J Mol Cell Cardiol 28, 2043–2050 (1996)

Blockade of the ATP-sensitive PotassiumChannel by Taurine in Rabbit VentricularMyocytesJin Han1, Euiyong Kim1, Won-Kyung Ho2 and Yung E. Earm2

1Department of Physiology and Biophysics, College of Medicine, Inje University, Gaegeum-Dong,Pusanjin-Ku, Pusan, 614–735, Korea and 2Department of Physiology and Biophysics, College ofMedicine, Seoul National University, Yonkeun-Dong, Chongno-Ku, Seoul, 110-799, Korea

(Received 23 January 1996, accepted in revised form 28 May 1996)

J. H, E. K, W.-K. H, Y. E. E. Blockade of the ATP-sensitive Potassium Channel by Taurine in RabbitVentricular Myocytes. Journal of Molecular and Cellular Cardiology (1996) 28, 2043–2050. Using patch-clamptechniques, the effects of taurine on properties of ATP-sensitive K+ (KATP) channel of rabbit ventricular myocyteswere examined. Intracellular taurine (20 m) markedly depressed the KATP channel activity. The taurineconcentration for half-inhibition (apparent Kd) was 13.5 m with a Hill coefficient, n, of 1.3. Intracellular taurinecaused channel inhibition without affecting channel inhibition by ATP. In control conditions, the ATP concentrationfor half-inhibition (Ki) and n were 73 l and 1.2 (n=6), respectively. In the presence of taurine, Ki and n were81 l and 1.3 (n=6), respectively.

Analysis of the open and closed time distributions showed that taurine decreased the life time of bursts andincreased the inter-burst interval and/or reduced the number of functional channels.

2,4-Dinitrophenol (DNP) activated KATP channel after a lag period. This lag period was much longer afterpretreatment with taurine (6.6±1.2 min, n=5) than in the absence of taurine (2.8±1.5 min, n=12). WhenDNP was removed in the bath solution, channel activity showed a gradual reduction with time and this processwas facilitated by the presence of external taurine (20 m).

From these results it is suggested that taurine blocks KATP channel activity in dose-dependent manner and thedepletion of taurine during myocardial ischemia contribute to the early activation of the KATP channel.

1996 Academic Press Limited

K W: Taurine; ATP-sensitive potassium channel; Ventricular myocytes.

myocardial ischemia. Several endogenous mod-Introductionulators of KATP channel activity have been identifiedincluding the ADP/ATP ratio, certain nucleotideIn the cardiac muscle, the ATP-sensitive K+ (KATP)

channels are closed under physiological conditions diphosphates, pH, lactate, G-proteins, and proteinkinases (Kirsch et al., 1990; Nichols and Lederer,but open when the ATP level falls below a critical

level following myocardial ischemia (for review see, 1991; Han et al., 1993). On the other hand, taurine(2-aminoethanesulfonic acid) is present in myo-Gross and Auchampach, 1992). Activation of KATP

channels has been suggested to be responsible for cardial cells at high concentration (about 10 m)(Huxtable and Sebring, 1980). There is considerablethe increased cellular K+ efflux and the shortening

of the action potential during myocardial ischemia evidence that taurine has a cardioprotective effectagainst the calcium paradox (Kramer et al., 1981),(Noma, 1983).

Various metabolic alterations occur and could isoprenaline-induced myocardial damage (Ohta etal., 1988), doxorubicin-mediated cardiotoxicityinfluence KATP channel activity under conditions of

Please address all correspondence to: Professor Yung E. Earm, Department of Physiology and Biophysics, College of Medicine, SeoulNational University, Yonkeun-Dong, Chongno-Ku, Seoul, 110-799, Korea.

