State-dependent Inhibition of the Mitochondrial KATP Channel by Glyburide and 5-Hydroxydecanoate*

Martin JaburekDagger , Vladimir Yarov-YarovoyDagger , Petr Paucek, and Keith D. Garlid§

From the Department of Biochemistry and Molecular Biology, Oregon Graduate Institute of Science and Technology, Portland, Oregon 97291-1000

    ABSTRACT
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Abstract
Introduction
Procedures
Results
Discussion
References

The mitochondrial KATP channel (mitoKATP) is hypothesized to be the receptor for the cardioprotective effects of K+ channel openers (KCO) and for the blocking of cardioprotection by glyburide and 5-hydroxydecanoate (5-HD). Studies on glyburide have indicated that this drug is inactive in isolated mitochondria. No studies of the effects of 5-HD on isolated mitochondria have been reported. This paper examines the effects of glyburide and 5-HD on K+ flux in isolated, respiring mitochondria. We show that mitoKATP is completely insensitive to glyburide and 5-HD under the experimental conditions in which the open state of the channel is induced by the absence of ATP and Mg2+. On the other hand, mitoKATP became highly sensitive to glyburide and 5-HD when the open state was induced by Mg2+, ATP, and a physiological opener, such as GTP, or a pharmacological opener, such as diazoxide. In these open states, glyburide (K1/2 values 1-6 µM) and 5-HD (K1/2 values 45-75 µM) inhibited specific, mitoKATP-mediated K+ flux in both heart and liver mitochondria from rat. These results are consistent with a role for mitoKATP in cardioprotection and show that different open states of mitoKATP, although catalyzing identical K+ fluxes, exhibit very different susceptibilities to channel inhibitors.

    INTRODUCTION
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Abstract
Introduction
Procedures
Results
Discussion
References

During steady-state respiration, K+ influx into mitochondria is balanced by K+ efflux on the K+/H+ antiporter, and steady-state volume is maintained. Opening the mitochondrial KATP channel (mitoKATP)1 will increase K+ influx into mitochondria and shift matrix volume to a higher steady state. The energetic costs of this futile cycle are small, between 100-150 nmol of H+/mg of protein·min at 25 °C, and we have concluded that the sole function of mitoKATP is to regulate matrix volume (1). It has been suggested that matrix expansion secondary to mitoKATP opening plays an important role in cell-signaling pathways calling for activation of electron transport and stimulation of fatty acid oxidation (2).

A pharmacological role for mitoKATP in cardiac ischemia seems clearer. During prolonged cardiac ischemia, myocyte ATP levels fall, and the heart does not survive reperfusion. Either pretreatment with K+ channel openers (KCO) or preconditioning with a brief period of ischemia protects the heart; during subsequent ischemia, ATP loss is reduced, and the heart recovers to nearly normal function upon reperfusion (3). Importantly, cardioprotection by either KCO or preconditioning is blocked by glyburide and 5-HD. This set of agents, KCO, glyburide, and 5-HD, identifies the receptor as a KATP channel, and pharmacological studies indicate that mitoKATP is the receptor for these effects (4).

A major problem with this hypothesis has been that glyburide appears to be ineffective as a specific inhibitor of K+ flux in intact, respiring mitochondria (5). Nonspecific inhibition of K+ flux does occur (5); however, we have attributed this effect, which occurs at high doses of glyburide, to low affinity reactions with key energy-transducing enzymes (6-8). The effect of these nonspecific actions is to reduce Delta Psi , the driving force for K+ uptake, and has nothing to do with mitoKATP. We have now verified this conclusion in experiments that examine the effects of glyburide on both respiration and respiration-driven cation uptake into mitochondria.

