| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
Anesth Analg 2008; 106:858-864 © 2008 International Anesthesia Research Society doi: 10.1213/ane.0b013e318163fd5b
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Abstract |
|---|
 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
BACKGROUND: Isoflurane activates vascular adenosine triphosphate sensitive potassium (KATP) channels, and may induce vasodilation. In the present study, we investigated whether hyperglycemia modifies isoflurane activation of vascular KATP channel.
METHODS: We used a cell-attached patch-clamp configuration to test the effects of isoflurane on KATP channel activity in vascular smooth muscle cells (VSMCs) after incubation for 24 h in medium containing normal glucose (NG, 5.5 mM d-glucose), l-glucose (LG, 5.5 mM d-glucose plus 17.5 mM l-glucose), or high glucose (HG, 23 mM d-glucose). Superoxide levels in aortas were measured by the lucigenin-enhanced chemiluminescence technique.
RESULTS: Isoflurane-induced open probabilities were significantly reduced in VSMCs from arteries incubated in HG (0.06 ± 0.01) compared with NG (0.17 ± 0.02; P < 0.05) and LG (0.15 ± 0.02; P < 0.05). Pretreatment of VSMCs with protein kinase C (PKC) inhibitors, calphostin C and PKC inhibitor 20–28, greatly reduced HG inhibition of isoflurane-induced KATP channel activity. In addition, a PKC activator, PMA, mimicked the effects of HG. Superoxide release was significantly increased in arteries incubated in HG (18.3 ± 11.5 relative light units (RLU) · s–1 · mg–1; P < 0.05 versus NG). Coincubated with polyethylene glycol-superoxide dismutase (250 U/mL), a cell-permeable superoxide scavenger, greatly reduced the HG-induced increase of superoxide, but failed to reduce HG inhibition of isoflurane-induced KATP channel activity.
CONCLUSIONS: Our results suggest that the metabolic stress of hyperglycemia can impair isoflurane-induced vascular KATP channel activity mediated by excessive activation of PKC. This could impede the coronary vasodilation response to isoflurane, causing ischemia or hypoxia in patients with perioperative hyperglycemia.
|
Introduction |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Perioperative hyperglycemia is one of the most important predictors of short- and long-term cardiovascular morbidity and mortality.1–3 Although the detailed mechanisms responsible for this increased risk remain unclear, it has been suggested that hyperglycemia impairs an endogenous protective signaling pathway4 and reduces the coronary microcirculatory response to ischemia.5
In vascular smooth muscle cells (VSMCs), adenosine triphosphate sensitive potassium (KATP) channels are critical for the regulation of vascular tonus, especially in the coronary artery, in response to hypoxia and ischemia.6,7 Studies have shown that vascular KATP channel activity can be affected by the metabolic stress of hyperglycemia and diabetes mellitus. Kinoshita et al. demonstrated that hyperglycemia largely attenuates KATP channel-mediated hyperpolarization and relaxation in human omental arteries.8 Miura et al. suggested that KATP channel dysfunction can contribute significantly to myocardial ischemia in patients with diabetes.9
Isoflurane-induced vasodilation of different vascular tissues has been reported.10,11 Previous studies have indicated that activation of vascular KATP channels plays an important role in isoflurane-induced vasodilation, especially in the coronary artery.12,13 Recently, we demonstrated direct evidence for the activation of native and recombinant vascular KATP channels by isoflurane.14 However, hyperglycemia impairs isoflurane-induced KATP channel activation, and the mechanisms by which this might occur remain to be determined. The present study was undertaken to examine whether hyperglycemia influences the effect of isoflurane on KATP channel activities in freshly isolated rat VSMCs.
|
METHODS |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
This study was approved by the Animal Investigation Committee of Tokushima University (Tokushima, Japan) and was conducted according to the animal-use guidelines of the American Physiologic Society (Bethesda, MD).
Preparation of Rat Aortas
Male Wistar rats (weighing 250–300 g) were anesthetized with ether, and 1.0 IU/g heparin was injected intraperitoneally 30 min before surgery. Aortas were dissected and incubated in Dulbecco's Modified Eagle's Medium (DMEM) with 10% fetal bovine serum (GIBCO, Grand Island, NY), 100 µg/mL streptomycin, and 100 µg/mL penicillin for 24 h at 37°C. DMEM was supplemented with 5.5 mM d-glucose (normal glucose, NG), 23 mM d-glucose (high glucose, HG), or 5.5 mM d-glucose plus 17.5 mM l-glucose (LG). l-Glucose, which is not metabolized, was used as an osmotic control. After incubation, vessels were prepared for patch-clamp experiments or superoxide measurements.