0022–2828/96/092043+08 $18.00/0 1996 Academic Press Limited2043

J. Han et al.2044

(Hamaguchi et al., 1988), cardiomyopathy (Azari resistance were pulled from borosilicate glass ca-pillaries (Clark Electrochemical, Pangbourne, UK)et al., 1980), congestive heart failure (Takihara et

al., 1986) and hypoxic injury (Sawamura et al., using a vertical puller (Narishige PP-83, Japan).Membrane currents were digitized at a sampling1986).

Taurine levels in hearts are normally fairly stable, rate of 48 kHz and stored in digitized format ondigital audio tapes using a Bio-logic DTR-1200however, ischemic heart disease is associated with

a decline in taurine content (Lombardini, 1980; recorder (Grenoble, France). For the analysis ofsingle-channel activity, the data were transferredKramer et al., 1981). There is little evidence in

heart muscle of modulation of KATP channel activity to a computer with pClamp software (Axon In-struments, Burlingame, CA, USA) through a 12-by taurine. In this study, therefore, the modulation

of cardiac KATP channel activity by taurine in rabbit bit Labmaster analog-to-digital converter interface.The open time histogram was formed from con-ventricular myocytes has been investigated. We

demonstrate that intra- and extracellular taurine tinuous recordings of more than 60 s. The openprobability (Po) was calculated using the formula:do inhibit KATP channel activity and consider the

possibility that the depletion of taurine during myo-cardial ischemia contributes to the early activation

Po=( RN

j=1tj j) / TdN) ,

of the KATP channel.

where tj is the time spent at current levels cor-responding to j=0,1,2, . . . N channels in the openstate, Td is the duration of the recording and N isMaterials and Methodsthe number of channels active in the patch. Po wascalculated over 20-s records.Single ventricular myocytes were isolated from rab-

bit hearts by enzymatic dissociation, as describedpreviously (Han et al., 1994). Initially, hearts wereperfused retrogradely for 5 min with Tyrode solu- Resultstion. Ca2+-free Tyrode solution was perfused for5 min and Ca2+-free Tyrode solution containing Many of the inside-out patches that we excised

from rabbit ventricular myocytes contained ATP-0.01% collagenase (5 mg/50 ml, Yakult, Japan) wasperfused for 15–25 min. After enzymatic treatment, sensitive potassium channels (KATP channels),

though channel activity usually declined rapidlyKraftsbruhe (KB) solution was perfused. Langen-dorff column was kept at 37°C during all previous after patch excision. In some patches, however,

a number of channels remained active, allowingsteps. Isolated ventricular cells were stored in a KBsolution at 4°C and used within 8 h. recordings made from a patch in which a large

number of channels were active. Figure 1 showsTyrode solution contained (m): 143 NaCl,5.4 KCl, 1.8 CaCl2, 0.5 MgCl2, 5.5 glucose, 5 HEPES; typical records of KATP channels in excised inside-

out membrane patches at−40 mV, with both sidespH 7.4 re-adjusted with NaOH. Patch pipettes werefilled with a solution contained (m): 140 KCl, of the patch bathed in isotonic KCl solution. When

the inside membrane of the patch membrane was2 CaCl2, 1 MgCl2, 10 glucose, 10 HEPES; pH 7.4with KOH. The bath solutions facing the inside of the exposed to ATP-free solution, the channel activity

revealed a fully open state with overlaps of upcell membrane in the inside-out patch recordingscontained (m): 127 KCl, 13 KOH, 1 MgCl2, 5 to three unitary currents of 2.83 pA which were

blocked by intracellular ATP (data not shown).EGTA, 10 glucose, 10 HEPES; pH 7.4 with KOH.ATP was used as the magnesium salt. After addition During the recording of the KATP channel, the ap-

plication of taurine (20 m) into the bath solutionof drugs to the test solution, the pH was re-adjustedto 7.4 with KOH. All drugs and chemicals were markedly depressed the channel activity [Fig. 1(a)].