Failure to inhibit mitoKATP seemed to be a property of both glyburide and 5-HD. We recognized, however, that these drugs had only been studied under conditions when no other ligands of mitoKATP were present, a condition that never obtains in vivo. We now report that glyburide and 5-HD are potent blockers of K+ flux through mitoKATP in open states in which Mg2+, ATP, and physiological (GTP) or pharmacological (KCO) openers are present. In intact rat heart mitochondria, K1/2 values for glyburide and 5-HD are about 1 and 50 µM, respectively. We infer that susceptibility to glyburide and 5-HD requires a ligand-induced conformational change in the mitochondrial sulfonylurea receptor (mitoSUR). These results are consistent with a role for mitoKATP in cardioprotection (4, 9).2

    EXPERIMENTAL PROCEDURES
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Abstract
Introduction
Procedures
Results
Discussion
References

Preparations-- Rat liver mitochondria were prepared according to Pedersen et al. (10), and rat heart mitochondria were prepared by the Glass-TeflonTM homogenization procedure according to Matlib et al. (11). The final mitochondrial pellet was washed and resuspended at 50 mg/ml (liver) or 20 mg/ml (heart) in 0.22 M mannitol, 0.07 M sucrose, and potassium salts of 5 mM TES and 0.5 mM EGTA. Mitochondria were kept on ice at pH 7.2 during the experiments. MitoKATP was purified and reconstituted as described previously (12).

Assay of Ion Transport in Intact Mitochondria-- K+ or TEA+ uptake was assayed by following swelling, which accompanies net salt transport, using previously established light-scattering techniques (13, 14). Reciprocal absorbance (A-1) at 520 nm varies linearly with matrix volume within three well defined regions, separated by transitions at 115 and 68 milliosmolal (13). beta  is a dimensionless parameter that normalizes A-1 for mitochondrial protein concentration, P (mg/ml),
&bgr;≡P/P<SUB>s</SUB>(A<SUP><UP>−</UP>1</SUP>−a), (Eq. 1)
where a is a machine constant (0.25 for our apparatus), and Ps equals 1 mg/ml.

To obtain initial rates (dbeta /dt), it is necessary to avoid the sharp discontinuities in the relationship between beta  and matrix volume. For ion flux measurements, we normally begin measurements at 115 milliosmolal, where the outer membrane begins to break (14). This technique is particularly important for light scattering of rat heart mitochondria, which is only weakly sensitive to volume changes in the isosmotic domain. Thus, kinetic curves in 250 milliosmolal salts exhibit an artifactual "lag" during salt uptake as volume goes through the first transition point (14).

115 milliosmolal assay media contained either K+ or TEA+ salts of chloride (45 mM), acetate (25 mM), EGTA (0.1 mM), and TES (5 mM), pH 7.4. Media also contained MgCl2 (0.1 mM), rotenone (5 µg/mg), and cytochrome c (10 µM). Respiratory substrates were either succinate (3 mM) or ascorbate (2.5 mM) plus TMPD (0.25 mM). Mitochondria were assayed at a concentration of 0.1 mg of protein/ml at 25 °C.

Measurement of Respiration-- Respiration was measured with a Yellow Springs oxygen electrode assembly in a hypotonic assay medium identical to the one used for measurement of K+ uptake, or in an isotonic assay medium consisting of K+ salts of chloride (120 mM), succinate (10 mM), phosphate (5 mM), TES (5 mM), and MgCl2 (0.1 mM), pH 7.4, supplemented with rotenone (2 µg/mg of protein). Mitochondria were assayed at 1 mg of protein/ml at 25 °C.

Assay of K+ Flux in Liposomes-- MitoKATP was partially purified from rat liver mitochondria and reconstituted into proteoliposomes loaded with PBFI according to previously published protocols (15). Internal medium contained TEA+ salts of sulfate (100 mM), EGTA (1 mM), and HEPES (25 mM) at pH 6.8. 15 µl of stock proteoliposomes (50 mg of phospholipids/ml) were added to 2 ml of external medium containing 150 mM KCl and TEA+ salts of EGTA (1 mM) and HEPES (25 mM), at pH 7.4. Temperature was maintained at 25 °C during assays. Electrophoretic K+ flux was initiated by the addition of 1 µM FCCP to provide charge compensation and measured from changes in PBFI fluorescence (12).

Chemicals and Reagents-- PBFI was obtained from Molecular Probes, Inc.; HEPES was obtained from Calbiochem; 5-HD was obtained from Research Biochemicals Inc.; and other drugs and chemicals were obtained from Sigma. The Tris salt of ATP was titrated to pH 7.2 with Tris base.

