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CARDIOVASCULAR |
1 Department of Cell Physiology and Pharmacology, University of Leicester, PO Box 138, Leicester LE1 9HN, UK
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Abstract |
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(Received 23 May 2006;
accepted after revision 2 July 2006;
first published online 6 July 2006)
Corresponding author N. B. Standen: Department of Cell Physiology and Pharmacology, University of Leicester, PO Box 138, Leicester LE1 9HN, UK. Email: nbs{at}le.ac.uk
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Introduction |
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Recent studies have shown that K+ channel activity can be affected by hyperglycaemia. Incubation of rat small coronary arteries for 24 h in a high (23 mM) concentration of glucose reduced voltage-activated K+ (Kv) currents of vascular smooth muscle cells (Liu et al. 2001), and high glucose also reduced KATP currents of human omental artery (Kinoshita et al. 2004). Both of these effects appear to involve production of superoxide (·O2–) in response to hyperglycaemia. Interaction of superoxide with nitric oxide (NO) may lead to the formation of peroxynitrite (ONOO–), which can inhibit both Kv channels and high-conductance Ca2+-activated (BKCa) channels (Brzezinska et al. 2000; Liu et al. 2002, 2004). Hyperglycaemia is thought to underlie many of the vascular complications of diabetes (Chukwuma, 1992; Williams, 1995; Way et al. 2001), and it has been suggested that K+ channel inhibition may contribute to diabetic vascular dysfunction (Liu et al. 2001, 2004). Vasodilator responses are impaired in diabetes (Williams, 1995), and many vasodilators exert part of their effects by activation of K+ channels (Quayle et al. 1994; Aiello et al. 1995, 1998; Wellman et al. 1998). Li et al. (2003) have shown recently that impaired cAMP-mediated vasodilator responses in coronary arteries incubated for 24 h in high concentrations of glucose could be attributed mainly to a reduction in Kv channel activity. Vascular Kv and KATP channels are also regulated by vasoconstrictors, which inhibit channel activity. For example, angiotensin II inhibits Kv and KATP channels both through activation of protein kinase C (PKC) and inhibition of protein kinase A (Clement-Chomienne et al. 1996; Kubo et al. 1997; Hayabuchi et al. 2001b,c) while ET-1 inhibits both channels via PKC (Shimoda et al. 1998; Park et al. 2005). However, the effects of glucose on K+ channel inhibition by vasoconstrictors have not been investigated.
In normal individuals, resting blood glucose is 4–6 mM, rising to around 9 mM after a meal. Glucose levels can rise much higher in diabetes, and above 10 mM glucose appears in the urine. The effects of high glucose on K+ channels described above have used diabetic levels of glucose, and have generally also involved several hours of incubation in hyperglycaemic solutions. In the present study, we have investigated the acute effects of changes in glucose within the physiological range, both on Kv currents and on their responses to the vasoconstrictor endothelin-1 (ET-1). We find that increases in glucose within the range 0–10 mM cause a modest but immediate reduction in Kv current, and have a profound effect on Kv channel inhibition by ET-1, so that 10 mM glucose abolishes inhibition by 10 nM ET-1. These effects require the metabolism of glucose. In contrast, ET-1 inhibition of KATP currents was unaffected by raising glucose to 10 mM.
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Methods |
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Adult male Wistar rats were killed by cervical dislocation. The care and killing of the animals conformed to the requirements of the UK Animals (Scientific Procedures) Act 1986. Smooth muscle cells were dissociated from small branches of mesenteric arteries as follows. Arteries were removed, cleaned and dissected in ice-cold solution containing (mM): 137 NaCl, 5.4 KCl, 0.42 Na2HPO4, 0.44 NaH2PO4, 1 MgCl2, 10 Hepes and 10 glucose, adjusted with NaOH to pH 7.4. Arteries were then transferred to the same solution except that CaCl2 was added at 0.1 mM (low-calcium solution) for 10 min, warmed to 35°C in a water-bath, and incubated for 30–35 min in low-calcium solution containing (mg ml–1): 0.9 albumin, 1.4 papain and 0.9 dithioerythritol. This was followed by further digestion for 12.5 min in low-calcium solution containing (mg ml–1): 0.9 albumin, 1.4 collagenase type F and 0.9 hyaluronidase type I-S. Arteries were then washed in low-calcium solution containing 0.9 mg ml–1 albumin. Single smooth muscle cells were obtained by gentle trituration in low-Ca2+ solution, stored at 4°C, and used on the day of preparation.
