Departments of 1 Physiology and Biophysics and 2 Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada T2N 4N1
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ABSTRACT |
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The effects of streptozotocin-induced diabetes (5-7 days or 7 wk) on cardiac ATP-sensitive potassium channels (KATP channels) were investigated with the use of single-channel and action potential recordings from dissociated ventricular myocytes isolated from control and diabetic rat hearts. In inside-out patches from diabetic myocytes (5-7 days), the IC50 for ATP inhibition was 82 ± 7.2 µM (mean ± SE, n = 8), twice that in controls (43 ± 3.6 µM, n = 12). For 7-wk diabetic rats, the IC50 was 75 ± 2.3 µM (n = 6). Increasing internal ADP concentration attenuated ATP-induced inhibition in both controls and diabetics. On reducing the internal pH from 7.4 to 6.8, both control and diabetic myocytes showed a 1.7-fold increase in the IC50 for ATP inhibition. No differences were observed in either intraburst kinetics or unitary conductance of single channels from control and diabetic myocytes. In diabetic myocytes, action potential duration at 90% repolarization (APD90) was longer and more variable than in controls and was significantly shortened by application of the KATP channel opener cromakalim (50 µM). Cromakalim scarcely affected APD90 in controls. Computer simulation of the longer diabetic APD90 required a lower background conductance during the plateau phase in addition to small, measured changes in the delayed rectifier current, transient outward current, and ATP-sensitive K+ current (KATP current, IKATP). The simulations reproduced the enhanced sensitivity of the diabetic APD90 to changes in IKATP. These results have important implications for cardiac function in diabetics and their treatment by sulfonylureas.
ATP-sensitive K+ channel; diabetes; heart; patch clamp
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INTRODUCTION |
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THE CARDIOVASCULAR COMPLICATIONS of diabetes mellitus often lead to the development of coronary and ischemic heart disease (19, 20, 32). Cardiac arrhythmias are also more common (32) and may contribute to an enhanced mortality (20). Intense research into these complications has given rise to controversial findings relating to the response of the diabetic heart to ischemic conditions (10). There is growing evidence that the diabetic heart is more resistant to ischemic injury (23, 27), although this is not uniformly accepted (31). Several mechanisms have been suggested to contribute to the reduced effects of ischemia in the diabetic heart. These include alterations in calcium handling or in pH regulation (10). Another possibility is that there are changes in the ATP-sensitive potassium channels (KATP channels) in the diabetic heart, based on the fact that action potential shortening during hypoxia is enhanced in diabetic hearts (1). In addition, direct measurements of KATP channel activity have also indicated diabetes-related alterations (35).
KATP channels are very abundant in cardiac tissue (30). These channels have been suggested to play a cardioprotective role during ischemic episodes (4, 14, 24, 28) by abbreviating the duration of the ventricular action potential, thus reducing calcium influx and attenuating contraction. This would reduce energy expenditure and also minimize calcium loading. In addition, activation of KATP channels would help to ensure a fully polarized diastolic potential, which would assist calcium efflux (via the Na/Ca exchanger) and thus further reduce calcium overload (28, 30). KATP channels may also be operative in the process of ischemic preconditioning (24, 25) and long-term adaptation to metabolic stress (22). However, deleterious consequences of the activation of these channels during ischemia may also occur (2).
KATP channels are controlled by many factors, and their activation or alteration has implications for arrhythmogenesis (36). Normally, millimolar concentrations of ATP inhibit channel activity, and opening occurs as ATP levels drop in a manner that depends on the level of ADP, the pH, and the metabolic status of the cell (5, 30). It is now becoming clear that under several different pathological conditions, such as metabolic inhibition (6), heart failure (22), or hypertrophy (3), there is a change in the ATP dependence of these channels. Because there is also evidence that alterations in hormonal status may affect these channels (18, 26), we set out in the present study to examine the characteristics of these channels in myocytes from diabetic rat heart. We found the IC50 for ATP-dependent inhibition of KATP channels to be about twofold higher for channels from diabetic hearts than in controls. This is one factor that contributes to the dramatic influence that a low level of ATP-sensitive K+ current (IKATP) activation can have on the relatively long-duration action potentials of diabetic ventricular myocytes.
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METHODS |
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All experimental procedures and animal handling were approved by the Animal Care Committee of the University of Calgary.