    RESULTS
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Abstract
Introduction
Procedures
Results
Discussion
References

Specific and Nonspecific Cation Flux in Respiring Heart Mitochondria-- Respiring mitochondria take up K+ by nonspecific and specific mechanisms, i.e. via diffusion and via mitoKATP. We used TEA+ to distinguish between these two parallel mechanisms, as demonstrated by the four traces in Fig. 1A. K+ flux (trace a) is greater than TEA+ flux (trace b). Addition of ATP inhibits K+ flux (trace c) but not TEA+ flux (trace d). These results, which are routinely observed in rat heart (Fig. 1) and liver (5) mitochondria, permit the following conclusions: (i) TEA+ is transported solely by diffusive leak (16) and is not transported by mitoKATP; and (ii) in the presence of ATP, K+ is transported solely by diffusion, and its flux equals that of TEA+. Thus, TEA+ flux may be used as a control for the component of K+ flux due to leak.


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Fig. 1.   ATP-dependent K+ uptake by mitochondria. Light-scattering traces from rat heart mitochondria respiring on ascorbate/TMPD in K+ or TEA+ medium, as described under "Experimental Procedures." A, mitoKATP is K+ selective: trace a, K+ influx in the absence of ATP; trace b, K+ influx in the presence of 0.2 mM ATP; trace c, TEA+ influx in the absence of ATP; and trace d, TEA+ influx in the presence of 0.2 mM ATP. B, failure of glyburide to inhibit K+ influx: trace a, K+ influx in the absence of ATP; trace b, K+ influx in the presence of 10 µM glyburide; and trace c, K+ influx in the presence of 0.2 mM ATP.

The traces in Fig. 1B show that 10 µM glyburide does not inhibit K+ flux under these conditions, despite the fact that mitoKATP is evidently open. 100 µM 5-HD was similarly ineffective (data not shown). To summarize a large body of experiments, these agents did not inhibit K+ flux at these doses in rat liver or heart mitochondria respiring on succinate or TMPD/ascorbate. This failure of glyburide and 5-HD to inhibit is the central problem addressed by this paper.

Nonspecific Effects of Glyburide on K+ Flux in Mitochondria-- In massive doses, glyburide does inhibit K+ flux, as previously reported by us (5) and by Belyaeva et al. (17) and Szewczyk et al. (18). We concluded, however, that this effect was secondary to inhibition of respiration (5). Cation uptake into respiring mitochondria is exquisitely sensitive to Delta Psi (16), and it is essential to differentiate between nonspecific inhibition due to reduced driving force and specific inhibition of mitoKATP. Accordingly, we examined the effect of glyburide on uncoupled respiration, on respiration-driven K+ and TEA+ uptake, and on respiration-driven K+ uptake in the presence of valinomycin.

The dose-response curves in Fig. 2 confirm that glyburide inhibits succinate utilization during uncoupled respiration. In hypotonic assay medium supplemented with acetate and cytochrome c, the K1/2 values for inhibition were 5.7 ± 2.7 µM (n = 3) in rat heart mitochondria and 157 ± 27 (n = 3) in rat liver mitochondria. In isotonic assay medium without acetate, the K1/2 values for inhibition were 5.3 ± 0.5 µM (n = 2) in rat heart mitochondria and 70 ± 2 µM (n = 2) in rat liver mitochondria (not shown).


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Fig. 2.   Glyburide inhibits respiration of rat liver and rat heart mitochondria. Oxygen consumption of rat heart (bullet ) and rat liver (open circle ) mitochondria (1 mg of protein/ml) respiring on succinate is plotted versus medium glyburide concentration. Mitochondria were uncoupled by addition of 0.25 µM CCCP.

A more direct demonstration of the nonspecific effect of glyburide on K+ uptake was obtained in protocols measuring respiration-dependent cation uptake. As shown in Fig. 3, cation uptake was inhibited by glyburide as a function of dose. In rat heart mitochondria (Fig. 3A), the K1/2 values were 6.4 ± 1.1 µM (n = 3) when succinate was used as substrate and 470 ± 35 µM (n = 2) when ascorbate/TMPD was used as substrate. In rat liver mitochondria (Fig. 3B), the K1/2 values were 63 ± 13 µM (n = 3) when succinate was used as respiratory substrate and 476 ± 34 µM (n = 3) when ascorbate/TMPD was used as substrate. Inhibition was nonselective---K+ flux and TEA+ flux were inhibited at the same doses---and the K1/2 values were essentially the same as K1/2 values for respiratory inhibition (Fig. 2). These findings demonstrate that inhibition of cation flux was due to reduction in driving force and not due to inhibition of mitoKATP. Similar results were obtained for valinomycin-induced swelling in potassium medium (data not shown).