Solutions and chemicals
For conventional whole-cell recording, the intracellular solution contained (mM): 110 KCl, 30 KOH, 1 MgCl2, 1 CaCl2, 10 Hepes, 10 EGTA, 1 Na2ATP and 0.5 GTP; adjusted to pH 7.2. The free [Ca2+], calculated using Maxchelator (http://www.stanford.edu/%7Ecpatton/maxc.html), was 20 nM. For perforated patch recording, amphotericin B was made up as stock solution (30 mg ml–1) in DMSO, and 7 µl of stock solution was diluted into 1 ml of pipette solution immediately before recording. Six millimolar K+ extracellular solution contained (mM): 134 NaCl, 6 KCl, 1 MgCl2, 0.1 CaCl2 and 10 Hepes, adjusted to pH 7.4. For intact artery recordings, CaCl2 was 1.8 mM and MgCl2 1.2 mM. Glucose, or other mono- or disaccharides were added to this solution as indicated in the Results, and mannitol was added where necessary to give a total concentration of 10 mM to maintain osmolarity. In order to minimize the activity of BKCa channels, external Ca2+ was lowered to 0.1 mM to reduce Ca2+ influx, and intracellular Ca2+ was buffered to a low level with EGTA. As we have reported previously (Hayabuchi et al. 2001c), under these conditions voltage-activated currents contained very little contribution from BKCa channels; the BKCa channel blocker penitrem A (100 nM) had no significant effect on the current in response to a 400 ms depolarization from –65 to +60 mV (control, 22.4 ± 0.8 pA pF–1; penitrem A, 22.2 ± 0.3 pA pF–1; n = 6 in each case). The external solution was changed by continuous perfusion of the experimental chamber (volume, 0.4 ml), and complete exchange took about 30 s. All chemicals were purchased from Sigma, except myristoylated protein kinase C inhibitor peptide 19–27 (PKC-IP) which was obtained from Calbiochem (UK).
Data recording and analysis
Whole-cell currents were recorded from single smooth muscle cells using the patch clamp technique. Currents were recorded using an Axopatch 200A amplifier (Axon Instruments) and, for voltage pulses, a P/6 leak subtraction protocol was used. Patch pipettes were made from thick-walled borosilicate glass. Whole-cell currents were filtered at 5 kHz and sampled at 10 kHz. Electrode resistances before sealing were 4–6 M
and after sealing were > 1 G. For recordings from intact arteries, segments of third-order mesenteric artery were pinned out under tension across a gap in a Sylgard-based chamber and penetrated with electrodes with resistances of 80–120 M when filled with 2 M KCl. A calibrated voltage source between the bath electrode and earth was used to measure membrane potential. Measurements were accepted if the membrane potential was stable for > 1 min and showed an abrupt return to baseline on withdrawal of the electrode. All experiments were done at 30–32°C. Current–voltage (I–V) relations were measured either at the peak of the current or, for steady-state current, at the end of 400 ms pulses to voltages between –60 and +60 mV. Inactivation time constants were fitted using custom software. Data are expressed as means ±
S.E.M. Intergroup differences were analysed by analysis of variance with Bonferroni's test or by Student's unpaired t test as appropriate. A value of P < 0.05 was considered statistically significant.
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Results |
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Whole-cell patch clamp recordings from rat mesenteric artery smooth muscle cells in a normal extracellular glucose (D-glucose) concentration of 4 mM revealed the presence of voltage-gated K+ (Kv) currents induced by 400 ms depolarizing steps from a holding potential of –65 mV to potentials of –30 mV and above (Fig. 1A). We examined the effect of alterations in extracellular glucose concentration by recording from cells in the presence of either 0 or 10 mM glucose. Cells were bathed in the solution for 10–15 min before recording. Mannitol was added to solutions where needed so that [glucose + mannitol] was 10 mM. Kv current densities were higher than control values in 0 mM glucose, but lower in 10 mM glucose, as can be seen from the example records of Fig. 1B and C and the mean current–voltage relations (normalized to cell capacitance) of Fig. 1D. Mean Kv current densities at +60 mV were 29.7 ± 0.9, 24.5 ± 1.5 and 22.7 ± 0.9 pA pF–1 in 0, 4 and 10 mM glucose, respectively (n = 6 in each case). Figure 1E shows mean activation curves measured from tail currents on repolarization to –30 mV. It can be seen that glucose reduced current amplitude without significantly affecting the voltage dependence of activation.