Experimental groups. Single rat ventricular myocytes were prepared by enzymatic dispersion from three groups of age-matched Sprague-Dawley rats (Biosciences, Univ. of Calgary). The three main groups were control rats, untreated rats, and rats that were made diabetic by two methods: in an acute model, rats were given streptozotocin (STZ; 100 mg/kg iv) 5-7 days before the experiments; in a chronic model, rats were given STZ (60 mg/kg iv) 7 wk before the experiments. Diabetic rats (and humans) often have reduced triiodothyronine (T3) levels (8). Therefore, to rule out possible indirect effects of a hypothyroid status, rather than direct effects of the diabetic condition, a fourth group of rats was given STZ (100 mg/kg) as well as T3 (daily ip injections, 0.3 mg/kg, for 5-7 days) (8). This was found to restore plasma T3 levels to or slightly above control values (control = 0.78 ± 0.17 nM, n = 18 animals; diabetic = 0.50 ± 0.16 nM, n = 23; diabetic+T3 = 1.06 ± 0.65 nM, n = 8).
Ventricular cells were prepared either 5-7 days or 7 wk after STZ treatment, at which time glucose levels were significantly elevated and insulin levels were significantly reduced due to destruction of most of the pancreaticCell isolation. Rats were ether anesthetized, the hearts were removed after cervical dislocation, and the aortas were cannulated on a Langendorff apparatus for retrograde perfusion (70 cmH2O, 37°C). The hearts were perfused initially with a normal, calcium-containing (1 mM) solution for 5 min, followed by a calcium-free solution for 10 min. This was followed by the enzyme solution containing 0.026 mg/ml collagenase (Yakult Honsha, Tokyo, Japan), 0.008 mg/ml protease (type XIV; Sigma, St. Louis, MO), 20 mM taurine, and 40 µM calcium. After 6-8 min, the free wall of the right ventricle was removed and cut into smaller pieces for further incubation (in a shaker bath at 37°C) in a solution containing 0.3 mg/ml collagenase, 0.2 mg/ml protease, 20 mM taurine, 10 mg/ml albumin, and 0.1 mM CaCl2. Aliquots of cells were removed over the next 30-60 min and stored in an enzyme-free solution in 0.1 mM CaCl2 (containing 20 mM taurine and 5 mg/ml albumin). Electrophysiological measurements were subsequently performed on cells with the use of the different protocols described in the following paragraphs.
Action potential recordings. Action potentials were recorded under current clamp conditions with the use of the conventional whole-cell suction electrode method. In these experiments, the superfusing solution contained (in mM) 140 NaCl, 5.4 KCl, 1.0 CaCl2, 1.0 MgCl2, 5 HEPES, and 5.5 glucose, pH 7.4. The pipette solution contained (in mM) 130 potassium aspartate, 10 KCl, 1.4 MgCl2, 10 HEPES, 10 glucose, and 1 MgATP, pH 7.4. On patch rupture, cells were allowed to dialyze with the pipette solution for 5-10 min before action potentials were measured. Series resistance was measured before and after action potential recordings, and data were discarded if series resistance changed by >20% during experiments. All recordings were done at 21-23°C.
Single-channel recordings.
The activity of the KATP channels
was recorded using standard patch-clamp recording techniques in the
inside-out configuration. Pipettes were pulled from borosilicate glass
(PG52151-4; World Precision Instruments, Sarasota, FL). The shanks were
coated with silicone resin (Sylgard 184; Corning, NY) near the tips,
which were then fire polished. The pipette resistances were typically in the range of 2-5 M. Tight seals (>10 G
) were
established, and excised patches were obtained by rapidly pulling the
pipette away from the cell. The internal face of the patches was then directly exposed to test solutions. These were applied through a
multi-input perfusion pipette with a common outlet at a rate of
100-150 µl/min. Solution changes were obtained in <2 s.
Recordings were done at 21-23°C. Single-channel currents were
recorded at selected holding potentials with an Axopatch 200 amplifier
(Axon Instruments, Foster City, CA), digitized (Neurocorder DR-384; Neuro Data Instruments, New York, NY), and then stored on video tape.
Data were replayed through a 4-pole Bessel filter (Warner model
LPF-100) using a computer interface (Axolab 1100, Axon Instruments) connected to a personal computer for analysis (see Figs. 4 and 5 for
values at which data were filtered and sampled).