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Fig. 3.   Glyburide nonspecifically inhibits cation flux into mitochondria. Dose-response curves for glyburide inhibition of respiration-driven mitochondrial swelling in K+ (open circle , square ) and TEA+ (bullet , black-square) media. K+ and TEA+ were inhibited identically in both succinate (square , black-square) and ascorbate/TMPD (open circle , bullet ). A, rat heart mitochondria; B, rat liver mitochondria.

We conclude that the only inhibition mediated by glyburide under these conditions is nonspecific, secondary to inhibition of respiration and a reduction of the driving force for cation uptake.

Nonspecific Effects of 5-HD on K+ Flux in Mitochondria-- An identical series of experiments was carried out using 5-HD. 5-HD had no effect on K+ flux under these conditions. In contrast to glyburide, 5-HD did not inhibit uncoupled respiration or cation uptake in either rat liver or heart mitochondria up to 500 µM (data not shown).

Open States in which Glyburide and 5-HD Specifically Inhibit Rat Heart MitoKATP-- Under the conditions of Fig. 1, mitoKATP is open because no inhibitory ligands are present. In vivo, mitoKATP would be opened by pharmacological agents (KCO), such as diazoxide or cromakalim (15), or physiological ligands, such as GTP (12). Moreover, ATP and Mg2+ would also be present in vivo. When mitochondria were studied under these more physiological conditions, glyburide and 5-HD were potent, specific inhibitors of K+ flux, as illustrated by the traces in Fig. 4. Control K+ flux (Fig. 4, trace a) was inhibited in the presence of ATP and Mg2+ (Fig. 4, trace b) and then restored to control values by diazoxide (Fig. 4, trace c). This pharmacologically induced K+ flux was strongly inhibited by 10 µM glyburide to the level associated with ATP inhibition (Fig. 4, trace d). Note that this glyburide dose had no effect on respiration in ascorbate/TMPD and no effect on TEA+ flux (see Fig. 3A). Therefore, the effect is specific for K+ flux through mitoKATP.


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Fig. 4.   Glyburide inhibits the pharmacological open state of mitoKATP. Light-scattering traces from rat heart mitochondria respiring on ascorbate/TMPD in K+ medium. Trace a, K+ influx in the absence of ATP; trace b, K+ influx in the presence of 0.2 mM ATP; trace c, reversal of inhibition by 10 µM diazoxide in the presence of 0.2 mM ATP; and trace d, reinhibition by 10 µM glyburide in the presence of 10 µM diazoxide and 0.2 mM ATP.

Fig. 5, A and B, contains the concentration dependences of specific glyburide and 5-HD inhibition of K+ flux. The opening effect of 10 µM diazoxide was reversed by glyburide with K1/2 = 1.1 µM (closed circles in Fig. 5A), and by 5-HD with K1/2 = 45 µM (closed circles in Fig. 5B). The opening effect of 50 µM GTP was reversed by glyburide with K1/2 = 6 µM (Fig. 5A, open circles), and by 5-HD with K1/2 = 58 µM (Fig. 5B, open circles).


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Fig. 5.   Specific inhibition of K+ influx in rat heart mitochondria by glyburide and 5-HD. K+ influx, estimated from the light-scattering assay, was measured in mitochondria respiring on ascorbate/TMPD in K+ medium containing 0.1 mM Mg2+. A, inhibition by glyburide. Dose-response curves were generated in the presence of pharmacological opener (bullet ), containing 0.2 mM ATP plus 10 µM diazoxide, and in the presence of physiological opener (open circle ), containing 0.2 mM ATP plus 50 µM GTP. B, inhibition by 5-HD. Dose-response curves were generated in the presence of pharmacological opener (bullet ), containing 0.2 mM ATP plus 10 µM diazoxide, and in the presence of physiological opener (open circle ), containing 0.2 mM ATP plus 50 µM GTP. In the absence of ATP (×), 5-HD failed to inhibit. Rates of ATP-dependent K+ influx were determined from light-scattering traces similar to those shown in Fig. 4.