In other experiments (n=8), channel openings ofobtained from Sigma (St Louis, MO, USA). Theexperiments were performed at the temperature of low frequency were observed in the presence of

taurine. The effect of taurine on the KATP channel22±3°C in the inside-out patch configuration. Forcell-attached patch configuration, the bath and was reversible. After wash-out of taurine, the KATP

channel activity reappeared within 1 min. Intra-perfusion solution were heated to 35±2°C.Single-channel currents were recorded in the cell- cellular taurine, therefore, directly interacts with

the KATP channel.attached and inside-out configuration of the patchclamp technique with a patch-clamp amplifier (EPC- To measure the concentration-dependence of

channel inhibition by taurine, taurine was applied7, LIST, Darmstadt, FRG). Pipettes of 5–10 MX

Blockade of KATP Channels by Taurine 2045

20

1.0

0.01

Taurine concentration (mM)

Rel

ativ

e op

en p

roba

bili

ty

0.8

0.6

0.4

0.2

5 10 15

Kd = 13.5 mM

Figure 2 The concentration–effect relationship for theblocking action of taurine. The ordinate represents rel-ative open probability during application of taurine nor-

(a)

140KC1

20 Taurine

c

c

c

c

c

Control(b)

20 mM Taurine

1 min 40 s

3 min3 pA

4 ms

3 pA

1 s

3 pA

1 minWash-out20 mM Taurine

malized in reference to that obtained before theFigure 1 Effect of taurine on the ATP-sensitive K+ chan- application of taurine, the points show means±...nel recorded from inside-out patch membrane. Patch The abscissa represents concentration of taurine.pipette contained 140 m K+ pipette solution. C indicatesthe closed state of the channels. (a), ATP-sensitive K+

channel was activated by ATP-free solution at a holdingpotential of −40 mV. The solution bathing the inside ofthe patch was changed to 20 m taurine solution asindicated. (b), the time scale was expanded to showmore clearly the channel activity. Note that taurineimmediately decreased the number of functional channelsand inhibited the channel activity in 3 min.

at concentrations between 1 and 20 m and openprobability (Po) was measured over a period of atleast 30 s under each condition. Figure 2 shows theconcentration–effect curve for channel inhibition bytaurine. The experimental results were fitted by

101

1.0

0.0

ATP concentration (mM)

Rel

ativ

e op

en p

roba

bili

ty

0.8

0.6

0.4

0.2

10010–110–210–310–4

expression:Figure 3 The effect of taurine on the ATP dependenceof the channel activity. The concentration–effect curvefor channel inhibition by ATP, measured in the absencerelative Po=1/1+([taurine]i/Kd)n

(Control,Χ) or presence (Taurine,Ο) of 13.5 m taurine.The open probability in each ATP solution was normalizedby referring to its value in ATP-free solution. Values arewith a Hill coefficient, n, of 1.3. The line in Figuremeans±... Taurine does not affect channel inhibition2 shows the best fit to all the individual values ofby ATP.relative Po and gives a taurine concentration for

half inhibition, apparent Kd of 13.5 m.A number of agents that modulate KATP channels

not significantly shifted from that measured inin cardiac muscle or other tissues have been showncontrol condition. The experimental results wereto act by modulating channel inhibition by ATP sofitted by the expression:as to shift the ATP-inhibition curve to higher or

lower [ATP] values. Intracellular taurine causedRelative Po=1/1+([ATP]i/Ki)n

channel inhibition without affecting channel in-hibition by ATP. The concentration–effect curve forATP in the presence of 13.5 m taurine is shown where Ki is the ATP concentration evoking the half-

maximal inhibition and n is the Hill coefficent. Inby (Ο) and continuous line in Figure 3, and was

J. Han et al.2046

500

135

0

Nu

mbe

r of

eve

nts

90

45

100 200 300 400

(a)

Burst durationτb = 41.5

Control

500

135

0

90

45

100 200 300 400

(b)

Burst durationτb = 16

Taurine

600

270

0Time (ms)

Nu

mbe

r of

eve

nts

180

90

200 400

(c)