Electrophysiological Measurements
Enzymatic isolation of single VSMCs was performed according to published methods.15 Cell-attached patch configurations were applied to record the current through single channels using a patch-clamp amplifier, as previously described.14,16 The bathing solution was composed of the following: 140 mM KCl, 10 mM HEPES, 5.5 mM d-glucose, and 1 mM EGTA. The pipette solution contained 140 mM KCl, 10 mM HEPES, and 5.5 mM d-glucose. The pH of all solutions was adjusted to 7.3–7.4 with KOH. Recordings were made at 36 ± 0.5°C. Patch pipettes were pulled with an electrode puller (PP-830; Narishige, Tokyo, Japan). The resistance of pipettes filled with internal solution and immersed in the Tyrode's solution was 5–7 M
. The sampling frequency of the single-channel data was 5 KHz with a low-pass filter (1 KHz).
pClamp version 7 software (Axon Instruments, Foster, CA) was used for data acquisition and analysis. The open probability (Po) was determined from current amplitude histograms and was calculated as described previously.17 Channel activity was expressed as NPo where N was the number of channels active in the patch. The steady-state NPo in the presence of isoflurane was compared among VSMCs from arteries incubated in each glucose solution.
Measurement of Superoxide
Superoxide levels in aortas were measured by the lucigenin-enhanced chemiluminescence technique as described previously.18 Briefly, after incubation in one of the three solutions of glucose described above, vessel segments were equilibrated in Krebs– HEPES buffer gassed with 95% O2/5% CO2 for 30 min at 37°C. Lucigenin-enhanced chemiluminescence was measured in 2 mL Krebs–HEPES buffer containing lucigenin (5 µM) using a luminometer (AB-2200, ATTO Corporation, Tokyo, Japan), modified to maintain a sample temperature of 37°C. Vessel segments in the HG group were also preincubated with the cell-permeable superoxide-anion scavenger, polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) at 250 U/mL for 30 min before the measurements, as indicated. Preliminary study showed that under our experimental conditions PEG-SOD had no influence on vascular KATP channel activity. The emitted relative light units (RLU) recorded by luminometer were integrated over 5 min. Dark current readings (the photomultiplier background signal) were automatically subtracted. Background counts, which were determined from vessel-free preparations, were subtracted from the readings obtained with vessels. Chemiluminescence was expressed as RLU per minute per milligram vessel dry weight.
Drugs
Isoflurane (Abbott, Tokyo, Japan) was delivered to the recording chamber as described previously.14 A clinically relevant concentration of isoflurane, 0.5 mM, was used and was equivalent to 2.4 vol%, or 1.7 minimum alveolar concentration. The concentration of isoflurane in the superfusate was determined to be 0.51 ± 0.03 mM by gas chromatography (G-3500; Hitachi, Tokyo, Japan). Glibenclamide and chlorophenylthio- cAMP (CPT-cAMP) were purchased from Sigma Aldrich, Japan (Tokyo, Japan). Calphostin C and cell-permeable myristoylated protein kinase C (PKC) inhibitor 20–28 were obtained from Calbiochem (San Diego, CA). Glibenclamide, CPT-cAMP, calphostin C, and PKC inhibitor 20–28 were dissolved in dimethyl sulfoxide. The final concentration of dimethyl sulfoxide was <0.05%. Dimethyl sulfoxide at a two-fold-higher concentration was shown to not affect KATP channel currents. Lucigen and PEG-SOD were purchased from Sigma-Aldrich (St. Louis, MO) and dissolved in phosphate buffered saline.
Statistical Analysis
Data were expressed as means ± sd. Statistical analysis was performed using either the Student's t-test or repeated measures of analysis of variance, followed by Scheffé test for multiple comparisons. Differences were considered to be statistically significant at P < 0.05.
|
RESULTS |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
High Glucose Impairs Isoflurane-Induced KATP Channel Activation in Rat VSMCs
We tested the effects of isoflurane on KATP channel activity during cell-attached recordings of VSMCs freshly isolated from rat aorta and incubated for 24 h in DMEM containing NG, LG, or HG. Figure 1A shows that the bath application of 0.5 mM isoflurane gradually activated KATP channel activity in VSMCs from arteries exposed to NG or LG, whereas isoflurane-induced KATP channel activity was suppressed in VSMCs exposed to HG. In all groups, the subsequent addition of 3 µM glibenclamide induced an immediate reversal of the effects of isoflurane (Fig. 1A). The current-voltage relation observed after application of isoflurane is shown in Figure 1B. There was no significant difference in single channel conductance among the three groups (NG = 37 ± 5 pS, LG = 35 ± 4 pS, and HG = 40 ± 6 pS).
|
), and HG (
). Each vertical bar represents measurements from 10 patches (mean ± sd). (C) The relationship between NPo and time after application of isoflurane for the traces shown in NG (•), LG (Figure 1C shows the relationship between isoflurane-induced NPo values and time for the traces in Figure 1A. In all VSMCs from arteries exposed to NG, LG, and HG, there was a delay of approximately 5–10 min after the bath application of isoflurane before the steady-state KATP channel activation occurred. However, isoflurane-induced steady-state NPo values (10–15 min after application of isoflurane) were significantly reduced in VSMCs from arteries incubated in HG (0.12 ± 0.02; n = 15) compared with NG (0.35 ± 0.04, n = 15; P = 0.01 versus HG) and LG (0.30 ± 0.04, n = 15; P = 0.02 versus HG). Identical control experiments in the absence of isoflurane resulted in no KATP channel activation or inhibition during the same time periods in VSMCs from arteries exposed to NG, LG, and HG (Fig. 1D).
