Volume 133, Issue 1 p. 193-199

Free Access

Glimepiride block of cloned β-cell, cardiac and smooth muscle K_ATP channels

Dae-Kyu Song,

Dae-Kyu Song

Department of Physiology, Keimyung University School of Medicine, 194 Dongsan Dong, Choong Gu, Taegu, 700-712 Korea

Current address: University Laboratory of Physiology, Parks Road, Oxford OX1 3PT

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Frances M Ashcroft,

Corresponding Author

Frances M Ashcroft

University Laboratory of Physiology, Parks Road, Oxford OX1 3PT

University Laboratory of Physiology, Parks Road, Oxford OX1 3PT. E-mail: [email protected]Search for more papers by this author

Dae-Kyu Song,

Dae-Kyu Song

Department of Physiology, Keimyung University School of Medicine, 194 Dongsan Dong, Choong Gu, Taegu, 700-712 Korea

Current address: University Laboratory of Physiology, Parks Road, Oxford OX1 3PT

Search for more papers by this author

Frances M Ashcroft,

Corresponding Author

Frances M Ashcroft

University Laboratory of Physiology, Parks Road, Oxford OX1 3PT

University Laboratory of Physiology, Parks Road, Oxford OX1 3PT. E-mail: [email protected]Search for more papers by this author

First published: 29 January 2009

https://doi.org/10.1038/sj.bjp.0704062

Citations: 62

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Abstract

We examined the effect of the sulphonylurea glimepiride on three types of recombinant ATP-sensitive potassium (K_ATP) channels.
K_ATP channels share a common pore-forming subunit, Kir6.2, which associates with different sulphonylurea receptor isoforms (SUR1 in β-cells, SUR2A in heart and SUR2B in smooth muscle).
Kir6.2 was coexpressed with SUR1, SUR2A or SUR2B in Xenopus oocytes and macroscopic K_ATP currents were recorded from giant inside-out membrane patches. Glimepiride was added to the intracellular membrane surface.
Glimepiride inhibited Kir6.2/SUR currents by interaction with two sites: a low-affinity site on Kir6.2 (IC₅₀=∼400 μM) and a high-affinity site on SUR (IC₅₀=3.0 nM for SUR1, 5.4 nM for SUR2A and 7.3 nM for SUR2B). The potency of glimepiride at the high-affinity site is close to that observed for glibenclamide (4 nM for SUR1, 27 nM for SUR2A), which has a similar structure.
Glimepiride inhibition of Kir6.2/SUR2A and Kir6.2/SUR2B currents, but not Kir6.2/SUR1 currents, reversed rapidly.
Our results indicate that glimepiride is a high-affinity sulphonylurea that does not select between the β-cell, cardiac and smooth muscle types of recombinant K_ATP channel, when measured in inside-out patches. High-affinity inhibition is mediated by interaction of the drug with the sulphonylurea receptor subunit of the channel.

British Journal of Pharmacology (2001) 133, 193–199; doi:10.1038/sj.bjp.0704062

Abbreviations:

K_ATP channel: ATP-sensitive potassium channel
SUR: sulphonylurea

Introduction

Sulphonylureas stimulate insulin secretion from pancreatic β-cells and are widely used in the treatment of type 2 diabetes mellitus. Their principal target is the ATP-sensitive potassium (K_ATP) channel, which plays a major role in controlling the β-cell membrane potential. Inhibition of K_ATP channels by glucose or sulphonylureas causes depolarization of the β-cell membrane; in turn, this triggers the opening of voltage-gated Ca²⁺ channels, eliciting Ca²⁺ influx and a rise in intracellular Ca²⁺ which stimulates the exocytosis of insulin-containing secretory granules (^{Ashcroft & Rorsman, 1989}).

K_ATP channels are also found at high density in a variety of other cell types including cardiac, smooth and skeletal muscle, and some brain neurones (^{Ashcroft & Ashcroft, 1990}). Although their roles in extra-pancreatic tissues are less well characterised, it is likely that they open in response to metabolic stress, such as that which occurs during cardiac and cerebral ischaemia (^{Nichols & Lederer, 1991}). They are also important in the control of vascular smooth muscle tone, and thus of blood pressure (^{Quayle et al., 1997}). It is therefore of importance to know the affinity of the different types of K_ATP channel for the various sulphonylureas.