Three additional ligands were required for specific glyburide inhibition of mitoKATP: Mg2+, ATP, and either GTP or a KCO. No single one of these, nor any combination of two, was effective.

Open States in Which Glyburide and 5-HD Specifically Inhibit Rat Liver MitoKATP-- An identical series of experiments was carried out with rat liver mitochondria, and the results were qualitatively identical to the results with rat heart mitochondria. We were also able to compare the effect of substrates on glyburide potency in liver mitochondria because the margin of safety for nonspecific inhibition during respiration on succinate is much wider in liver than in heart mitochondria (compare Fig. 3, A and B). The results are summarized in Table I. The K1/2 for glyburide inhibition was 3.4 µM when either succinate or ascorbate/TMPD was the respiratory substrate. 5-HD also inhibited cromakalim-opened mitoKATP in liver mitochondria respiring on either succinate or ascorbate/TMPD with equal potency (K1/2 = 73 µM).

                              
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Table I
Specific inhibition of mitoKATP by glyburide and 5-HD
The table compares the mean values of half-maximal inhibition (±S.D., n = 3) by glyburide and 5-HD in three different preparations. Intact mitochondria were respiring on succinate or ascorbate/TMPD in K+ medium, and K+ influx was estimated from the light scattering assay. Assay media for mitochondria contained varying doses of glyburide or 5-HD and 0.1 mM Mg2+. When added, ATP was 0.2 mM. K+ flux through reconstituted rat liver mitoKATP was determined from fluorescence of PBFI. Assay media for liposomes contained varying doses of glyburide or 5-HD and 0.5 mM Mg2+. When added, ATP was 0.5 mM. ND, not determined.

Specific Inhibition of Reconstituted MitoKATP by Glyburide and 5-HD-- Table I also summarizes the effects of glyburide and 5-HD on reconstituted mitoKATP purified from rat liver mitochondria. In the presence of Mg2+, ATP, and cromakalim, both glyburide and 5-HD inhibited mitoKATP. Glyburide inhibited with K1/2 = 90 nM, and 5-HD inhibited with K1/2 = 85 µM. In the absence of ATP, 5-HD had no effect, but glyburide inhibited K+ flux with K1/2 = 250 nM. The latter result is consistent with our previous results on reconstituted mitoKATP in the presence of Mg2+ (19). Glyburide was also a potent inhibitor (K1/2 = 80 nM) of the reconstituted mitoKATP in the presence of Mg2+, ATP, and GTP.

    DISCUSSION
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Abstract
Introduction
Procedures
Results
Discussion
References

There is growing evidence for the hypothesis that mitoKATP is the receptor for the cardioprotective actions of K+ channel openers and the cardio-damaging actions of glyburide and 5-HD (4, 9). Glyburide is a prototypical sulfonylurea inhibitor that acts on all KATP channels and blocks the protective effects of both KCO and cardiac preconditioning (20, 21). 5-HD, which is structurally unrelated to glyburide, has been characterized as an ischemia-selective inhibitor of KATP channels (22, 23). Like glyburide, 5-HD selectively blocks the protective effects of both KCO (22) and cardiac preconditioning (24, 25). There have been no previous studies of the effects of 5-HD on mitochondria. The hypothesis that mitoKATP is involved in cardiac protection has been clouded by the lack of a crucial piece of evidence: a convincing demonstration that glyburide and 5-HD inhibit ATP-dependent K+ uptake in intact mitochondria.

MitoKATP activity can readily be elicited in respiring mitochondria, as demonstrated by the data in Fig. 1. We showed previously that glyburide inhibits K+ flux under these conditions; however, inhibition required high doses that inhibit respiration in the presence of succinate, and we concluded that this inhibition was nonspecific (5). Belyaeva et al. (17) concluded to the contrary that mitoKATP was specifically inhibited by 150 µM glyburide. To resolve this disagreement, we carried out a thorough study of the nonspecific effects of glyburide, as reported under "Results." We found that glyburide is a potent inhibitor of uncoupled respiration in both liver and heart mitochondria when succinate was used as the respiratory substrate (Fig. 2). Over the same dose range, glyburide also inhibited diffusive K+ and TEA+ fluxes (Fig. 3). TEA+ is transported solely by leak pathways; accordingly, glyburide inhibited K+ and TEA+ fluxes by depression of Delta Psi and not by inhibition of mitoKATP. Thus, glyburide inhibition of K+ flux under these conditions is nonspecific.

