Inhibitory Effect of High Concentration of Glucose on Relaxations to Activation of ATP-Sensitive K+ Channels in Human Omental Artery
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Abstract
Objective— The present study was designed to examine in the human omental artery whether high concentrations of D-glucose inhibit the activity of ATP-sensitive K+ channels in the vascular smooth muscle and whether this inhibitory effect is mediated by the production of superoxide.
Methods and Results— Human omental arteries without endothelium were suspended for isometric force recording. Changes in membrane potentials were recorded and production of superoxide was evaluated. Glibenclamide abolished vasorelaxation and hyperpolarization in response to levcromakalim. D-glucose (10 to 20 mmol/L) but not l-glucose (20 mmol/L) reduced these vasorelaxation and hyperpolarization. Tiron and diphenyleneiodonium, but not catalase, restored vasorelaxation and hyperpolarization in response to levcromakalim in arteries treated with D-glucose. Calphostin C and Gö6976 simultaneously recovered these vasorelaxation and hyperpolarization in arteries treated with D-glucose. Phorbol 12-myristate 13 acetate (PMA) inhibited the vasorelaxation and hyperpolarization, which are recovered by calphostin C as well as Gö6976. D-glucose and PMA, but not l-glucose, significantly increased superoxide production from the arteries, whereas such increased production was reversed by Tiron.
Conclusions— These results suggest that in the human visceral artery, acute hyperglycemia modulates vasodilation mediated by ATP-sensitive K+ channels via the production of superoxide possibly mediated by the activation of protein kinase C.
Increasing evidence suggests that ATP-sensitive K+ channels play important roles in physiological and pathophysiological vasodilation.1 Previous studies on the diabetic animal models suggest that hyperglycemia impairs the activity of ATP-sensitive K+ channels in the vascular smooth muscle cells.2,3 Although a recent study on coronary arterioles from the diabetic patients has documented the reduction of vasorelaxation mediated by ATP-sensitive K+ channels,4 the acute effect of high glucose on the activity of K+ channels has not been studied in the human blood vessels.
Studies using several diabetic animal models indicate that superoxide reduces the activity of ATP-sensitive K+ channels in the vascular smooth muscle cells.5 However, the evidence showing that hyperglycemia-induced formation of reactive oxygen species modulates the activity of ATP-sensitive K+ channels is scarce. Recent studies on the rat as well as the rabbit demonstrated that protein kinase C activation inhibits ATP-sensitive K+ channels expressed on vascular smooth muscle cells.6,7 In animal models, hyperglycemia is reportedly capable of increasing the activity of protein kinase C, whereas this has not been well-documented in the human vasculature.8 In addition, it is unclear whether in the human blood vessels the activation of protein kinase C via acute exposure of high glucose may induce increased production of superoxide, resulting in the inhibitory effect on the function of K+ channels.
Therefore, the present study was designed to examine in the human omental artery, whether high concentrations of D-glucose inhibit the activity of ATP-sensitive K+ channels, and whether this inhibitory effect is mediated by the production of superoxide via the activation of protein kinase C.
Methods
The institutional research committee approved this study and the written informed consent was obtained from each patient enrolled in this study. The part of human greater omentum was obtained from patients scheduled for the elective gastric surgery, and all of enrolled patients (40 patients, aged 40 to 75 years) were without heart disease and coronary risk factors, including diabetes mellitus, hypertension, and hypercholesterolemia. Immediately after the resection, the greater omentum was put in ice-cold modified Krebs-Ringer bicarbonate solution (control solution, pH 7.4).9 All experiments were performed in the presence of D-glucose (11 mmol/L) in the control condition.