The K_ATP channel is a hetero-octameric complex of two structurally distinct proteins: an inwardly-rectifying K-channel, Kir6.2, and a sulphonylurea receptor, SUR (^{Aguilar-Bryan et al., 1995}; ^{Inagaki et al., 1995}; ¹⁹⁹⁶; ¹⁹⁹⁷; ^{Isomoto et al., 1996}; ^{Sakura et al., 1995}; ^{Clement et al., 1997}; ^{Shyng & Nichols, 1997}). The former acts as an ATP-sensitive K-channel pore while SUR is a channel regulator which endows Kir6.2 with sensitivity to drugs such as the inhibitory sulphonylureas and the K-channel openers (^{Tucker et al., 1997}). K_ATP channels in different tissues usually share a common Kir6.2 subunit, but possess different types of SUR subunit, which accounts for their different drug sensitivities (^{Ashcroft & Gribble, 1998}; ¹⁹⁹⁹). The β-cell K_ATP channel is composed of Kir6.2 and SUR1, the cardiac type of Kir6.2 and SUR2A and that in some smooth muscle types, probably, of Kir6.2 and SUR2B (smooth muscle channels may also be composed of Kir6.1 and SUR2B subunits). Both Kir6.2/SUR1 and Kir6.2/SUR2B combinations are also found in the brain. Although wild-type K_ATP channels require both types of subunit (Kir6.2 and SUR) for functional activity, a mutant form of Kir6.2 with a C-terminal truncation of ∼20 – 40 amino acids (Kir6.2ΔC) is capable of independent expression (^{Tucker et al., 1997}). Kir6.2ΔC therefore provides a useful tool for studying the effects of drugs on the pore-forming subunit of the K_ATP channel.

A number of studies suggest that the different types of K_ATP channel exhibit different specificities towards the various sulphonylureas. In particular, both tolbutamide and gliclazide inhibit Kir6.2/SUR1, but not Kir6.2/SUR2A, channels by interaction with a high-affinity site located on SUR1 (^{Gribble et al., 1997b}; ^{Gribble & Ashcroft, 1999}). Similar results have been reported for glibenclamide block of native β-cell and cardiac K_ATP channels (^{Trube et al., 1986}; ^{Ventakesh et al., 1991}). These results suggest that only SUR1 possesses a high-affinity binding site for these sulphonylureas. In contrast, meglitinide, a benzamido derivative equivalent to the non-sulphonylurea moiety of glibenclamide, mediates high-affinity inhibition of both β-cell and cardiac types of K_ATP channel (native and recombinant) (^{Garrino et al., 1985}; ^{Gribble et al., 1997b}; ¹⁹⁹⁸). These results have been interpreted to indicate that both SUR1 and SUR2A may possess a benzamido-binding site. Like meglitinide, but in contrast to tolbutamide, glibenclamide blocks both native and recombinant β-cell and cardiac K_ATP channels with high affinity (^{Gribble et al., 1998}; ^{Zünckler et al., 1988a}; ^{Barret-Jolley & McPherson, 1998}; ^{Findlay, 1992}). Because glibenclamide contains both the sulphonylurea and benzamido moieties, this suggests that the drug may bind simultaneously to both tolbutamide and benzamido-binding sites of SUR1, but only to the benzamido-binding site on SUR2A. This may account for the fact that inhibition of Kir6.2/SUR1 currents by glibenclamide is only poorly reversible in electrophysiological experiments, while inhibition of Kir6.2/SUR2A and Kir6.2/SUR2B currents is readily reversed (^{Ashcroft & Gribble, 1999}).

Glimepiride (Figure 1) is a sulphonylurea that stimulates insulin secretion and has recently been introduced for the treatment of type-2 diabetes. Despite blocking K_ATP channels in pancreatic β-cells with high affinity (^{Schwanstecher et al., 1994}) it has been suggested that the mechanism of action of glimepiride differs from that of other sulphonylureas (^{Kramer et al., 1994}, ¹⁹⁹⁶; ^{Müller et al., 1994}). In this paper we examine the effect of glimepiride on three types of recombinant K_ATP channels expressed in Xenopus oocytes: Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B. These correspond to the β-cell, cardiac and smooth muscle types of K_ATP channel, respectively. We conclude that the drug blocks all three types of K_ATP channel with similar efficacy in excised membrane patches, and that its mechanism of action is similar to that of glibenclamide.