Interburst durationτf = 5

τs = 60

600

135

0Time (ms)

90

45

200 400

(d)

Interburst durationτf = 6

τs = 130

Figure 4 Distribution of open and closed times before (control) and during (taurine) application of 13.5 m taurine.Histograms of life-time of bursts [(a), (b)] and inter-burst duration [(c), (d)] analysed with a low pass filter of 0.1 kHz.Holding potential was−40 mV. The time constants of the bursts (sb) obtained under two different conditions were bestfitted by single exponentials. Time constants of inter-burst duration were fitted to two exponentials (sf and ss). Taurinedecreased the time constants of the bursts (sb) and increased the time constant of the slow component in the distributionof long closed times (ss).

control conditions, Ki and n were 73 l and 1.2, tribution was also best fitted by a single exponentialwith a time constant (sc) of 0.3 ms. Both open andrespectively. In the presence of taurine, Ki and n

were 81 l and 1.3, respectively. closed time distributions were unaffected by taurine.The time constants of the distribution of open andA comparison of the kinetics of KATP channels

under control conditions and in the presence of closed times were not significantly affected by taur-ine (so=2.4 ms, sc=0.3 ms).taurine suggests that the major effect of taurine

was to increase the long closed times between burst The duration of each bursting opening was meas-ured from the records sampled at 0.1 kHz (Fig. 4).of openings and/or reduce the number of functional

channels. Most of the patch contained more than The open time histogram was well fitted to a singleexponential function. In these histograms, the timeone functional KATP channel. In two experiments,

however, single channel recordings were obtained constant of burst duration (sb) was decreased from41.5 to 16 ms by taurine. The inter-burst timeand the open- and closed time of KATP channel

were successfully analyzed in both control and the histograms were fitted with two exponential func-tions. The time constant of the fast exponentialpresence of taurine. Figure 4 shows representative

results of the experiment measured at−40 mV. As component (sf) was unaffected by taurine (from 5to 6 ms). The time constant of the slow exponentialhas been described, the channel opening appeared

in a burst. The fast open and closed kinetics within component (ss) was increased from 60 to 130 msby taurine.the bursts were analysed from the records sampled

at 10 kHz. In control, the open time distribution In order to confirm the blocking effect of KATP

channel of taurine in more physiological condition,was described by a single exponential with a timeconstant (so) of 2.65 ms. The closed time dis- experiments were performed using the cell-attached

Blockade of KATP Channels by Taurine 2047

(a) Control

Gilbenclamide 30 µM

DNP 0.2 nM

c-

7 pA

1 min

c-

(b) after 2 minc-

(c) after 2 min 30 s

10 pA

90 ms

DNP 0.2 mM

(a) before DNP application

DNP 0.2 mM

(b) Taurine pretreatment

Glibenclamide 30 µM

DNP 0.2 mM

7 pA

1 min

c-

(b) after 6 minc-

(c) after 7 min 30 s

10 pA

90 ms

(a) before DNP application

c-

c- c-

Figure 5 Effect of taurine pretreatment on KATP channels activated by DNP perfusion in cell-attached membranepatches. The holding potential was 0 mV. 0.2 m DNP induced ATP-sensitive K+ channels in 2–5 min. The channelactivity decreased after 30 l glibenclamide treatment (a). When the cell was pretreated with 20 m taurine, DNP-induced KATP channel activation showed a delayed onset (usually it takes more than 6 min). Channel activities activatedby DNP were rapidly inhibited after 30 l glibenclamide treatment. Lower panel shows the traces with expanded timescale in each condition. Before application of DNP, inward rectifier K+ (iK1

) channels are observed. Low pass filter, 1 kHz.