KATP channel open probability was
expressed as NP0,
the product of the number of channels in the patch
(N) and the mean open probability
(P0). NP0 was
calculated by dividing the mean patch current over a 10- to 30-s test
period by the mean unitary current amplitude from the same patch. For
measurements of ATP sensitivity,
NP0 was usually expressed in normalized form for each patch
[NP0 (test
ATP)/NP0 (zero
ATP)]. After excision, patches were exposed to 1 mM ATP, except
for a brief exposure to test solutions, and 0 ATP at the start and end
of experiments to estimate N as well
as the degree of rundown (25). Data were excluded in patches showing
>25% rundown (~20% of all patches).
Drugs and reagents. ATP (as MgATP; Sigma) was added as required from a fresh 10 mM stock. Cromakalim (as levcromakalim), a generous gift from SmithKline Beecham Pharmaceuticals (Brentford, UK), was stored as a 50 mM stock in DMSO. It was diluted immediately before use. The concentration of DMSO present (<0.1%) has been shown to be without effect on KATP channels (12).
Computer simulations of action potentials. Action potentials in normal and diabetic rat myocytes were simulated using OXSOFT HEART version 4.4 [the model is updated from DiFrancesco and Noble (7)]. Calculations of the contribution of IKATP were based on the work of Nichols and Lederer (29). Under physiological ionic conditions, the KATP conductance was represented as an ohmic conductance, the inhibition of which with increasing ATP concentration ([ATP]) is described by a saturating function with a Hill coefficient of 2. Our own calculations used the slightly higher external K+ concentration of our experiments and our measured IC50 values for ATP inhibition [controls, 0.043 mM; diabetic, 0.082 mM; cf. 0.1 mM in the calculations of Nichols and Lederer (29)]. For our control case, a small adjustment in the background K+ conductance (GBK) to 0.025 µS (reduced from 0.030 µS), with no change in the background Na+ conductance (GBNA), was used to give a somewhat closer simulation of observed action potentials. For the diabetic condition, in accord with previous work (34), the maximal values of the delayed rectifier current and the maximal transient outward conductance were reduced, respectively, to 0.825× and 0.7× the default values in OXSOFT HEART version 4.4. These experimentally measured changes produced only minimal lengthening of the action potential duration at 90% repolarization (APD90) compared with the control calculation. Thus, to approximate the durations observed with diabetic animals, plateau membrane resistance was increased by reducing the GBK and GBNA, setting GBK = 0.0055 µS and GBNA = 0.0013 µS (reduced from 0.005 mS). These values were used in the calculations illustrated and were chosen so as to increase APD90 without drastically changing the resting potential. Other combinations were also used to increase APD90 into the diabetic range, but these led to the same qualitative results and thus to the same conclusions. In the simulations, the contribution of IKATP to the total current was varied by varying the [ATP] in the range of 10-100× IC50, i.e., in the range of 0.43-8.2 mM. This means that the simulated effects of IKATP on APD90 result from activation of only a small minority (~0.01-1.0%) of the available KATP channels. In the calculations, decreasing [ATP] electrically mimics the result of activation of IKATP with cromakalim.
Statistics. The significance of differences between groups was evaluated using Student's paired t-test, with P < 0.05 considered significant. All values in the text are given as means ± SE.
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RESULTS |
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Effects of KATP channels on the action potential. To assess the relative contributions of KATP channels to the action potential waveform in diabetic and normal ventricles, action potential measurements were undertaken. In control myocytes, the addition of 50 µM cromakalim, with 1 mM ATP in the pipette solution, had very little effect. In 12 cells, the APD90 was 51.8 ± 4.5 ms (mean ± SE). Addition of cromakalim did not significantly affect this duration (producing an increase of 3.5 ± 1.9 ms). In contrast, there was a marked effect of cromakalim in myocytes from diabetic rats. As reported previously (1, 34, 35), action potentials in the diabetic state are prolonged compared with control conditions because of a reduction in the magnitude of repolarizing K+ currents (34). In nine cells from diabetic rats, the ADP90 was 178.7 ± 25 ms, which is significantly (P < 0.001) longer than in control myocytes. Cromakalim shortened the APD90 by 49.5 ± 17.5 ms, which is significantly (P < 0.05) different from the effect in the control group. Figure 1 shows examples from two control and two diabetic myocytes in which the effects of cromakalim are shown to be reversed either by washout or by using glibenclamide (10 µM), a KATP channel blocker (12). Thus, in single myocytes (at room temperature), the pharmacological activation of KATP channels results in a greater shortening of the action potential in cardiac cells from diabetic rats, as was also found by Smith and Wahler (35), using papillary muscles at 37°C. An increased influence of KATP channel activation might play a role in the response of the diabetic heart to ischemia (see DISCUSSION).
