Operative Condition–Dependent Response of Cardiac ATP-Sensitive K⁺ Channels Toward Sulfonylureas

From the Division of Cardiovascular Diseases, Department of Medicine and Pharmacology, Mayo Clinic, Mayo Foundation, Rochester, Minn.

Correspondence to Andre Terzic, MD, PhD, Guggenheim 7, Mayo Clinic, Rochester, MN 55905. E-mail terzic.andre{at}mayo.edu

	Abstract

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Abstract—A defining property of ATP-sensitive K⁺ (K_ATP) channels is inhibition by sulfonylurea drugs, yet the response of cardiac K_ATP channels toward sulfonylureas during myocardial ischemia is not consistent. Altered channel sensitivity toward sulfonylureas has, in part, been ascribed to antagonism by cytosolic nucleotide diphosphates, although the mechanism of interaction remains unclear. Herein, in inside-out patches excised from cardiomyocytes, we observed a dual response of K_ATP channels toward the sulfonylurea drug, glyburide, in the presence of cytosolic UDP. Specifically, glyburide failed to inhibit spontaneous K_ATP channel activity in the presence of UDP but inhibited UDP-induced channel activity after rundown of spontaneous channel openings. Such behavior of K_ATP channels cannot be explained by differences in the level of channel activity or by UDP-induced displacement of glyburide. Rather, the dual response toward the sulfonylurea could be attributed to a property of K_ATP channels to switch between operative conditions (spontaneous versus UDP-induced) each associated with a distinct responsiveness toward ligands. Conversion of post-rundown K_ATP channels to the spontaneously operative channel condition, by Mg-ATP, restored the ability of UDP to antagonize the inhibitory action of glyburide lost after rundown, suggesting that the response of the channel to glyburide is phosphorylation dependent. The existence of distinct operative conditions of cardiac K_ATP channels could be the basis for the inconsistent response of the channel toward sulfonylurea drugs and should be considered when sulfonylureas are used to implicate the opening of K_ATP channels in the myocardium.

Key Words: ATP-sensitive K⁺ channel • sulfonylurea • nucleotide diphosphates • ischemia • heart

	Introduction

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Potassium flux through ATP-sensitive K⁺ (K_ATP) channels is regulated by intracellular nucleotides and synthetic sulfonylureas,^{1 2 3 4 5 6} which bind to channel subunits.^{7 8 9 10 11 12 13 14} Such regulation allows K_ATP channels to couple the metabolic status of the cell with membrane excitability and to serve as a specific target in sulfonylurea-treated patients.^{6 15 16 17} Although sulfonylurea sensitivity is a defining pharmacological property of K_ATP channels,^{6 18 19 20 21 22 23} the efficacy with which sulfonylureas regulate K⁺ efflux, action potential duration, and cardioprotection associated with opening of cardiac K_ATP channels during hypoxia and ischemia is inconsistent.^{24 25 26 27 28 29 30} Moreover, under certain conditions, such as extreme cellular hypoxia, sensitivity toward sulfonylureas may be lost.^{24 25 26} Such findings question the established relationship between sulfonylurea-drug action and K_ATP channel opening in the cardiac cell.

Among various factors that regulate channel activity, intracellular nucleotide diphosphates, which are known to increase during ischemia, may be important, since they limit the efficacy with which sulfonylureas block cardiac K_ATP channels.^{24 31} The action of nucleotide diphosphates cannot be explained by competitive antagonism of a sulfonylurea.^{24 31} Thus, the mechanism of interaction remains unclear.

The interaction between intracellular nucleotide diphosphates and other inhibitory ligands of the K_ATP channel is known to be complex.^{32 33} Specifically, in the presence of nucleotide diphosphates, K_ATP channels exhibit a dualistic response toward ATP and diadenosine polyphosphates depending on the operative condition of the channel.^{32 33 34} Two operative conditions of cardiac K_ATP channels have been described: the spontaneous operative condition and, after rundown of spontaneous activity, the UDP-induced operative condition.^{32 33} In the presence of nucleotide diphosphates, each operative condition exhibits a distinct responsiveness toward inhibitory ligands.^{32 33 34} This suggests that the operative condition, an intrinsic property of the cardiac K_ATP channel, may determine its response toward a ligand.^{5 32 33 34 35}

Whether such a concept also applies to the interaction between sulfonylureas and K_ATP channels has not been established. To address this, we investigated the inhibitory gating of cardiac K_ATP channels by sulfonylurea drugs under different operative conditions of the channel. Our data support the notion that the operative condition of cardiac K_ATP channels represents a critical determinant of the channel's responsive behavior toward sulfonylurea drugs.