patch configuration (Figs 5 and 6). In these ex- KATP channel after a lag period. This lag period wasmuch prolonged in the group of taurine pretreatedperiments, the potential in the patch pipette was

held at 0 mV and thus the membrane potential was cells [6.6±1.2 min, n=5, Fig. 5(b)] than in thecontrol cells [2.8±1.5 min, n=12, Fig. 5(a)]. Inheld at the resting potential which is assumed to be

about−70 mV with 5.4 m K+ in the extracellular order to see whether there is an additional effectby external taurine, 20 m taurine was appliedsolution. As previously observed by others (Noma,

1983; Kakei et al., 1985), KATP channel activity was during the washing-out period with normal Tyrodesolution and the results were shown in Figurenot observed from cell-attached patches and only

openings of small inward rectifier K+ (iK1) channels 6. When DNP was removed with normal Tyrodesolution 1–2 min after the activation of KATP chan-were recorded. The addition of 2,4-dinitrophenol

(DNP) (0.2 m) in bath solution opened KATP chan- nel, channel activity showed a gradual decreaseand final recovery with time by taurine (20 m)nels, which were easily distinguished from iK1 chan-

nels because of their larger unitary current [(Fig. 6(b)], but this recovery was very much slowerin the absence of external taurine (n=8) [(Fig.amplitude. The result suggests that inhibition of

ATP synthesis by DNP results in the channel ac- 6(a)]. In addition to these findings the recoveryfrom DNP treatment or reduction of KATP channeltivation in the cell-attached patch. Under these

experimental conditions the effect of taurine on the activity by external taurine was much more pro-nounced and faster in the cells with taurine-pre-development of KATP channel was tested. In taurine-

pretreated cells (20 m taurine pretreated in stor- treatment [(Fig. 6(c)]. From these results it issuggested that intracellular taurine has direct rolesage KB solution for 2–5 hours in addition to normal

Tyrode solution for 10 min prior to application of in the inhibition of KATP channel and/or may playa role on the preservation of intracellular ATPDNP), DNP caused channel activation more slowly

than it did in the cells without taurine-pretreatment. concentration (i.e. slows down ATP breakdown),which leads to the delayed activation of KATP chan-In both group of cells DNP consistently activated

J. Han et al.2048

(a) Control

DNP 0.2 mM

c-

c-

c-

(b) Control

(c) Taurine pertreatment

DNP 0.2 mM

DNP 0.2 mMTaurine 20 mM

Taurine 20 mM

1 min10 pA

10 pA1 min

10 pA1 min

Figure 6 Effects of external taurine on single-channel currents activated by DNP. Continuous records obtained fromcell-attached membrane patches. The holding potential was 0 mV. The K+ concentration of the pipette solution was140 m. In the control cell (a), 0.2 m DNP (first indication) evoked the channels after a lag period. Removal of DNPin perfusate induced a slow decrease of channel activity. When DNP was washed out with normal Tyrode containing20 m taurine, reduction of KATP channel activation was much enhanced (b). In the taurine-pretreated cell (c), the lagperiod for the activation of single-channel currents by DNP was much longer than in control cells (8 min in this caseafter the application of 0.2 m DNP in the bath). Note that the decrease in the channel activity during taurineapplication was so much faster in cells pretreated with taurine.

nel. And external taurine has blocking effect on experimental model for hypoxia or ischemia in aKATP channel activity. single cardiac cell.

The activity of the KATP channel was inhibited bythe internal application of taurine in the inside-outconfiguration, or by the bath application of taurineDiscussionunder the cell-attached patch condition. This find-ing might be explained by assuming that taurineIn the present study the effects of taurine on KATPis transported in the lipid membrane and affectedchannel activity in rabbit ventricular myocytesthe KATP channel, or the channel may have a taurinewere demonstrated. The main results of the presentbinding site on both sides of the membrane.study are that intracellular taurine inhibits KATP

The inhibitory action of taurine is comparedchannel activity in the inside-out patch con-with that of ATP. The dose–response relationshipfiguration and extracellular taurine inhibits themeasured for the internal application of taurine fitactivation of DNP-induced KATP channels in the cell-well with a Hill coefficient of 1.3, suggesting theattached patch configuration. It was assumed that