Organ Chamber Experiments
Each omental artery (2-mm ring, 0.5 to 1.0 mm in diameter) without endothelium was connected to an isometric force transducer. We removed endothelium to avoid the involvement of endothelium-derived factors in this study. Optimal tension was achieved at ≈1.0 g. During contraction in response to a prostaglandin H2/thromboxane receptor agonist U46619 (10−7 mol/L), concentration-response curves to levcromakalim (a generous gift from GlaxoSmithKline PLC, Greenford, United Kingdom) or diltiazem were obtained in the absence or in the presence of glibenclamide, D-glucose, l-glucose, or phorbol 12-myristate 13-acetate (PMA) in combination with calphostin C, Gö 6976, Tiron, diphenyleneiodonium (DPI), catalase, genistein, or PD98059, which were added 60 minutes or 15 minutes (for PMA) before the contraction to U46619. The relaxations were expressed as a percentage of the maximal relaxation to papaverine (3×10−4 mol/L).9
Electrophysiological Experiments
Arterial rings were longitudinally cut and fixed on the bottom of an experimental chamber. The arteries were continuously perfused with control solution (37°C) bubbled with 95% O2–5% CO2 gas mixture. A glass microelectrode (tip resistance 40 to 80 mol/LΩ) filled with 3 mol/L KCl and held by a micromanipulator (Narishige, Tokyo, Japan), was inserted into a smooth muscle cell from the intimal side of the vessel.10,11 The electrical signal was amplified using a recording amplifier (Electro 705; World Precision Instruments Inc). The membrane potential was continuously monitored and recorded on a chart recorder (SS-250F-1; SENKONIC Inc). The validity of a successful impalement was assessed by a sudden negative shift, followed by a stable negative voltage for >2 minutes.10,11 Changes in membrane potentials produced by levcromakalim (10−5 mol/L) were continuously recorded. D-glucose, l-glucose, glibenclamide, calphostin C, Gö 6976, Tiron, or DPI was applied 60 minutes before membrane potential recordings.
Chemiluminescence Detection of Superoxide
Superoxide yielded from human omental arteries without endothelium was detected by using a luciferin analog, 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-α]pyrazin-3-one (MCLA; Tokyo Kasei Kogyo, Tokyo, Japan), as a chemiluminescence probe.12 Pieces of the omental artery, dissected 1-cm-long, opened longitudinally to expose the internal surface, were put into dishes of a 96-well multititer plate of 40 μmol/L MCLA-containing Krebs–HEPES (70 μL). This multiplate was then promptly transferred to a dark room to perform the following steps under red safe lights. A 70-μL aliquot of drugs dissolved in Krebs–HEPES–MCLA buffer was added to each well containing vessel segments. The plate was then covered with a blue light-sensitive roentgen film, especially equipped for chemiluminescence detection of immunoblotting experiments (Hyperfilm ECL; Amersham Biosciences). After a 15-minute exposure to vessel segments, the film was developed using an automatic X-ray film processor. The film was then scanned and the optical density of each well was evaluated by using an image processing ImageJver 1.30 (Research Services Branch, National Institute of Mental Health). The intensity of chemiluminescence from each well was expressed as percentage, assuming the optical density of autoradiography from the buffer of 0% and that from vessels loaded with 20 mmol/L D-glucose to be 100%.
Statistical Analysis
The data are expressed as means±SD, and n refers to the number of patients from whom the omental artery was taken. Statistical analysis was performed using repeated measures analysis of variance, followed by Scheffe F test for multiple comparisons. Differences were considered to be statistically significant at P<0.05.
Results
Organ Chamber Experiments
During submaximal contraction to U46619 (10−7 mol/L), a selective ATP-sensitive K+ channel opener, levcromakalim (10−8 to 10−5 mol/L) induced concentration-dependent relaxation in the human omental artery without endothelium treated with l-glucose (20 mmol/L) (please see http://atvb.ahajournals.org.). A selective ATP-sensitive K+ channel antagonist, glibenclamide, completely abolished this vasorelaxation, whereas it did not affect the basal tone of the omental artery.
D-glucose (10 to 20 mmol/L) concentration-dependently reduced vasorelaxation induced by levcromakalim (Figure 1), whereas D-glucose (20 mmol/L) did not affect vasorelaxation produced by a voltage-dependent Ca2+ channel antagonist diltiazem (10−7 to 10−4 mol/L).
Figure 1. Concentration-response curves to levcromakalim in the absence or in the presence of l-glucose or D-glucose, obtained in the human artery without endothelium. *Difference between rings treated with l-glucose and rings treated with D-glucose is statistically significant (P<0.05).
A superoxide scavenger, Tiron (10 mmol/L), and a NAD(P)H oxidase inhibitor, DPI (10−6 mol/L), restored vasorelaxation in response to levcromakalim in the omental arteries treated with D-glucose (20 mmol/L), whereas a hydrogen peroxide scavenger catalase (1200 U/mL) did not alter the inhibitory effect of D-glucose (20 mmol/L) (Figure 2a). These inhibitors themselves did not affect the vasorelaxation produced by levcromakalim. Protein kinase C inhibitors, calphostin C (3×10−7 mol/L), and Gö 6976 (3×10−7 mol/L) restored vasorelaxation in response to levcromakalim in the omental arteries treated with D-glucose (20 mmol/L) (Figure 2b), whereas these inhibitors themselves did not alter the vasorelaxation produced by levcromakalim. Phorbor 12-myristate 13-acetate ester, PMA (10−7 mol/L), impaired vasorelaxation in response to levcromakalim in the arteries treated with l-glucose (20 mmol/L), which is completely recovered by calphostin C (3×10−7 mol/L) or Gö 6976 (3×10−7 mol/L) (Figure 2c). A nonselective tyrosine kinase inhibitor genistein (10−6 mol/L) and a mitogen-activated protein kinase inhibitor PD98059 (10−5 mol/L) did not affect the inhibitory effect induced by D-glucose (20 mmol/L) (Figure 2d). In each Figure, maximal relaxations in response to papaverine (3×10−4 mol/L) were not different between groups.