Details are in the caption following the image — **Figure 1**
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Molecular structures of tolbutamide, glibenclamide,glimepiride and meglitinide.

Methods

Molecular biology

Mouse Kir6.2 (Genbank D50581; ^{Inagaki et al., 1995}; ^{Sakura et al., 1995}), rat SUR1 (Genbank L40624; ^{Aguilar-Bryan et al., 1995}), SUR2A (Genbank D83598; ^{Inagaki et al., 1996}) and SUR2B (Genbank D86038; ^{Isomoto et al., 1996}) cDNAs were cloned into the pBF vector. A truncated form of Kir6.2 (Kir6.2ΔC36), which lacks the C-terminal 36 amino acids and forms functional channels in the absence of SUR, was prepared as described previously (^{Tucker et al., 1997}). Capped mRNA was prepared using the mMESSAGE mMACHINE large scale in vitro transcription kit (Ambion, Austin, TX, U.S.A.), as previously described (^{Gribble et al., 1997a}).

Oocyte collection

Female Xenopus laevis were anaesthetized with MS222 (2 g l⁻¹ added to the water). One ovary was removed via a mini-laparotomy, the incision sutured and the animal allowed to recover. Immature stage V – VI oocytes were incubated for 60 min with 1.0 mg ml⁻¹ collagenase (Sigma, type V) and manually defolliculated. Oocytes were either injected with ∼1 ng Kir6.2ΔC36 mRNA or coinjected with ∼0.1 ng Kir6.2 mRNA and ∼2 ng of mRNA encoding either SUR1, SUR2A or SUR2B. The final injection volume was 50 nl per oocyte. Isolated oocytes were maintained in Barth's solution and studied 1 – 4 days after injection (^{Gribble et al., 1997a}).

Electrophysiology

Patch pipettes were pulled from borosilicate glass and had resistances of 250 – 500 kΩ when filled with pipette solution. Macroscopic currents were recorded from giant excised inside-out patches at a holding potential of 0 mV and at 20 – 24°C (^{Gribble et al., 1997a}). Currents were evoked by repetitive 3 s voltage ramps from −110 mV to +100 mV and recorded using an EPC7 patch-clamp amplifier (List Electronik, Darmstadt, Germany). They were filtered at 10 kHz, digitized at 0.4 kHz using a Digidata 1200 Interface and analysed using pClamp 8 software (Axon Instruments, Foster City, U.S.A.). Records were stored on videotape and resampled at 20 Hz for presentation in the figures.

The pipette (external) solution contained (mM): KCl 140, MgCl₂ 1.2, CaCl₂ 2.6, HEPES 10 (pH 7.4 with KOH). The intracellular (bath) solution contained (mM): KCl 107, MgCl₂ 2, CaCl₂ 1, EGTA 10, HEPES 10 (pH 7.2 with KOH; final [K⁺]∼140 mM). Glimepiride (supplied by IRIS) was prepared as a 50 mM stock solution in DMSO, and the pH of the bath solution was readjusted after drug addition. The final [K⁺] was about 140 mM after addition of glimepiride.

Rapid exchange of solutions was achieved by positioning the patch in the mouth of one of a series of adjacent inflow pipes placed in the bath. Test solutions were applied in random order, and patches were exposed to 1 mM MgATP at intervals throughout the experiment, to reverse channel rundown.

In a previous study of glimepiride on native K_ATP currents (^{Schwanstecher et al., 1994}), pancreatic β-cells were preincubated with the drug and the K_ATP current subsequently measured as the whole-cell current activated on washout of cellular ATP. The current amplitudes were then compared with those of β-cells that had not been exposed to the drug. This strategy relies on two assumptions: (i) that all cells express approximately the same amount of K_ATP current (because it is not possible to record the control current, in the absence of the drug, in the same β-cell); and (ii), that the drug does not accumulate inside the cell to a concentration higher than that in the external solution. Neither of these assumptions is valid for K_ATP channels heterologously expressed in Xenopus oocytes. The level of expression may vary from oocyte to oocyte; furthermore, the lipid-soluble sulphonylureas appear to accumulate within the oocyte (which has a high lipid content) because drugs like tolbutamide, which are readily reversible in excised patches, are not reversible on intact oocytes. We therefore added glimepiride to the intracellular surface of excised inside-out membrane patches.