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ATP sensitivity. Intracellular ATP inhibits the spontaneous activity of the KATP channels in a concentration-dependent manner. However, in patches from myocytes prepared from diabetic rats, the sensitivity to ATP was significantly diminished. This was found in myocytes prepared from rats made diabetic for either 5-7 days (100 mg/kg STZ) or for 7 wk (60 mg/kg STZ). Figure 2, A and B, shows examples of channel activity (~10 channels present) in the absence of ATP and after addition of 100 µM ATP in a patch from a control myocyte (Fig. 2A) and in one from a (7 days) diabetic rat (Fig. 2B). Figure 2C shows the dependence of channel activity (given as the normalized NP0) on ATP concentration. The curves were obtained by using the least squares method (see equation below) from 12 patches from control myocytes, 8 patches from 5- to 7-day diabetic myocytes, 6 patches from 7-wk diabetic myocytes, and 7 patches from (5-7 days) diabetic rats treated with T3. The IC50 values of the channels were 43, 82, 75, and 101 µM, respectively. The T3-treated group was not significantly different from the diabetic group. The Hill coefficients were 2.1 (control), 2.0 (5- to 7-day diabetic), 1.75 (7-wk diabetic), and 2.2 (5- to 7-day diabetic, T3 treated).
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pH dependence of ATP sensitivity. It is now well established that, whereas the baseline intracellular pH in cardiac cells is unchanged in diabetes mellitus, the regulation of pH is altered (21). This is due in large part to an inhibition of the Na+/H+ exchanger, the major route of hydrogen extrusion in these cells (21). Thus, after an acid load, such as under ischemia, the recovery of pH during reperfusion was found to be slower. This actually has beneficial effects, since sodium overloading and calcium overloading are minimized (21). KATP channels are pH sensitive, becoming less susceptible to ATP inhibition as intracellular pH decreases (5). Because lowered pH and diabetes both lead to an increase in the IC50 for ATP inhibition, it was of importance to establish whether this pH dependence was altered under diabetic conditions.
The effect of ATP on KATP channel activity was thus examined at an internal pH of 6.8, a value thought to occur during periods of mild to moderate hypoxia/ischemia (9). In control myocytes, the IC50 for ATP inhibition was increased from 43 (pH 7.4) to 71 µM (pH 6.8), a 1.65-fold increase. In KATP channels from diabetic hearts, the IC50 for ATP inhibition was also increased, from 82 (pH 7.4) to 136 µM, a 1.66-fold increase. Thus a similar shift in ATP sensitivity in response to lowered pH occurs in KATP channels from both control and diabetic myocytes. This result is shown in Fig. 3.
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Effects of ADP. It is well established (30, 36) that a key determinant of KATP channel opening is the ATP/ADP ratio rather than ATP levels alone. An increase in ADP levels at a given level of ATP will increase channel activity. In an additional set of experiments, we tested whether there was a difference in the response of control and diabetic myocytes to the addition of ADP. In five patches from diabetic cells and in four patches from control cells, addition of 250 µM ADP with 100 µM ATP present increased channel activity by a similar amount. The ADP-induced increase in NP0 was 31 ± 5.1% (mean ± SE) in diabetic myocytes and 38 ± 12.0% in control myocytes.
Kinetic analysis and single-channel conductance. To more completely examine KATP channel properties in the diabetic state, it was decided to investigate whether STZ-induced diabetes caused any other changes in the properties of KATP channels from ventricle, such as mean dwell times and unitary conductance.
The high density of KATP channels in cardiac tissue makes single-channel patches highly improbable. However, it was possible with the use of high-resistance pipettes (10-15 M
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Action potential simulations.
To further explore the possible effects of alterations in
KATP channels on action potential
configuration, we used the rat ventricular myocyte model developed by
DiFrancesco and Noble (7), as implemented in OXSOFT HEART version 4.4. Specific details of our calculations are provided in
METHODS. Simulations for the conditions of our experiments give the results shown in Fig.