Figure 2. a, Concentration-response curves to levcromakalim in the absence or in the presence of Tiron, catalase, or DPI obtained in the human artery without endothelium treated with D-glucose. *Difference between rings treated with D-glucose and rings treated with D-glucose in combination with Tiron or DPI is statistically significant (P<0.05). b, Concentration-response curves to levcromakalim in the absence or in the presence of calphostin C or Gö 6976 obtained in the human artery without endothelium treated with D-glucose. *Difference between rings treated with D-glucose and rings treated with D-glucose in combination with calphostin C or Gö 6976 is statistically significant (P<0.05). c, Concentration-response curves to levcromakalim in the absence or in the presence of phorbol 12-myristate 13-acetate (PMA) in combination with calphostin C or Gö 6976, obtained in the porcine coronary artery without endothelium treated with l-glucose. *Differences between rings treated with l-glucose plus PMA and rings treated with l-glucose or rings treated with l-glucose plus PMA in combination with calphostin C or Gö 6976 are statistically significant (P<0.05). d, Concentration-response curves to levcromakalim in the absence or in the presence of PD98059 or genistein obtained in the human artery without endothelium treated with D-glucose.
Electrophysiological Experiments
Levcromakalim (10−5 mol/L) produced hyperpolarization of smooth muscle cells of the human mental artery treated with l-glucose (20 mmol/L), which is abolished by glibenclamide (5×10−6 mol/L), and this hyperpolarization was reduced by the treatment with D-glucose (20 mmol/L) (Figure 3). Tiron (10 mmol/L), DPI (10−6 mol/L), calphostin C (3×10−7 mol/L), and Gö 6976 (3×10−7 mol/L) restored hyperpolarization in response to levcromakalim in the omental arteries treated with D-glucose (20 mmol/L) (Figures 4 and 5⇓). Resting membrane potentials did not differ among the groups studied (see legends for Figures 3, 4, and 5⇓⇓).
Figure 3. Changes in membrane potential of smooth muscle cells induced by levcromakalim (10−5 mol/L) in the human omental artery. Levcromakalim-induced hyperpolarization is significantly reduced by glibenclamide plus l-glucose or D-glucose (*P<0.05). Resting membrane potentials did not differ among the groups studied (l-glucose [20 mmol/L]=−37.6±2.6 mV; l-glucose [20 mmol/L] plus glibenclamide [5×10−6 mol/L]= −42.6±4.3 mV; D-glucose [20 mmol/L]=−40.8±4.8 mV).
Figure 4. Changes in membrane potential of smooth muscle cells induced by levcromakalim (10−5 mol/L), in the human omental artery treated with D-glucose. Levcromakalim-induced hyperpolarization is significantly recovered by calphostin C or Gö 6976, respectively (*P<0.05). Resting membrane potentials did not differ among the groups studied (D-glucose [20 mmol/L]= −43.8±4.6 mV; D-glucose [20 mmol/L] plus calphostin C [3×10−7 mol/L]=−42.4±3.8 mV; D-glucose [20 mmol/L] plus Gö 6976 [3×10−7 mol/L]45.6±2.4 mV, respectively).
Figure 5. Changes in membrane potential of smooth muscle cells induced by levcromakalim (10−5 mol/L) in the human omental artery treated with D-glucose. Levcromakalim-induced hyperpolarization is significantly recovered by Tiron or DPI, respectively (*P<0.05). Resting membrane potentials did not differ among the groups studied (D-glucose [20 mmol/L]= −44.2±1.5 mV; D-glucose [20 mmol/L] plus DPI [10−6 mol/L]=−45.0±1.6 mV; D-glucose [20 mmol/L] plus Tiron [10 mmol/L]=−42.8±1.9 mV, respectively).
Chemiluminescence Detection of Superoxide
The intensity of MCLA-dependent chemiluminescence from human omental arteries loaded with D-glucose or PMA was significantly higher than those loaded with l-glucose (Figure 6). A superoxide scavenger, Tiron, remarkably decreased the chemiluminescence from vessels loaded with D-glucose (Figure 6).