Data analysis

The slope conductance was measured by fitting a straight line to the current-voltage relation between −20 mV and −100 mV: the average of five consecutive ramps was calculated in each solution. Data are presented as mean±1 s.e.mean.

Dose-response curves were fit to the following equation (^{Gribble et al., 1997b}):

where G is the conductance in the presence of glimepiride, G_c is the conductance in control solution, x is a term describing the high-affinity site and y is a term describing the low-affinity site.

where [Glim] is the glimepiride concentration, IC₅₀₍₁₎, IC₅₀₍₂₎ are the glimepiride concentrations at which inhibition is half maximal at the high and low-affinity sites, respectively; h1, h2 are the Hill coefficients (slope factors) for the high and low-affinity sites, respectively; and L is the fractional conductance remaining when the high-affinity sites are maximally occupied. When only a single site is present, the equation reduces to

(eqn 4). Data were fit using Microcal Origin software.

To control for the rundown of channel activity that occurs in excised patches, dose-response curves for Kir6.2/SUR1 currents were constructed by expressing the conductance in the presence of glimepiride as a fraction of the conductance measured in control solution before addition of the drug. Because the drug was essentially irreversible on the time scale of our experiments, it was not possible to calculate the mean conductance in control solution before and after drug addition. The lack of reversibility also meant that a drug concentration could only be applied to a given patch once. Thus each data point represents a different oocyte.

Results

Macroscopic currents were recorded in inside-out membrane patches from Xenopus oocytes coexpressing Kir6.2 and either SUR1, SUR2A or SUR2B. In all cases, the currents were small in the cell-attached configuration but increased markedly when the patch was excised into nucleotide-free solution, consistent with the idea that the K_ATP channel is blocked in the intact oocyte by cytoplasmic nucleotides such as ATP.

Figure 2 shows that application of 1 μM glimepiride to the intracellular membrane surface blocked all three types of K_ATP channel, to a similar extent. The mean block of Kir6.2/SUR1 currents was 80±2% (n=7), of Kir6.2/SUR2A currents was 78±2% (n=12), and of Kir6.2/SUR2B currents was 80±3% (n=8). The very slow decline in current observed in the presence of glimepiride in some patches is probably due to rundown of channel activity, as a similar decrease is also observed in control solution (^{Tucker et al., 1997}). It is believed to result from a gradual fall in the membrane concentration of the phospholipid PIP₂ (^{Baukrowitz et al., 1998}; ^{Shyng & Nichols, 1998}).

The block of Kir6.2/SUR1 currents was not reversible on the time scale of our experiments for any drug concentration (Figure 2). In contrast, inhibition of Kir6.2/SUR2A and Kir6.2/SUR2B currents by glimepiride concentrations of <100 μM was partially reversed on return to control solution; at higher drug concentrations, however, the block was also irreversible.

The relationship between the glimepiride concentration and the K_ATP current for Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B channels is shown in Figure 3. As with other sulphonylureas, inhibition of Kir6.2/SUR1 currents by glimepiride (Figure 3a) was best fit by assuming that the drug interacted with both high and low-affinity sites. The IC₅₀s of these sites were 3.0±0.5 nM and 234±139 μM (n=5 – 13), respectively. Likewise, glimepiride blocked Kir6.2/SUR2A (Figure 3b) and Kir6.2/SUR2B (Figure 3c). currents by interaction with both a high-affinity and a low-affinity site. The IC₅₀s were 5.4±0.1 nM and 104±56 μM (n=6 – 12), respectively, for Kir6.2/SUR2A currents and 7.3±0.2 nM and 98.9±75 μM (n=5 – 13), respectively, for Kir6.2/SUR2B currents.

The Hill coefficients for the high-affinity site were 0.64±0.06 (n=5 – 13) and 0.69±0.09 (n=6 – 12) for channels containing SUR1 and SUR2A, respectively. The fact that the Hill coefficient is less than unity may indicate that there is more than one binding site for the drug and that there is negative cooperativity between these sites. This may reflect the fact that the channel is a tetramer (^{Clement et al., 1997}; ^{Shyng & Nichols, 1997}). In the case of glibenclamide, it appears all four subunits bind the drug although occupation of a single site is sufficient to induce channel closure, (^{Dörschner et al., 1999}).