	Materials and Methods

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Isolated Cardiomyocytes
Ventricular myocytes were isolated by enzymatic dissociation.^{36 37} Solutions were prepared on the basis of a "low-Ca²⁺ medium" (in mmol/L): NaCl 100, KCl 10, KH₂PO₄ 1.2, MgSO₄ 5, glucose 20, taurine 50, and HEPES 10 (pH 7.2 to 7.3). Guinea pigs were anesthetized with pentobarbital (1 mL/100 mg of weight IP). After cardiotomy, the heart was retrogradely perfused (at 37°C) with the following: medium 199 (Sigma) for 2 to 3 minutes, followed by Ca²⁺-EGTA–buffered low-Ca²⁺ medium (pCa 7) for 80 seconds, and finally low-Ca²⁺ medium containing pronase E (8 mg per 100 mL, Serva), proteinase K (1.7 mg per 100 mL, Boehringer Mannheim), bovine albumin (0.1 g per 100 mL, fraction V, Sigma), and 200 µmol/L CaCl₂. Ventricles were separated from atria and cut into small fragments (6 to 10 mm³) in the low-Ca²⁺ medium enriched with 200 µmol/L CaCl₂. Single cells were then isolated by stirring the tissue (at 37°C) in a solution containing pronase E and proteinase K supplemented with collagenase (5 mg per 10 mL, Worthington). After 10 minutes, the first aliquot was removed, filtered through a nylon sieve, centrifuged (at 300 to 400 rpm), and washed twice. Remaining tissue fragments were reexposed to collagenase, and isolation continued for two to three such cycles. Isolated cardiomyocytes were stored in low-Ca²⁺ medium with 200 µmol/L CaCl₂. Rod-shaped cardiomyocytes with clear striations and smooth surface were used for electrophysiological recordings. Experiments were performed with the approval of the Institutional Animal Care and Use Committee.

Single-Channel Recording
Fire-polished pipettes, coated with Sylgard (resistance 5 M), were filled with "pipette solution" (in mmol/L): KCl 140, CaCl₂ 1, MgCl₂ 1, and HEPES-KOH 5 (pH 7.3). Cardiac cells were superfused with "internal solution" (in mmol/L): KCl 140, MgCl₂ 1, EGTA 5, and HEPES-KOH 5 (pH 7.3), in the absence or presence of the sulfonylurea drug glyburide and/or nucleotides (UDP or ATP), and recordings were made at room temperature (20°C to 22°C) as described.^{38 39 40 41} Unless otherwise indicated, experiments were performed in the presence of Mg²⁺, which is necessary for UDP to activate channel opening,⁴² allowing direct comparison of the effect of sulfonylurea under different operative conditions of the channel. Glyburide (Sigma) was dissolved in dimethylsulfoxide as concentrated stock solution. The final concentration of dimethyl sulfoxide was <0.1%, which did not affect K_ATP channels. UDP (Boehringer Mannheim) and ATP (potassium salt, Sigma) were dissolved in internal solution before use. Single-channel recordings in the inside-out configuration were monitored on-line on a high-gain digital storage oscilloscope (VC-6025, Hitachi) and stored on tape using a PCM converter system (VR-10, Instrutech). Data were reproduced, low pass–filtered at 1 kHz (-3 dB) by a Bessel filter (Frequency Devices 902), sampled at an 80-microsecond rate, and further analyzed using the "BioQuest" software.³⁷