Figure 6. Cumulative data showing effects of D-glucose as well as PMA and the modification produced by Tirom on superoxide production from human omental arteries. The percent response of superoxide production was calculated assuming the optical density of autoradiographed chemiluminescence from the buffer of 0%, and that from vessels loaded with 20 mmol/L D-glucose to be 100%. *Differences between rings treated with l-glucose and D-glucose and those between rings treated with l-glucose and l-glucose in combination with PMA are statistically significant (P<0.05).
Discussion
In the human omental artery, glibenclamide abolished vasorelaxation as well as hyperpolarization in response to levcromakalim.13,14 However, glibenclamide did not affect the basal tension as well as membrane potential of the omental artery, indicating that ATP-sensitive K+ channels may not play a role in the resting tone of visceral circulation in humans. In contrast to this finding, a recent human study has documented that direct administration of glibenclamide to the large coronary artery provokes reduction of resting vessel diameter, suggesting that these channels may modulate resting tone of the large coronary artery in humans.15 We cannot rule out the possible involvement of the regional difference in the modulator role of ATP-sensitive K+ channels in the human vascular tone.
In the current study, addition of 10 or 20 mmol/L D-glucose, but not 20 mmol/L l-glucose, reduced vasorelaxation and hyperpolarization mediated by ATP-sensitive K+ channels, whereas 20 mmol/L D-glucose did not alter vasorelaxation induced by a voltage-dependent Ca2+ channel antagonist. These results suggest that in the human visceral artery, acute exposure of high concentration D-glucose (>378 mg/dL) inhibits the activity of ATP-sensitive K+ channels in vascular smooth muscle cells in an osmolarity-independent fashion, in which the effect is relatively selective on K+ channels. Our results with high glucose appear to be consistent with a recent study on diabetic patients, demonstrating the reduction of vasorelaxation induced by hypoxia via ATP-sensitive K+ channels in the human coronary arteriole.4 Similarly, high glucose impaired the preconditioning effects toward the ischemic in the canine heart, indicating the inhibitory effect of high glucose on the activity of mitochondrial ATP-sensitive K+ channels in animals.16 These results also suggest that acute exposure of high glucose may simultaneously modulate the activity of different subtypes of ATP-sensitive K+ channels expressed on blood vessels as well as mitochondria.17,18
In animals, incubation of vascular smooth muscle cells with high glucose reportedly increases intracellular levels of diacylglycerol, subsequently leading to protein kinase C activation.19 In the human omental artery, calphostin C and Gö 6976 restored vasorelaxation as well as hyperpolarization in response to levcromakalim in the arteries treated with D-glucose, although the restoration induced by Gö 6976 was rather augmented. Mutual targets of the protein kinase C isozyme for calphostin C and Gö 6976 are reportedly α-isozymes and β- isozymes.20,21 Therefore, it is speculated that protein kinase C α-isozymes and β- isozymes may contribute to the inhibitory effect induced by acute exposure of high glucose on the activity of ATP-sensitive K+ channels in the human visceral arterial smooth muscle cells. This conclusion is also supported by the notion from previous studies, demonstrating the activation of protein kinase C β- isozymes induced by the high concentrations of glucose.8 In the current study, PMA impairs vasorelaxation as well as hyperpolarization in response to levcromakalim, which is completely recovered by calphostin C as well as Gö 6976. In addition, neither calphostin C nor Gö 6976 affected vasorelaxation to levcromakalim in arteries treated with l-glucose. These results simultaneously support the conclusion that protein kinase C activation may selectively play a role in the inhibitory effects induced by acute exposure to high glucose on the activity of ATP-sensitive K+ channels. Our results are in agreement with previous animal studies, showing that the protein kinase C activation inhibits vasorelaxation as well as currents via ATP-sensitive K+ channels.6,7,22–26
The ATP-sensitive K+ channel is a complex of 2 proteins: the sulfonylurea receptor (SUR) and the pore forming subunit, which belongs to the inward rectifier K+ channel (Kir) family.17 Because the SUR of ATP-sensitive K+ channel is a primary target of the channel openers, the action of D-glucose on some components of SUR may play a role in these inhibitory effects.27 Protein kinase C activation seems to be capable of modulating the limited subtype of ATP-sensitive K+ channel expressed in the vascular smooth muscle cells (SUR 2B + Kir6.1).28,29 Importantly, the activity of the channel subtypes produced by SUR 2B and Kir6.2 was not altered by the kinase, suggesting the crucial role of Kir6.1 compartment of ATP-sensitive K+ channels in the modulator effect of protein kinase C.29 Therefore, it is also possible that D-glucose may modulate Kir6.1 compartment of ATP-sensitive K+ channels, leading to the inhibition of vasorelaxation mediated by these channels in the human omental artery.