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To determine the time course of the effect of glucose on Kv current, we recorded currents in response to voltage steps to +40 mV, repeated every 5 s. Under these conditions, currents ran down slowly with time (Fig. 3A). Raising glucose from 0 to 4 mM caused a rapid reduction in Kv current that was complete within 200 s, and could be reversed on removal of glucose (Fig. 3B). Glucose has been shown to activate PKC in blood vessels (Way et al. 2001), and PKC has been proposed to play a role in modulating the vasodilator response to hyperglycaemia in human visceral arteries (Kinoshita et al. 2004). To test whether the reduction in Kv currents by D-glucose seen here involves PKC, we pre-incubated the cells for 15 min with the membrane-permeant myristoylated PKC inhibitor peptide 19–27 (PKC-IP, 50 µM), which we have previously shown to inhibit PKC activity in these cells (Hayabuchi et al. 2001b,c). Following the period of pre-incubation with PKC-IP, the inhibitory effect of increasing D-glucose concentration from 0 to 4 mM on peak Kv current was abolished, indicating that this process is dependent on activation of PKC by D-glucose (Fig. 3C and D).
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The vasoconstrictors angiotensin II and ET-1 have been shown to cause PKC-dependent inhibition of Kv currents in arterial smooth muscle (Clement-Chomienne et al. 1996; Shimoda et al. 1998; Hayabuchi et al. 2001c). Since changes in glucose concentration alter the amplitude of Kv currents in a PKC-dependent manner, we postulated that the modulation of K+ currents by vasoconstrictors that activate PKC might be affected by glucose concentration. To test this possibility, we examined the effect of ET-1 on Kv currents in normal and high-glucose solutions.
Figure 4A shows examples of Kv currents recorded in response to 400 ms voltage steps from a cell bathed in 4 mM glucose before and after the application of 10 nM ET-1. It can be seen that ET-1 both caused substantial inhibition of Kv currents and induced a marked inactivation during the 400 ms pulse, similar effects to those of angiotensin II in the same preparation (Hayabuchi et al. 2001c). Mean current–voltage relations for six cells are shown in Fig. 4B; ET-1 reduced the current at +60 mV from 23.5 ± 3.3 to 12.1 ± 3.1 pA pF–1 (n
= 6, P < 0.001). The time constants of inactivation, 
, measured by fitting a single exponential to the current decay, are shown in Fig. 4C. At +60 mV, 10 nM ET-1 decreased from 1496 ± 90 to 380 ± 80 ms (P < 0.001). These actions of ET-1 were PKC dependent, since pre-incubation of the cells for 15 min with 50 µM PKC-IP abolished the effects of ET-1 in all six cells tested (Fig. 4D, E and F).
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When smooth muscle cells were bathed in solution containing 10 mM D-glucose, we found that ET-1 neither reduced peak Kv current nor induced the marked inactivation that was observed in 4 mM D-glucose. A family of Kv currents recorded in 10 mM D-glucose in the absence and presence of 10 nM ET-1 is shown in Fig. 5A and B, and it can be seen that there was little difference in the currents with and without ET-1, as indicated by the mean current–voltage curves at the end of 400 ms pulses (Fig. 5C). Mean currents at +60 mV before and after the addition of ET-1 in 10 mM D-glucose were 22.5 ± 2.5 and 20.6 ± 2.3 pA pF–1 (Fig. 5C; n = 6). To assess whether the effect of glucose showed specificity for the D-isomer, we examined the effect of ET-1 after replacing D-glucose with L-glucose, which is metabolically inert. Figure 5D–F shows that 10 mM L-glucose did not block the effect of ET-1 in inhibiting Kv current and increasing its rate of inactivation. Mean currents at +60 mV before and after the addition of ET-1 in 10 mM L-glucose were 27.4 ± 3.1 and 13.7 ± 1.3 pA pF–1 (Fig. 5F; n = 6, P < 0.001). These findings suggest that D-glucose affects ET-1 inhibition of Kv by an action that requires metabolism of glucose. It is possible that such metabolic effects might be modified by dialysis of ATP into the cell from the pipette solution, though we would not expect this to provide tight control of intracellular ATP. To investigate this possibility, we compared Kv inhibition by ET-1 in 4 and 10 mM glucose in cells recorded using amphotericin-perforated patches to avoid intracellular dialysis. Figure 5G and H shows that, as for conventional recording, ET-1 inhibited Kv currents in 4 mM glucose (Fig. 5G), but was ineffective in 10 mM glucose (Fig. 5H), suggesting that the effects of glucose are not substantially modified by conventional whole-cell recording.
