine were examined. In both the aortic rings
isolated from WT and KO mice, pinacidil and diazoxide produced a
concentration-dependent vasorelaxing effect
(Figure 6). The EC50 values of
pinacidil for the vasorelaxing effect were 1.29 and 1.66 µmol/L in
aortic preparations isolated from WT and KO mice, respectively. The
EC50 values of diazoxide for vasorelaxing
effects were 3.42 and 4.61 µmol/L in WT and KO aortas, respectively
(Figure 6d). There were no significant differences in these
EC50 values of pinacidil or diazoxide between
aortic preparations of WT and KO mice. Thus, KCOs produced vasodilation
in vascular tissues isolated from WT and KO mice with similar
potency.
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Hemodynamic
Measurements
There were no significant differences in the basal
hemodynamic values between WT and KO mice
anesthetized with urethane. The basal values of HR in WT and KO
mice were 642±24 and 638±12 bpm, respectively. The basal values of
mean arterial pressure (MAP) in WT and KO mice were
65.1±2.9 mm Hg and 73.5±4.0 mm Hg, respectively.
Intravenous injection of pinacidil (0.3 mg/kg) decreased
MAP and increased HR in WT and KO to a similar extent
(Figure 7). There were no significant differences in the
magnitude of MAP decrease and HR increase in response to pinacidil
between WT and KO mice.
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Northern Blot Analysis
Kir6.2 mRNA was expressed in hearts of WT mice (n=4)
but not in those of KO mice (n=4), whereas Kir6.1 mRNA was expressed in
hearts of both WT and KO mice
(Figure 8a). Kir6.1 mRNA was expressed in both aortic
preparations of WT (n=4) and KO mice (n=4), whereas Kir6.2 mRNA was not
detectable in either preparation. Expressed levels of Kir6.1 mRNA in KO
hearts
(Figure 8b) and aortas
(Figure 8c) were similar to those observed in respective
preparations of WT mice.
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Discussion |
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Coexpression of SUR2A and Kir6.2 produces a
80 pS
KATP channel resembling that found in native
cardiac cells.11 The channel
activity is inhibited by ATP with an IC50 value
of 100 µmol/L and by glibenclamide with less sensitivity compared
with pancreatic-type KATP channel (ie,
SUR1/Kir6.2). SUR2A, which showed 68% identity of amino acids with
SUR1, was expressed at high levels in heart and skeletal muscle. Such
pharmacological data, conductances, and tissue distributions suggested
that the cardiac KATP channel may be composed of
SUR2A and Kir6.2. The present study has confirmed directly that
Kir6.2 is essential for the function of sarcolemmal
KATP channels in cardiac cells. In open-cell
attached patches of ventricular cells of
Kir6.2+/+ mice, we could record the
KATP channel activity, which showed a slope
conductance of 79 pS and was inhibited by application of ATP or
glibenclamide. However, we did not observe any
KATP channel activity in membrane patches of
Kir6.2-/- ventricular cells
even in the presence of Mg-UDP and/or pinacidil. In addition, the KCO
pinacidil activated the glibenclamide-sensitive outward current
in ventricular cells of WT but not of KO mice. These
findings indicate that Kir6.2 forms the pore of cardiac
KATP channels. This concept was further
strengthened by Kir6.2 rescue experiments. In neonatal myocytes of
Kir6.2-/- mice, adenoviral gene transfer
of Kir6.2 restored the surface KATP current that
was activated by P-1075 and blocked by HMR1098. P-1075 and
HMR1098 have been shown to be a specific activator and a
blocker of sarcolemmal KATP channel,
respectively.23 Therefore,
Kir6.2 is essential for the function of sarcolemmal
KATP channel in cardiac cells. The present study has also demonstrated that sarcolemmal KATP channels mediate the depression of cardiac function by KCO. Pinacidil markedly shortened APD and decreased cardiac contractile function assessed by LVDP and dp/dt in WT but not in KO hearts. In Kir6.2+/+ hearts, the action potential shortening induced by pinacidil might lead to a decrease in Ca2+ influx via Ca2+ channels and/or Na+-Ca2+ exchange system, resulting in a negative inotropic response. Similar pinacidil-induced negative inotropy associated with action potential shortening was observed with guinea pig papillary muscles.17 However, such electromechanical response to pinacidil was absent in Kir6.2-/- hearts. We also found that the action potential shortening under metabolic inhibition was absent in Kir6.2-/- ventricular cells (M.S., N.S., H.N., unpublished observations, 1999). The action potential shortening in hypoxic and ischemic conditions is expected to decrease Ca2+ influx, resulting in reduction of mechanical contraction, amelioration of intracellular Ca2+ overload, and energy sparing. Administration of KCO would accelerate the functional alterations and thereby protect ischemic myocardium. However, there is recent evidence that mitochondria may harbor another type of KATP channel, an additional site of action of KCOs, and that the mitochondrial KATP channel rather than the sarcolemmal KATP channel may be important for cardioprotection by KCOs and ischemic preconditioning.24 25 Because action potential shortening would not be observed during myocardial ischemia or administration of KCO, the Kir6.2-deficient mouse may be a useful model to define the underlying mechanism(s) of cardioprotection afforded by KCOs or ischemic preconditioning.