Analysis of Channel Activity
The threshold for judging the open state of K_ATP channels was set at half single-channel amplitude. The degree of channel activity was assessed by digitizing segments of current records, and expressed as NP₀, where N represents the number of channels in the patch and P₀ the probability of each channel to be open. In addition, NP₀ values were expressed in a cumulative manner where appropriate, and the slope of cumulative NP₀ values were fitted by linear regression. Computed slopes of cumulative NP₀ are less dependent on fluctuations of channel activity than commonly used average NP₀, the latter reflecting stochastic channel behavior rather than integrative channel activity.^{37 40 41} Because fluctuations in NP₀ during experimental time could be large, making interpretation of changes in channel activity difficult, concentration-response relationships were constructed on the basis of ratios between slopes of cumulative NP₀ measured in the presence of a drug and the value obtained in the absence of a drug. Results are expressed as mean±SE; n refers to the number of myocytes used in each analysis. Vertical bars in the graphs correspond to SE.

	Results

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Glyburide Fails to Inhibit Spontaneous K_ATP Channel Opening in the Presence of UDP
After excision of a membrane patch from a ventricular myocyte, K_ATP channel activity was spontaneously operative (Fig 1A). Application of the nucleotide diphosphate UDP (1 mmol/L) did not significantly alter spontaneous K_ATP channel activity (average slope of cumulative NP₀=3.79±1.65 s^-1 before UDP and 3.87±1.08 s^-1 after the addition of UDP, n=6). In the continuous presence of UDP, addition of glyburide (3 µmol/L) did not inhibit channel opening (average slope of cumulative NP₀=3.31±1.0 s^-1 in UDP and 3.30±1.01 s^-1 in UDP plus glyburide, n=5). On washout of UDP, glyburide (3 µmol/L) inhibited K_ATP channel activity (average slope of cumulative NP₀=3.67±2.58 s^-1 before and 0.02±0.001 s^-1 after addition of glyburide, n=5). Thus, the nucleotide diphosphate prevented the sulfonylurea from inhibiting spontaneously operative K_ATP channels (Fig 1A). This effect of UDP required the presence of Mg²⁺. In the absence of Mg²⁺, glyburide inhibited K_ATP channel activity despite the presence of UDP. Specifically, the cumulative NP₀ was measured at 2.43±1.15 s^-1 in the presence of UDP (1 mmol/L) alone but decreased to 0.03±0.01 s^-1 in the presence of UDP plus glyburide (3 µmol/L, n=4), a value not significantly different from that obtained in the presence of glyburide alone.

View larger version (36K): [in this window] [in a new window]   Figure 1. UDP antagonizes glyburide-induced inhibition of spontaneously operative, but not of UDP-induced post-rundown, KATP channels. A, Spontaneously operative channels after excision of a membrane patch at time 0. In the presence of UDP, glyburide could not inhibit channel activity. In this patch, washout of both ligands led to a transient decrease in the level of channel activity (perhaps due to different rates of washout of the hydrophobic glyburide compared with the hydrophilic UDP), with subsequent return of channel activity to preligand levels. In the absence of UDP, glyburide inhibited spontaneously operative channels. B, After rundown of spontaneous channel activity, the UDP-induced KATP channel openings were inhibited by glyburide. Upper traces in both panels show continuous channel records. Dotted lines correspond to zero-current level. Holding potential was -60 mV. Lower traces in both panels show NP0 values (where N represents the number of channels in the patch and P0 the probability of each channel to be open), corresponding to respective trace records, that were calculated over 2.56-second–long intervals.

Glyburide Inhibits UDP-Induced "Post-Rundown" K_ATP Channel Opening
Spontaneous K_ATP channel activity declines (rundown), with a varying time-course, after excision of a membrane patch. After rundown, 1 mmol/L UDP could restore channel opening (from an NP₀ of 0 to 4.22±0.75, n=18).⁴² The level of UDP-induced K_ATP channel activity (mean NP₀=4.51±0.1, Fig 1B) was similar to that measured in spontaneously operative channels before rundown (mean NP₀=4.1±0.03, Fig 1B). UDP-induced channel activity was readily blocked by glyburide (2 µmol/L) despite the continuous presence of the nucleotide diphosphate (mean NP₀ of 0, Fig 1B). Washout of glyburide was associated with partial reappearance of UDP-induced K_ATP channel activity (mean NP₀=0.96±0.15, Fig 1B). In other patches so tested, post-rundown UDP-induced K_ATP channel openings (average slope of cumulative NP₀=2.19±0.22 s^-1, n=3) were also inhibited by glyburide (2 µmol/L, average slope of cumulative NP₀=0.04±0.02 s^-1, n=3) despite the continuous presence of the nucleotide diphosphate. After washout of the sulfonylurea, the UDP-induced channel activity was partially restored (average slope of cumulative NP₀=0.17±0.05 s^-1, n=3). Thus, in contrast to spontaneous channel activity in which UDP antagonized the action of glyburide (Fig 1A), in UDP-induced post-rundown K_ATP channels, UDP could not antagonize the action of glyburide (Fig 1B) despite a high level of channel activity under both operative conditions.