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To confirm that the effects of high glucose require its metabolism, we investigated the ability of other mono- or disaccharides to substitute for glucose in preventing Kv channel inhibition by ET-1. In each case, the carbohydrate was present at 10 mM, and Kv currents were measured before and 9 min after the addition of 10 nM ET-1. Figure 6 shows that fructose, which can enter glycolysis via the fructose-1-phosphate pathway, prevented Kv current inhibition (Fig. 6A) and inactivation (Fig. 6B) by ET-1 in a similar way to D-glucose. However, sucrose and mannitol (and L-glucose), which are not metabolized, did not affect the inhibitory action of ET-1 (Fig. 6). It can also be seen that the Kv current density is somewhat smaller in D-glucose and fructose than in the non-metabolizable sugars, suggesting that the effect of glucose in reducing Kv current amplitude also requires its metabolism. To test for possible involvement of oxygen free radicals in the effect of glucose on Kv modulation by ET-1, we examined the effect of ET-1 in cells that were exposed to 10 mM D-glucose in the presence of the free radical scavenger N-(2-mercaptopropionyl)-glycine (300 µM). The free radical scavenger did not affect the block of ET-1 inhibition in high-glucose conditions (Fig. 6).
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To address the possibility that high glucose caused a non-specific inhibition of the response to endothelin, possibly through a decrease in endothelin receptor function, we examined the effect of ET-1 on a different channel, the KATP channel, under control and high-glucose conditions. KATP currents, activated by 10 µM pinacidil, were readily observed in arterial smooth muscle cells and were measured as inward currents in symmetrical 140 mM K+ at –60 mV to minimize contamination from Kv currents as we have previously described (Hayabuchi et al. 2001a,b). As for Kv currents, 10 nM ET-1 inhibited the pinacidil-induced KATP current under control conditions, and the effect of ET-1 was blocked by PKC-IP (Fig. 8A, B and D). When external D-glucose was raised to 10 mM, however, ET-1 remained as effective at inhibiting KATP channels as under control conditions, and the inhibition was still PKC dependent (Fig. 8C and D). These results indicate that endothelin receptors were still able to activate PKC in 10 mM D-glucose, and that the effect of high glucose appears specific for Kv channels.
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Discussion |
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The acute reduction in Kv current in response to increased extracellular D-glucose concentration is complete within a few minutes (Fig. 3), and the effect is relatively small, so that mean Kv current density is about 24% lower in 10 mM glucose than in glucose-free solution. The acute effect of increasing glucose even from 0 to 4 mM is clear within an individual cell (e.g. Fig. 3B). Previous studies in small coronary arteries have shown that more extreme hyperglycaemia (23 mM glucose) applied for 24 h can cause a slightly larger reduction in Kv currents than those we observed (Liu et al. 2001). This longer term effect has been suggested to result from the reaction of superoxide (·O2–), produced in response to hyperglycaemia, with nitric oxide formed by inducible NO synthase to form peroxynitrite (ONOO–; Li et al. 2004). Peroxynitrite has been shown previously to inhibit BKCa channels (Brzezinska et al. 2000; Liu et al. 2002), and Li et al. (2004) have recently shown that incubation in hyperglycaemic solution leads to increased nitration of tyrosine residues in 
-subunits of the channel Kv1.2. Furthermore, ONOO– reduced whole-cell Kv currents in coronary smooth muscle cells and reduced opening of single Kv channels in patches excised from the same cells (Li et al. 2004). While it is possible that such a mechanism is involved in the acute effects of glucose we observe, it seems less likely because our effects occur in isolated arterial smooth muscle cells in the absence of an endothelial source of NO, whereas in the previous studies, intact arteries were incubated in hyperglycaemic solution before isolation of cells. The acute reduction in Kv channel activity by increased glucose does, however, require activation of PKC, since it was abolished in the presence of PKC inhibitor peptide. Hyperglycaemia has been shown to increase levels of diacylglycerol, leading to increased activation of PKC in both cultured aortic smooth muscle cells and in fresh aortic tissue (Inoguchi et al. 1992, 1994; Kunisaki et al. 1994, 1996; Way et al. 2001), and PKC has been implicated in the reduction of KATP channel-mediated hyperpolarization and relaxation in human omental arteries exposed to high glucose concentrations (Kinoshita et al. 2004). The involvement of PKC has not, however, been reported in previous studies of Kv inhibition by hyperglycaemia (Liu et al. 2001, 2004).
Prevention of endothelin inhibition by raised glucose concentration
The present study provides the first report, to our knowledge, of a profound effect of extracellular glucose on vasoconstrictor inhibition of Kv channels. In common with several other vasoconstrictors, ET-1 inhibits K+ channels by activation of PKC (Fig. 4; Shimoda et al. 1998; Park et al. 2005). Endothelin-1 is a potent inhibitor of Kv currents in mesenteric arterial smooth muscle; 10 nM ET-1 reduced currents by about 50% in 4 mM glucose. Increasing D-glucose to 10 mM abolished the inhibitory action of ET-1. This effect cannot be explained simply in terms of increased glucose having already caused maximal inhibition so that ET-1 can have no further effect, since the inhibitory effect of ET-1 is considerably greater than that of 10 mM glucose. In addition, ET-1 substantially increased the rate of Kv current inactivation, reducing the time constant for inactivation about fourfold, whereas high glucose did not have this effect.