Currents attributed to KATP channels have been observed in a number of vascular and visceral smooth muscle preparations, such as rabbit mesenteric artery,26 portal vein,27 guinea pig trachealis,28 and urinary bladder.29 In terms of SUR of smooth muscle cells, Isomoto et al13 have proposed that SUR2B, a splice variant of SUR2A having different carboxyl-terminal amino acids, is the subunit constituting the smooth muscle–type KATP channel as inferred from pharmacological properties and tissue distribution. In smooth muscle cells of murine colon14 and guinea pig bladder,15 the pore region of the KATP channels was reported to comprise SUR2B and Kir6.2.
There is still controversy as to physiological properties of KATP channels in vascular smooth muscle cells. KATP channels of large conductance (120 to 258 pS) were reported in vascular smooth muscle cells from rabbit mesenteric artery30 31 and rat tail artery.32 Edwards and Weston33 postulated that the large-conductance K+ channel might be a Ca2+-activated K+ (KCa) channel. KATP channels having small or intermediate conductance (15 to 50 pS) were observed in various vascular smooth muscle cells.33 34 35 They were inhibited by glibenclamide and activated by KCOs and NDPs. Because these characteristics were closely similar to the "KNDP channel" composed of SUR2B and Kir6.1, Yamada et al16 suggested that vascular KATP channel may be composed of Kir6.1 rather than Kir6.2. The present study has demonstrated that KCOs relaxed the WT and KO aortic preparations precontracted by norepinephrine with similar potency and pinacidil induced the glibenclamide-sensitive current to a similar extent in vascular smooth muscle cells isolated from WT and KO aortas. These findings indicate that Kir6.2 is not necessary for the vasodilation by KCOs in mouse aorta. Strong support for this concept is the finding that Kir6.1 mRNA, but not Kir6.2 mRNA, was detected in both WT and KO aortas. In this study, not only pinacidil but also diazoxide relaxed the precontracted aortic preparations. Because the benzothiadiazine KCO, diazoxide, activated the KATP channels composed of Kir6.2/SUR2B13 but not Kir6.2/SUR2A,11 the SUR subunit in mouse aorta might be SUR2B.
It may be of importance to examine the effect of KCO on the resistance vessels rather than conductance vessels such as thoracic aortas. Therefore, we examined the effect of pinacidil on systemic blood pressure in anesthetized WT and KO mice. There were no significant differences in baseline values and decrease of MAP in response to pinacidil between WT and KO mice. The target of pinacidil in resistance vessels might not be the KATP channel having Kir6.2 as a pore subunit. It has been suggested that KATP channels in vascular smooth muscle cells may be activated by metabolic inhibition and endogenous substances such as adenosine, calcitonin gene-related peptide, and prostacyclin.26 Further studies may be needed to identify the pore subunit of KATP channels involved in the regulation of vascular tones under metabolic changes and released endogenous substances using the gene-targeted animal.
In conclusion, we provide direct evidence that Kir6.2 forms the pore region of cardiac KATP channel but not of vascular KATP channel and that Kir6.2 is essential for the action potential shortening and depressed cardiac contractility in response to KCOs.
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Acknowledgments |
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This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Mitsui Life Insurance Research Foundation; and K. Watanabe Research Fund. This work was also supported by grants from the NIH (Grant R37 HL36957 to E.M.) and the Heart and Stroke Foundation of Canada (fellowship to R.A.L.). E.M. holds the Michel Mirowski, MD Professorship of Cardiology at The Johns Hopkins University.
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Footnotes |
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Original received December 8, 2000; revision received January 29, 2001; accepted February 2, 2001.
This manuscript was sent to James T. Willerson, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
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