Respiration using ascorbate/TMPD is relatively insensitive to inhibition by glyburide and 5-HD, and the flux experiments using these substrates (Fig. 3) permit a further conclusion: glyburide and 5-HD, at any dose, are completely ineffective under the conditions that have routinely been used to study inhibition of K+ flux through mitoKATP, namely respiration on succinate with rotenone.

These findings presented a serious obstacle to studies of the pharmacological regulation of mitoKATP in mitochondria. We finally recognized, however, that the conditions routinely used, namely, in the absence of other ligands of mitoKATP, are far from those present in vivo. In a living cell, the open channel would never be exposed to glyburide under such conditions. Rather, the channel would be exposed to ATP and Mg2+ and then opened by GTP or a K+ channel opener (12, 15). Indeed, when the in vitro experiments were adjusted to mimic these in vivo conditions, we found glyburide and 5-HD to be potent, specific blockers of K+ flux in the open states induced by physiological or pharmacological ligands (Figs. 4 and 5 and Table I). We emphasize that three components, Mg2+, ATP, and a physiological or pharmacological opener, were required to achieve inhibition by either of these drugs. No single component nor any combination of two components was sufficient. This phenomenon was observed in both heart and liver mitochondria.

Results with reconstituted mitoKATP qualitatively reflect results in intact mitochondria (Table I). With glyburide, the K1/2 value was reduced when studied in the pharmacological open state. With 5-HD, no inhibition was observed in the absence of ATP, but 5-HD inhibited in the pharmacological open state, when ATP and a KCO were present.

Some aspects of these findings raise new scientific questions. (i) What renders mitoKATP susceptible to these inhibitors in one open state and not the other? In view of the fact that K+ fluxes are identical in all open states, we conclude that the protein must be in a different state. Thus, we infer that Mg2+, ATP, and an opener induce a conformation in mitoSUR that renders it susceptible to glyburide and 5-HD. (ii) Why is glyburide a potent inhibitor of reconstituted mitoKATP under conditions in which it is ineffective in intact mitochondria? The logical inference is that mitochondria are regulated by a factor that is lost during reconstitution. These hypotheses are under investigation.

In conclusion, our results are consistent with the hypothesis that mitoKATP is the essential drug receptor involved in ischemic cardioprotection. They also remove the previous deterrent to pharmacological studies on mitoKATP in intact mitochondria.

    ACKNOWLEDGEMENTS

We thank Yuliya Yarova-Yarovaya and Craig Semrad for excellent technical assistance.

    FOOTNOTES

* This research was supported in part by National Institutes of Health Grant GM55324 (to K. D. G.) from the National Institutes of General Medical Sciences and by a National Scientist Development Grant 9630004N (to P. P.) from the American Heart Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger This work was in partial fulfillment of requirements for the Ph.D. degree.

§ To whom correspondence and reprint requests should be addressed: Dept. of Biochemistry and Molecular Biology, Oregon Graduate Institute of Science and Technology, P. O. Box 91000, Portland, OR 97291-1000. Tel.: 503-690-1680; Fax: 503-690-1464; E-mail: garlid{at}bmb.ogi.edu.

1 The abbreviations used are: mitoKATP, mitochondrial ATP-sensitive potassium channel; KCO, potassium channel opener(s); 5-HD, 5-hydroxydecanoate; PBFI, potassium-binding benzofuran isophthalate; TEA+, tetraethylammonium cation; TES, N-tris(hydroxymethyl) methyl-2-aminoethanesulfonic acid; TMPD, N,N,N,N'-tetramethyl-p-phenylenediamine; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; CCCP, carbonyl cyanide p-chlorophenylhydrazone; mitoSUR, mitochondrial sulfonylurea receptor.

2 A preliminary account of these findings was reported in abstract form (26).

    REFERENCES
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Abstract
Introduction
Procedures
Results
Discussion
References

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