It is clear that block of ET-1 inhibition by glucose requires metabolism of the sugar, since fructose, which is metabolized in essentially the same way as glucose, also abolished the action of ET-1, while the non-metabolized sugars L-glucose, sucrose and mannitol were without effect. Furthermore, the effect of D-glucose can be prevented by blocking glycolysis with iodoacetic acid, and addition of pyruvate as a substrate downstream of glycolysis restores inhibition of the effect of endothelin. The mitochondrial uncoupler 2,4-dintrophenol, which dissipates the mitochondrial membrane potential and so the energy gradient for ATP synthesis, was also able to restore Kv current inhibition by ET-1 in the presence of 10 mM D-glucose, suggesting that glucose must be metabolized as far as ATP synthesis to exert its effect on vasoconstrictor inhibition. Our results do not, however, support the idea that the effect of raised glucose occurs through production of oxygen free radicals such as ·O2–, since 10 mM D-glucose still prevented Kv current inhibition by ET-1 in the presence of the free radical scavenger N-(2-mercaptopropionyl)-glycine. The effect of increased glucose also seems unlikely to occur at the level of the ET-1 receptor or receptor coupling to PKC activation, since ET-1 inhibition of KATP channels, which also occurs through activation of PKC (Park et al. 2005), was not affected by increasing D-glucose from 4 to 10 mM (Fig. 8). It is possible that the effect of high glucose concentration on the action of ET-1, like its effect on Kv current density, occurs through activation of PKC. Hyperglycaemia has been reported to activate primarily, but not exclusively, the ß-isoform of PKC (Way et al. 2001). Inhibition of KATP channels by ET-1 and of KATP and Kv channels by angiotensin II in arterial smooth muscle occurs through PKC-
(Hayabuchi et al. 2001b,c; Park et al. 2005). Thus, it is possible that PKC-ß activation by glucose might modulate PKC--dependent channel inhibition by ET-1. The exact mechanism by which glucose regulates ET-1 signalling to Kv channels and the possible roles of different PKC isoforms remain to be established, and will form the subject of future investigation.
Possible functional implications
Voltage-activated K+ channels make an important contribution to the membrane potential of vascular smooth muscle (Leblanc et al. 1994; Knot & Nelson, 1995; Standen & Quayle, 1998; Cheong et al. 2002; Liu & Gutterman, 2002; Cox, 2005) and may play a role in limiting depolarization (Nelson & Quayle, 1995). Our finding that increased glucose, which inhibits Kv, depolarizes isolated smooth muscle cells is consistent with a role for Kv in the resting membrane potential. Our results also suggest a small depolarization in intact arterial segments. Such an effect might be greater in arteries depolarized in response to physiological intra-arterial pressures, where the activation of Kv channels would be expected to be greater.
Voltage-activated K+ channels are also activated by ß-adrenoceptor stimulation and by activation of PKA, and so are likely to be involved in vasodilator reponses to agents that activate the cAMP–PKA pathway (Aiello et al. 1995, 1998), suggesting that such responses might be impaired under hyperglycaemic conditions. Consistent with this, Li et al. (2003) have reported that dilatations in response to isoprenaline or forskolin are attenuated in coronary arteries that have been incubated in high-glucose solution. Our results show that changes in glucose concentration can also have profound effects on Kv channel inhibition by a vasoconstrictor. These effects on vasoconstrictor action occur rapidly and with relatively small changes in glucose concentration, which are within the physiological range. Such effects might serve to reduce some of the effects of impaired vasodilator function in response to hyperglycaemia by ensuring that, while Kv channel activity is reduced, its further reduction by vasoconstrictors is also limited. Since the effects of increased glucose on ET-1 action are rapid, it is also conceivable that they could play a role during short-term physiological changes in glucose concentration. In future studies it will be important to establish whether glucose can affect channel modulation by other vasoconstrictors in addition to ET-1.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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) and 10 mM glucose (•); n
= 10 cells in each case. E, mean current (relative to cell capacitance) at +60 mV in cells bathed in 4, 0 and 10 mM glucose; n
= 6 cells in each case, *P < 0.05 versus 0 mM glucose. F, mean activation curves, measured from tail currents on repolarization to –30 mV from a 400 ms pulse to the indicated voltage in 0 (