DNP-induced KATP channel activation is a type of stoichiometry for binding may be 1:1. Recently Qin

Blockade of KATP Channels by Taurine 2049

et al. (1989) indicated that binding of one ATP 1980). The mechanism of taurine loss during myo-cardial ischemia is still not clear, however, it hasmolecule may cause a transition from the open

state to the closed conformation of the KATP channel. been suggested that the increase of intracellularsodium leads to increase of the coupled loss of NaThe kinetic properties are also similar. ATP affects

burst duration and long-lasting closed state without and taurine from the cell via Na–taurine co-transport mechanism (Chapman et al., 1993). Thischanging the gating of the channels during bursts,

like in the block by taurine. mechanism may be particularly important whenNa pump activity is reduced, as during hypoxia orTo activate the KATP channel under the cell-

attached condition 0.2 m DNP was used in the ischemia. This is because the gradient for Na isused by the heart to regulate intracellular pH andbath. It has been demonstrated that DNP activates

a very large outward current which shortened intracellular [Ca2+]. Clearly, any reduction of therise in [Na+]i will delay the onset of irreversibleaction potential duration and abolished cardiac

excitability to external stimuli (Isenberg and Benn- changes to the cell. Therefore, the loss of taurinewith Na during ischemia from the cardiac cellsdorf, 1990). It was found that DNP evoked KATP

channels after a lag period. This lag period was means it reduces cell damage. In addition to thiseffect it is likely that combination of taurine lossmuch longer in cells pretreated with taurine. The

increase of the lag period may be due to following and ATP depletion during myocardial ischemia in-duces a further increase in the KATP channel activity.reasons: (1) intracellular taurine slows down the

decrease of intracellular ATP concentration; (2) it In this respect, it has been suggested that activationof the KATP channel under ischemic conditions con-increases the sensitivity of the KATP channel to ATP;

and (3) it directly interacts with the KATP channel. fers protection against the ischemic insult (Cole etal., 1991; Auchampach et al., 1992; Gross et al.,It should be noted, however, that taurine does not

inhibit the KATP channel activity by modulating the 1994). Theoretically, activation of KATP channelscould result in various metabolic effects by short-binding of ATP. This is because of two results: (1)

the inhibition by taurine was observed in the ATP- ening the action potential duration during theplateau phase and attenuating membrane de-free solution; (2) taurine did not shift the con-

centration–effect curve for ATP significantly. polarization. These effects could lead to reducedcalcium concentrations, a rapid loss of contractileTaurine, containing two methylene units situated

between an amino group and a sulfonic acid moiety, activity, and reduced ATP utilization. However, ithas been found that taurine enhances Ca2+-releaseis found in very high concentrations, especially in

the heart (Kocsis et al., 1976; Bohles et al., 1987). from sarcoplasmic reticulum and increases intra-cellular Ca2+ concentration (Steele et al., 1990;It has been suggested that it affects cellular function

and is altered in patients suffering from cardio- Earm et al., 1993). Thus, myocardial contractileforce could be reduced under taurine-depleted con-vascular disease. Both extracellular and intra-

cellular effects of taurine have been recognized. ditions. This mechanism could also help the pre-servation of intracellular ATP levels.The extracellular effects are generally induced by

concentrations well above the physiological levelof 50–200 l (Sperelakis et al., 1989; Earm et al.,

Acknowledgement1990). Change in intracellular taurine, from itsphysiological level of 10–30 m, affect the sus-

This work was supported by the grants from KOSEFceptibility of the heart to damage (McBroom and(94-4003-12-01-3), Ministry of Science and Tech-Welty, 1977; Schaffer et al., 1987; Steel et al.,nology and Dong-A Pharmaceutical Co. Ltd.1990). Since the ability of taurine to alter calcium

movement has been proposed, the cardioprotectiveeffect of taurine against several types of calcium

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