Low-affinity inhibition of Kir6.2/SUR1 and Kir6.2/SUR2A channels by other sulphonylureas is not conferred by the sulphonylurea receptor, because it is observed when truncated Kir6.2 subunits (Kir6.2ΔC36) are expressed in the absence of SUR (^{Gribble et al., 1997b}; ¹⁹⁹⁸). To investigate whether the low-affinity site for glimepiride inhibition is also independent of SUR, we tested the effect of the drug on Kir6.2ΔC36 channels. Figure 4 shows that glimepiride blocked Kir6.2ΔC36 currents at low affinity, with an IC₅₀ of around 0.4 mM, suggesting that the low-affinity site for glimepiride inhibition lies on Kir6.2 itself. It was not possible to dissolve the drug at concentrations greater than 0.5 mM, so that the IC₅₀ could not be accurately determined. Fitting of equation 4 to the data, however, gave an estimated IC₅₀ of 388±95 μM (n=2 – 12).

Discussion

Our results demonstrate that glimepiride blocks Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B channels by interaction with both a high-affinity and a low-affinity site. The high-affinity sulphonylurea site is located on the SUR subunit, while the low-affinity site is likely to reside on the Kir6.2 subunit, because it was also observed for Kir6.2ΔC36 currents.

The IC₅₀ for high-affinity inhibition of Kir6.2/SUR1 currents by glimepiride was 3 nM. This value is in good agreement with the K_i for binding of [³H]-glimepiride to intact β-cells or β-cell membranes (0.7 to 6.8 nM: ^{Müller et al., 1994}; ^{Schwanstecher et al., 1994}). It is, however, about 10 fold higher than that observed for inhibition of whole-cell K_ATP currents in isolated β-cells (IC₅₀ of 0.3 nM, ^{Schwanstecher et al., 1994}), This difference probably reflects differences in the experimental protocols. Our experiments were conducted on inside-out patches, rather than intact cells, to avoid the complicating effects of intracellular nucleotides on sulphonylurea inhibition. In contrast, ^{Schwanstecher et al. (1994)} preincubated β-cells with glimepiride and measured the whole-cell current activated by washout of ATP from the cell. This may be advantageous when the on-rate of the drug is slow, but may give a higher affinity if glimepiride accumulates inside the β-cell to a concentration higher than that in the extracellular solution. In contrast to the experiments reported here for K_ATP channels in excised patches, high-affinity block by glimepiride was complete in whole-cell recordings from β-cells, and thus low-affinity inhibition was not observed (^{Schwanstecher et al., 1994}). Similar findings have also been reported for tolbutamide and glibenclamide, and have been attributed to the presence of intracellular Mg-nucleotides (^{Trube et al., 1986}; ^{Zünckler et al., 1988b}; ^{Gribble et al., 1997b}).

Direct photoaffinity labelling of β-cell membrane proteins with radiolabelled sulphonylureas revealed that glibenclamide binds to a 140 kDa membrane protein, the sulphonylurea receptor (^{Aguilar-Bryan et al., 1995}; ^{Kramer et al., 1994}). In contrast, glimepiride selectively binds to a 65 kDa protein (^{Kramer et al., 1994}). Both sulphonylureas are able to displace binding of the other ligand to their respective receptors. These results have been interpreted by ^{Kramer et al. (1994}, ¹⁹⁹⁶⁾ to indicate that the K_ATP channel complex contains both 140 kDa and 65 kDa subunits, which interact allosterically; and that glimepiride binds to 65 kDa subunit and glibenclamide to the 140 kDa subunit. Our results support a different interpretation. We observed that glimepiride blocks Kir6.2/SUR currents but not Kir6.2ΔC36 currents with high affinity, indicating that high-affinity inhibition requires the presence of a sulphonylurea receptor subunit. It therefore seems probable that glimepiride, like glibenclamide, binds to the 140 kDa sulphonylurea receptor subunit. Recent studies have shown that mild trypsinization of SUR1 produces a 65 kDa fragment (^{Matsuo et al., 1999}). A possible explanation of the photoaffinity labelling studies, therefore, is that the SUR subunit is less susceptible to proteolysis when glibenclamide (but not glimepiride) is bound.