Sulfonylurea Inhibition Under Different Operative Conditions of K_ATP Channels
In the absence of UDP, initial application of glyburide could readily inhibit sustained spontaneous K_ATP channel activity (mean NP₀=7.61±0.05 before and 0 after the addition of 3 µmol/L glyburide, Fig 2A). Washout of glyburide was associated with partial recovery of spontaneous K_ATP channel activity (mean NP₀=2.74±0.09, Fig 2A). Similar results were obtained in five patches. In the presence of UDP, repetitive application of glyburide (3 and 10 µmol/L) failed to inhibit sustained spontaneous K_ATP channel activity (mean NP₀=1.59±0.01 before the addition of UDP, 1.6±0.01 after the addition of 1 mmol/L UDP, 1.55±0.01 in UDP plus 3 µmol/L glyburide, and 1.6±0.02 in UDP plus 10 µmol/L glyburide; Fig 2B). Similar results were obtained in five patches. Thus, inhibition of spontaneously operative channel activity by glyburide could not occur even after repeated exposure of the K_ATP channel to the sulfonylurea in the presence of UDP.

View larger version (30K): [in this window] [in a new window]   Figure 2. A, Initial application of glyburide inhibits spontaneous KATP channel activity. B, Repeated application of glyburide failed to inhibit spontaneous KATP channel activity in the presence of UDP. Upper traces in panels A and B show continuous channel records. Dotted lines correspond to zero-current level. Holding potential was -60 mV. Lower traces in panels A and B show NP0 values (where N represents the number of channels in the patch and P0 the probability of each channel to be open), corresponding to respective trace records, that were calculated over 1.28- second–long intervals. C, Comparison of the effect of glyburide on KATP channel opening, in the absence and presence of UDP, under distinct operative conditions of the channel. indicates spontaneous operative condition in the absence of UDP; , spontaneous operative condition in the presence of UDP (1 mmol/L); , UDP-induced post- rundown operative condition in the presence of UDP (1 mmol/L). Data points are from 3 to 7 patches. Relative effect of glyburide was calculated in each patch as a ratio of the slopes of cumulative NP0 measured in the presence of glyburide to the value obtained in the absence of glyburide. Solid line was drawn according to the following equation: y={1+[glyb/Kd]n}-1, where y is relative effect, glyb is the concentration of glyburide, Kd is glyburide concentration at half-maximal effect, and n is the Hill coefficient. Dashed line indicates linear regression.

To determine the relationship between UDP and glyburide, the inhibitory effect of glyburide on K_ATP channels was compared under different operative conditions of the channel (Fig 2C). In the absence of UDP, spontaneously operative K_ATP channel activity was abolished by glyburide at concentrations in excess of 10 µmol/L, with an estimated inhibitory K_d value and Hill coefficient of 0.13 µmol/L and 0.95, respectively (Fig 2, open circles). In the presence of UDP, spontaneously operative K_ATP channel could not be inhibited by glyburide, even at concentrations up to 100 µmol/L (Fig 2, solid circles). After rundown of spontaneous channel activity, K_ATP channel activity induced by 1 mmol/L UDP channel activity was inhibited by glyburide with an apparent efficacy (in the micromolar range; Fig 2, solid triangles) similar to that obtained for spontaneously operative channels in the absence of UDP (Fig 2, open circles). Thus, UDP did not act through competitive displacement of the sulfonylurea but appeared to "switch off" the glyburide sensitivity of spontaneous, but not of UDP-induced post-rundown, K_ATP channels.