6. Our simulation results suggest the
following. 1) The known decreases in
K+ conductances associated with
diabetes (34) are insufficient to account for the longer
APD90 values observed, and some
additional decrease in plateau conductance is needed, simulated here by
a decrease in GBK and GBNA. 2) The
long-duration action potential in diabetic cells is substantially more
sensitive to activation of
IKATP than is the
shorter control action potential, because the activated
IKATP contributes
a larger proportion of the net transmembrane current during
repolarization. This is true even though fractional activation of
IKATP is very
small (~0.01-0.0001, corresponding to
[ATP]/IC50 ratios of
10-100), as expected in the physiological range of
[ATP]. These conclusions are also qualitatively consistent
with the larger predicted effect of
IKATP on the
longer-duration guinea pig ventricular action potential than on the
shorter rat action potential illustrated in the OXSOFT HEART manual.
3) The relatively large variability
of the APD90 observed in
individual diabetic cells over time, and from cell to cell, results
from the fact that very small conductance changes dramatically affect the duration because of the razor-edge balance of small depolarizing and repolarizing currents during the plateau. Action potential durations can change over long periods within trains because of the
changing initial conditions for each cycle of depolarization and
repolarization. Under conditions that give very long action potential
durations, depending on initial conditions, the duration can increase
or decrease significantly during a train, in some cases leading to
cessation of firingessentially a simulated, single-cell "heart
attack." To standardize the calculations presented here, four action
potentials were calculated as part of a single train; two successive
action potentials were calculated at an intermediate [ATP]
(1 or 2 mM) to check for superposition, and then two further action
potentials were calculated at [ATP] = 10×
IC50 and 100×
IC50, respectively.
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DISCUSSION |
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Summary of findings and relation to previous work. The results presented here provide evidence for a reduction in the ATP sensitivity of KATP channels that develops within 5 days after induction of insulin-dependent (type I) diabetes. This effect persists for at least 7 wk after induction of diabetes. No significant changes were found in either unitary channel conductance or the intraburst kinetics of KATP channels from diabetic and control hearts. The effects of the KATP channel opener cromakalim on the action potential were augmented in diabetics, as previously reported by Smith and Wahler (35). Calculations using a theoretical model of the diabetic rat ventricular action potential (7, 29) predict that a small change in the activation of IKATP from 0.1 to 0.17% (achieved by decreasing [ATP] from 2 to 0.82 mM; see the two shorter-duration action potentials; Fig. 6B) should decrease APD90 by almost 50%. Thus the twofold increase in IC50 that we observed would significantly contribute to the enhanced response of the diabetic heart to IKATP activation. However, the large magnitude of the observed changes in APD90 in response to IKATP activation also requires a reduced background conductance relative to control animals.
Our findings regarding the altered ATP dependence of the channels differ from those of Smith and Wahler (35), who reported no change in ATP sensitivity. This may be of significance, since these authors used an even longer duration of diabetes (10-12 wk) as opposed to our measurements, made at 5-7 days and at 7 wk after induction of diabetes. It has been reported that the sensitivity to ischemia of the diabetic heart can change from a reduced to an enhanced state as the duration of diabetes is prolonged (37). One possible explanation for the difference in the results may lie in the use of different perfusing solutions (symmetrical KF and no divalent ions in Ref. 35). We repeated these experiments using control myocytes under the same conditions (i.e., symmetrical KF and no divalent cations, as used by Smith and Wahler). However, in three patches, the IC50 we obtained was 77 µM. This differs from the results of Smith and Wahler but is consistent with the results of Findlay (11), who reported an increase in IC50 in the absence of divalent ions. Smith and Wahler also suggest that changes in the inward rectification of this channel under diabetic conditions may be important. We did not find any changes in rectification. However, their studies were performed in the absence of magnesium, which is a key factor regulating rectification properties.Significance and implications. Our results suggest that there is a potential for an increased influence of KATP channels (when activated) on the action potential configuration in the diabetic heart. This may account for the increased shortening seen under hypoxic/ischemic conditions in diabetic conditions (1). It should be emphasized that under baseline conditions, the contribution of the KATP channel to the diabetic action potential is minimal. The substantial prolongation of the action potential in diabetic animals, relative to controls, appears to result from a general decrease in repolarizing (33) and background currents. The predicted increase in sensitivity to IKATP activation is then based on two factors: 1) the general decrease in membrane conductance during the plateau and 2) the increased IC50 for ATP inhibition, which moves the range of steep [ATP] dependence a factor of ~2 toward the normal cytoplasmic range of [ATP]. Paradoxically, this represents a decrease in the absolute sensitivity of the KATP channels to ATP but leads to an increase in their influence on the action potential near the physiological range. The dramatic net result is clearly seen in Fig. 6B.