Previous studies demonstrated that protein tyrosine phosphorylation as well as augmented activity of mitogen-activated protein kinase modulate the activity of ATP-sensitive K+ channels.30–34 However, in the current study, neither genistein nor PD98059 affected the effects produced by high glucose. Therefore, it is unlikely that tyrosine and mitogen-activated protein kinases mediate the inhibitory effect of high glucose exposure on ATP-sensitive K+ channels in the human artery.35–37
Acute exposure toward high glucose produced increased levels of superoxide in smooth muscle cells of the human omental artery. Our results are in agreement with previous studies on human blood vessels, showing that high concentrations of glucose can induce augmentation of production of superoxide in the endothelial cells.38 In the human omental artery, protein kinase C activation by a phorbor ester, similar to high glucose, increased superoxide production in the vascular smooth muscle cells, indicating that activation of the kinase contributes to the augmented production of superoxide by acute exposure to high glucose in the human visceral artery. Our results are certainly concurrent with previous studies demonstrating an important role of protein kinase C activation in the increased production of superoxide in the blood vessels.39–41
Studies using several diabetic animal models indicate that superoxide reduces the activity of ATP-sensitive K+ channels in the vascular smooth muscle cells.5 Our results with acute exposure to high glucose have demonstrated the evidence supporting the inhibitory effects of superoxide produced by high glucose on the activity of ATP-sensitive K+ channels. A similar inhibitory effect of superoxide on K+ channels was reported in the study on the rat coronary artery, documenting the inhibitory effect of high glucose on voltage-dependent K+ channel currents.42 In the current study, the inhibitory effects of high glucose on vasorelaxation as well as hyperpolarization mediated by ATP-sensitive K+ channels were abolished by Tiron or DPI, suggesting that the increased production of superoxide seen in arteries treated with high glucose may be mediated by NAD(P)H oxidase in the smooth muscle cells, which has been shown to be activated by protein kinase C.41,43 However, further studies are warranted in this aspect, because the activity of NAD(P)H oxidase was not evaluated in our study.
This is the first study examining the acute effects of high glucose on the activity of ATP-sensitive K+ channels in the human blood vessel. Results in the current study suggest that in the human visceral artery, acute hyperglycemia modulates vasodilation mediated by ATP-sensitive K+ channels via the production of superoxide possibly mediated by the activation of protein kinase C. It appears that in the visceral circulation, similar to the cerebral one, acidosis corresponding with ischemia activates ATP-sensitive K+ channels, resulting in visceral arterial dilation.44,45 Therefore, it is speculated that even short-term acute exposure to high glucose reduces the beneficial effect via ATP-sensitive K+ channels, which may play important roles in regulation of human visceral circulation during diverse pathophysiological situations. In addition, it is not clinically rare to administer vasodilators, such as nicorandil, which act via ATP-sensitive K+ channels, to diabetic patients. Our results indicate that in that occasion, one might have to consider the possibility that these vasodilator compounds acting on ATP-sensitive K+ channels cannot afford to produce their effects to support appropriate visceral blood flow.46
Acknowledgments
This work was supported in part by grants-in-aid 16390458 (H.K.), 16659426 (H.K.), and 13470327 (Y.H.) for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, Tokyo, and 11–7 for Medical Research from Wakayama prefecture, Wakayama, Japan (H.K.). This work was presented in part at the annual meeting of the American Society of Anesthesiologists, San Francisco, Calif, October 11 to 15, 2003.
- Received August 8, 2004.
- Accepted September 28, 2004.
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- Inhibitory Effect of High Concentration of Glucose on Relaxations to Activation of ATP-Sensitive K+ Channels in Human Omental ArteryHiroyuki Kinoshita, Toshiharu Azma, Katsutoshi Nakahata, Hiroshi Iranami, Yoshiki Kimoto, Mayuko Dojo, Osafumi Yuge and Yoshio HatanoArteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2290-2295, originally published December 2, 2004https://doi.org/10.1161/01.ATV.0000148006.78179.c7
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- Inhibitory Effect of High Concentration of Glucose on Relaxations to Activation of ATP-Sensitive K+ Channels in Human Omental ArteryHiroyuki Kinoshita, Toshiharu Azma, Katsutoshi Nakahata, Hiroshi Iranami, Yoshiki Kimoto, Mayuko Dojo, Osafumi Yuge and Yoshio HatanoArteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2290-2295, originally published December 2, 2004https://doi.org/10.1161/01.ATV.0000148006.78179.c7