Interaction Between UDP and Glyburide Is Modulated by Mg-ATP
Mg-ATP treatment has been reported to convert post-rundown K_ATP channels into spontaneously operative channels.^{15 33} After rundown of spontaneous K_ATP channel activity, treatment (10 to 15 minutes) of excised membrane patches with millimolar concentrations of Mg-ATP (5 mmol/L) restored spontaneous channel activity (Fig 3A, from a mean NP₀ of 0 before treatment to 5.3±0.2 after Mg-ATP treatment). Under this condition, UDP (1 mmol/L) prevented glyburide (3 µmol/L) from inhibiting K_ATP channel opening (Fig 3A, mean NP₀=5.95±0.06 in UDP alone and 5.94±0.02 in UDP plus glyburide). After washout of both UDP and glyburide, K_ATP channel activity remained vigorous (mean=5.78±0.11, Fig 3A) but could then be inhibited by glyburide (Fig 3A). Removal of glyburide was associated with partial recovery of spontaneous K_ATP channel activity (mean=1.71±0.2, Fig 3A). Thus, restoration of spontaneous channel activity by Mg-ATP is associated with loss of sensitivity of K_ATP channels toward glyburide in the presence of UDP.

View larger version (30K): [in this window] [in a new window]   Figure 3. . Conversion from rundown to spontaneously operative KATP channels by Mg-ATP is required for UDP to antagonize glyburide-induced channel inhibition. The upper traces of panels A and B show original channel records from excised patches; the lower traces show the corresponding NP0 values (where N represents the number of channels in the patch and P0 the probability of each channel to be open) calculated over 2.56-second–long intervals. Treatments (from 105 to 590 seconds of the record shown in panel A and from 90 to 525 seconds of the record in panel B) of rundown KATP channels with Mg-ATP (followed by its removal) did (in panel A) or did not (in panel B) restore spontaneous channel activity. This was associated with UDP preventing (in panel A) or failing to prevent (in panel B) glyburide-induced channel block (from 630 to 670 seconds of the record in shown in panel A and from 570 to 610 seconds of the record shown in panel B). Dotted line with original trace corresponds to zero-current level. Holding potential was -60 mV.

Restoration of spontaneous channel activity by Mg-ATP was observed in four of eight patches so tested. An example of the response to glyburide in a patch in which Mg-ATP did not restore spontaneous openings is shown in Fig 3B. After rundown, UDP (5 mmol/L) induced vigorous channel activity (mean NP₀=7.06±0.16, Fig 3B), which was readily inhibited by ATP (500 µmol/L, Fig 3B). After washout of Mg-ATP, restoration of spontaneous K_ATP channel activity did not occur (Fig 3B). Under this condition, reapplication of UDP (5 mmol/L) again induced strong K_ATP channel activity (mean NP₀=7.04±0.21, Fig 3B) that was inhibited by glyburide (Fig 3B). Washout of glyburide was associated with partial reappearance of UDP-induced channel activity (mean NP₀=1.65±0.12, Fig 3B). Thus, in the absence of spontaneous K_ATP channel activity, UDP failed to prevent inhibition of channel opening by glyburide.

	Discussion

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Our results suggest that the response of cardiac K_ATP channels toward sulfonylureas in the presence of nucleotide diphosphates is determined by the operative condition of the channel. Spontaneous channel activity was associated with apparent loss of sensitivity toward glyburide in the presence of UDP. However, UDP-induced channel activity, after rundown of spontaneous channel openings, was sensitive toward glyburide despite the presence of UDP. Conversion from rundown to spontaneously operative channel activity by Mg-ATP restored channel insensitivity toward glyburide in the presence of UDP. Thus, cardiac K_ATP channels may exhibit distinct responses in the presence of the same ligands as the channel switches from one operative condition to the other.