Our results suggest a possible basis for the finding that the diabetic heart is more resistant to the effects of ischemia. This is obviously contingent on the hypothesis that activation of KATP channels is beneficial to the ischemic heart, which may be true only under some conditions but not others (10, 37). There have been several reports showing that cardioprotection by KATP activation may be poorly correlated with action potential shortening (13, 26a), since KATP activation may be beneficial even in the absence of action potential shortening (41). Clearly, other mechansims are also involved in cardioprotection. The results of Smith and Wahler (35), showing no change in the ATP dependence of the channels, together with differential responses to ischemia after short- vs. long-duration diabetic conditions, suggest that there may be additional changes in the properties of KATP channels over a period of weeks after the onset of diabetes. However, our findings are consistent with results obtained in several different pathologies, all of which show changes similar to the one reported here. Specifically, the ATP dependence of KATP channel activity shows a similar (rightward) shift (indicating a reduced ATP sensitivity) in heart failure (22), in cardiac hypertrophy (3), during metabolic inhibition (6), and under hypothyroid conditions (18, 26). Thus there may be some intrinsic property of the channel that changes in a similar manner after a variety of pathologies, all of which are associated with changes in metabolism. The pH dependence of ATP sensitivity is maintained under diabetic conditions. This suggests that the chronic decrease in ATP sensitivity in diabetic myocytes and the short-term decrease after acidification may result from different modulatory mechanisms that exert separate, cumulative influences on ATP sensitivity. It is likely that KATP channel activity helps to shape the action potential in diabetic hearts under ischemic conditions when intracellular pH is reduced, leading to a greater shortening of the action potential in diabetic compared with control hearts under similar ischemic conditions. Future studies are needed to address the precise mechanism that leads to the change in ATP sensitivity observed. This may be related to alterations in expression of different KATP channel subunits or in associated proteins. The KATP channel is now known to consist of at least two subunits, the sulfonylurea receptor and the pore-forming inward rectifier subunit Kir 6.2 (16, 38). Although truncated subunits of Kir 6.2 alone exhibit ATP sensitivity, the sulfonylurea receptor subunit also modulates the ATP sensitivity of the channel complex. It is therefore not possible at this stage to say how and where diabetes changes the properties of the channel at the molecular level. Of possible relevance is a report that KATP channels are preferentially regulated by glycolytically derived ATP (39). However, another study suggests that ATP generated from oxidative phosphorylation may be more important than ATP derived from glycolysis (33). In this context, our results do not show any change in the sensitivity to ADP under diabetic conditions. This suggests that it is a change in the ATP sensitivity per se that is altered. Another possibility may be related to changes in protein kinase C activity that have been reported to occur in diabetes (17, 40), since protein kinase C appears to be an important regulator of these channels (15, 25). ![]() |
ACKNOWLEDGEMENTS |
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We thank Dr. W. Giles for discussion, support, and encouragement during the course of the work.
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FOOTNOTES |
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This work was supported by grants from the Medical Research Council of Canada (MRC), including core support from a Group Grant on the Biophysics of Ion Channels and Transporters (Principal Investigator, W. Giles), the Heart and Stroke Foundation of Alberta, the Alberta Heritage Foundation for Medical Research (AHFMR), and the Canadian Diabetes Association (CDA). R. J. French is an AHFMR Medical Scientist and an MRC Distinguished Scientist. Y. Shimoni was supported by a grant from the CDA in honor of Mary Selina Jamieson. P. E. Light was supported by a grant from the CDA in honor of Gordon Russell Hodgson.
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. §1734 solely to indicate this fact.
Address for reprint requests: Y. Shimoni, Dept. of Physiology and Biophysics, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Received 9 January 1998; accepted in final form 19 June 1998.
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