The responses of both Kir6.2/SUR1 and Kir6.2/SUR2A currents to glimepiride are qualitatively similar to those previously observed with glibenclamide, which also blocked both Kir6.2/SUR1 and Kir6.2/SUR2A currents at high- and low-affinity sites. The sensitivity of the high-affinity site on SUR1 to glibenclamide is similar to that for glimepiride, with IC₅₀s of 4.2 nM (^{Gribble et al., 1998}) and 3.0 nM, respectively. Likewise, glimepiride is roughly as potent as glibenclamide at blocking Kir6.2/SUR2A currents, the IC₅₀s being ∼5 nM and ∼27 nM (^{Gribble et al., 1997b}; ¹⁹⁹⁸), for glimepiride and glibenclamide respectively. Similar values were reported for whole-cell native cardiac K_ATP currents activated by rimakalim: an IC₅₀ of 32 nM was obtained for glimepiride block and one of 7 nM for glibenclamide block (^{Geisen et al., 1996}). This is perhaps not surprising, given the structural similarity of the two drugs. Thus it appears that both SUR1 and SUR2 possess a high-affinity site for glimepiride.

The block of Kir6.2/SUR1 currents by glimepiride, like that of glibenclamide, is effectively irreversible in electrophysiological experiments, while block of Kir6.2/SUR2A and Kir6.2/SUR2B currents is partially reversible at the lower drug concentrations. These data are consistent with the idea that SUR2 does not possess a high-affinity site for the sulphonylurea moiety of glibenclamide and glimepiride, and that these drugs block Kir6.2/SUR2 currents primarily through interaction with the benzamido site.

Glimepiride and glibenclamide blocked Kir6.2ΔC36 currents with IC₅₀s of ∼400 μM and 42 μM, respectively, suggesting that the low-affinity site on Kir6.2 is not very sensitive to the structural differences between the two drugs. When a therapeutic dose of glimepiride is administered orally, the reported free plasma drug concentration is less than 10 μM (^{Lehr & Damm, 1990}; ^{Schwanstecher et al., 1994}). Thus the inhibitory effect of glimepiride on Kir6.2 is unlikely to be of clinical relevance and the effect of the drug on insulin secretion is mediated entirely via the high-affinity site.

Our results demonstrate that, like glibenclamide, glimepiride blocks all three types of recombinant K_ATP channel with similar affinity in excised patches; and that the affinity for both drugs is similar. Yet a number of studies in the literature claim that glimepiride has less effect on the electrical properties of the heart in vivo than glibenclamide and has led to the suggestion that glibenclamide, but not glimepiride, decreases ‘ischemic preconditioning’ by blocking K_ATP channel activation (^{Geisen et al., 1996}; ^{Klepzig et al., 1999}). The reason for the differences between glibenclamide and glimepiride observed in vivo are unclear. One possibility is that the effects of glimepiride and glibenclamide on native cardiac K_ATP channels may not be identical in the intact cell. It is also worth pointing out that inhibition of whole-cell K_ATP currents by glimepiride may vary between different tissues, despite being identical in excised patches. In particular, intracellular Mg-nucleotides enhance the inhibitory effect of sulphonylureas in β-cells, but reduce inhibition in cardiac muscle (^{Zünckler et al., 1988b}; ^{Ventakesh et al., 1991}; ^{Gribble et al., 1998}). This finding, together with the fact that cardiac K_ATP channels are thought to be closed under physiological conditions and open only in response to ischaemic stress (^{Nichols & Lederer, 1991}), may help explain why sulphonylureas have relatively few side effects on the heart and why cardiac mortality is not different for diabetic patients on insulin or sulphonylurea therapy (^{UKPDS, 1998}).

In conclusion, our results suggest that therapeutic concentrations of glimepiride (10 μM; ^{Lehr & Damm, 1990}) block three types of recombinant K_ATP channel – Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B (corresponding to the β-cell, cardiac and smooth muscle types of K_ATP channel) with similar affinity in excised patches. They also indicate that this inhibition is produced by interaction of the drug with the SUR subunit of the channel.

Acknowledgments

We thank Dr Denis Ravel for discussion and advice. The work was supported by the Institut de Recherches Internationales Servier (IRIS).

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Citing Literature

Volume133, Issue1

May 2001

Pages 193-199

Glimepiride block of cloned β-cell, cardiac and smooth muscle K_ATP channels