The inhibitory action of sulfonylureas on K_ATP channels distinguishes these channels from other inwardly rectifying K⁺ channels.^{3 6 16 19 20 21 43 44 45} Yet the sensitivity of cardiac K_ATP channels toward sulfonylureas can be affected by several factors extrinsic to the channel proteins. These include changes in the ratio of intracellular nucleotides,^{24 46} extreme hypoxia,²⁵ intracellular protons,³⁷ and disruption of the cytoskeletal network in the channel microenvironment.⁴⁷ The present study indicates that, in addition to these factors, an intrinsic property of the cardiac K_ATP channel may also be important in regulating channel response toward sulfonylureas.

Evidence that an intrinsic property of K_ATP channels may govern its response toward nucleotides has been reported previously.^{5 32 33 34 35} Specifically, the operative condition of cardiac K_ATP channels was shown to determine channel response toward ATP,³³ as well as diadenosine tetraphosphate and pentaphosphate.³⁴ However, this observation could not be established as a general property of K_ATP channels because of possible confounding effects between nucleotides used in previous studies. The present study suggests that inhibitory gating of the cardiac K_ATP channel by a nonnucleotide, such as a sulfonylurea drug, appears also to be a direct function of the operative condition of the channel. Thus, the operative condition–dependent response toward ligands is a general property of cardiac K_ATP channels.

The inability of glyburide to inhibit spontaneously operative K_ATP channels in the presence of UDP is in accord with previous studies that found that various sulfonylureas, even at hundreds of micromoles, could not block cardiac K_ATP channels in the presence of nucleotide diphosphates when the channel is in the spontaneously operative state.^{24 46} However, the observation that glyburide could inhibit the UDP-restored openings of post-rundown K_ATP channels indicates that UDP and sulfonylureas do not compete under this condition, as also reported for ADP and glyburide.⁴⁶ We have been unable to determine whether the nucleotide binding site that antagonizes the effect of the sulfonylurea during spontaneous channel openings is distinct from the site that induces openings in post-rundown channels. However, since both required the presence of Mg²⁺, it is possible that a single Mg²⁺-dependent mechanism of action of nucleotide diphosphates is responsible for both the sulfonylurea antagonism in the spontaneous operative condition and the stimulation of channel opening after the rundown of spontaneous channel activity.^{24 33 42 46}

Our finding that Mg-ATP could "switch on" UDP regulation of glyburide-inhibitory gating suggests that a phosphorylation process may underlie changes in the operative condition. Previously, it has been shown that K_ATP channel activity and transition between operative conditions of the channel depend on a Mg-ATP–dependent process affecting the channel itself or its microenvironment.^{33 48 49 50 51 52 53} It is now known that K_ATP channel subunits possess phosphorylation sites^{7 8 9 10 11 12 13 14} that can be modulated by protein kinase activity.⁵¹ Phosphorylation of the channel has been proposed also to be a requirement for the UDP-induced regulation of ATP-dependent inhibitory channel gating.³³ Thus, the phosphorylation state of the K_ATP channel or associated proteins may be a critical determinant of the channel's responsive behavior toward inhibitory ligands. However, phosphorylation of channel proteins is not the sole determinant of the channel's dual response to inhibitory ligands, since in the absence of a nucleotide diphosphate K_ATP channels displayed unaltered sensitivity to either sulfonylurea (present study) or ATP.³³ Thus, UDP modulates the behavior of phosphorylated channel proteins that, in turn, set the operative state of the channel. Although the physiological role of UDP in a cardiomyocyte is not fully understood, previous findings with ADP suggest that this may be a general property of nucleotide diphosphates.^{24 46}

In summary, the present study describes the property of cardiac K_ATP channels to function as regulators of their response toward sulfonylureas. This finding could have important implications for the use of sulfonylurea drugs as therapeutic agents, since the outcome of their action will depend not only on their actual concentration and/or levels of cytosolic nucleotide diphosphates but also on the operative condition of the cardiac K_ATP channel.

	Acknowledgments

 
This study was supported through the Bruce and Ruth Rappaport Program in Vascular Biology and Gene Delivery. Dr Terzic is a recipient of research grants from the Miami Heart Research Institute, the American Heart Association, the George M. Einseberg Cardiovascular Research Fund, and the Harrington Professorship Fund. Dr Brady is a recipient of a General Mills Clinician-Investigator Fellowship.

Received April 18, 1997; accepted October 24, 1997.

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