The High-Glucose Effect Depends on PKC
Glucose has been shown to activate PKC in blood vessels, and the KATP channel is modulated by PKC.19 Therefore, we examined whether the reduction in isoflurane-induced KATP channel currents by HG involved PKC using two general PKC inhibitors, calphostin C and PKC inhibitor 20–28. Pretreatment of VSMCs with calphostin C (500 nM) or PKC inhibitor 20–28 (10 µM), added to the bath solution 10 min before current recoding, greatly reduced HG inhibition of isoflurane-induced KATP channel activity (Fig. 2A). Identical control experiments in the presence of calphostin C or PKC inhibitor 20–28 alone resulted in no KATP channel activation or inhibition during the same time periods in VSMCs from arteries exposed to NG, LG, and HG (data not shown).
|
The isoflurane-induced NPo during treatment with calphostin C or PKC inhibitor 20–28 is summarized in Figure 2B. The NPo values in VSMCs from arteries incubated in HG were 0.12 ± 0.02 (n = 15) without PKC inhibitor (P = 0.02 versus NG), 0.33 ± 0.06 (n = 15) with calphostin C (P = 0.7 versus isoflurane alone), and 0.34 ± 0.04 (n = 15) with PKC inhibitor 20–28 (P = 0.7 versus isoflurane alone). Figure 2B also shows that both PKC inhibitors had no effect on isoflurane-induced KATP channel activation in NG and LG groups.
An Activator of PKC Inhibits Isoflurane-Induced KATP Channel Activation
To further demonstrate that stimulation of PKC is involved in the reduction of isoflurane-induced KATP channel currents by HG, we studied the effects of PMA, a PKC activator, on these currents in the NG and LG groups. As shown in Figure 3A, PMA (100 nM) pretreatment of VSMCs from arteries exposed to NG suppressed the effects of isoflurane. The isoflurane- induced NPo values observed after pretreatment with PMA in the NG and LG groups are summarized in Figure 2B. PMA mimicked the effects of HG, which were recovered by adding calphostin C (500 nM) or the PKC inhibitor 20–28 (10 µM).
|
In contrast, increased protein kinase A (PKA) activation by bath application of CPT-cAMP (100 µM), a membrane permeable activator of the PKA-dependent cAMP pathway, in cell-attached patches restored the isoflurane effects in the HG group (n = 5, Fig. 4A) as well as in the PMA-treated NG group (n = 5, Fig. 4B).
|
Superoxide Production Is Not Involved in the High-Glucose Effect
To assess whether acute glucose induced superoxide in the rat aortic artery, we measured superoxide production from arteries incubated in NG, LG, and HG by lucigenin-enhanced chemiluminescence (Fig. 5A). Similar superoxide production levels were observed from NG (5.2 ± 2.9 RLU · s–1 · mg–1) and LG arteries (7.1 ± 4.5 RLU · s–1 · mg–1). Superoxide release was significantly increased in arteries incubated in HG (18.3 ± 11.5 RLU · s–1 · mg–1; P = 0.02 versus NG). The effect of the superoxide scavenger, PEG-SOD (250 U/mL), on arteries exposed to HG was also examined. Coincubation with PEG-SOD greatly reduced the HG-induced increase of superoxide (Fig. 5A).
|
We next used the patch-clamp technique to examine whether the reduction in isoflurane-induced KATP channel currents by HG involved HG-induced elevation of superoxide. Coincubation of HG arteries with PEG-SOD (250 U/mL) failed to reduce HG inhibition of isoflurane-induced KATP channel activity (Fig. 5B). The isoflurane-induced NPo in VSMCs from HG arteries coincubated with or without PEG-SOD are summarized in Figure 5C. The NPo values in VSMCs from arteries incubated in HG were 0.12 ± 0.02 (n = 15) without PEG-SOD (P = 0.02 versus LG) and 0.14 ± 0.03 (n = 15) with PEG-SOD (P = 0.02 versus LG).
|
DISCUSSION |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Acute hyperglycemia has been demonstrated to cause vascular KATP channel dysfunction.8 Although volatile anesthetics, including isoflurane, produce coronary vasodilatation by activating vascular KATP channels,12,13 it is unknown whether hyperglycemia impairs isoflurane-induced vascular KATP channel activation. In the current study, we tested the effects of acute exposure of rat aorta to HG on the activation of KATP channels by 0.5 mM isoflurane using the cell-attached patch-clamp configuration on freshly isolated rat VSMCs. Our results demonstrate that exposure to HG, but not LG, for 24 h significantly impairs isoflurane-induced vascular KATP channel activation when compared with NG. These results demonstrate that hyperglycemia metabolically affects the isoflurane–KATP channel interaction, resulting in impaired isoflurane-induced KATP channel activation.
In cardiomyocytes, volatile anesthetics protect the myocardium against myocardial ischemia and reperfusion injury through a signal-transduction pathway that includes cardiac (mitochondrial and sarcolemmal) KATP channels.20 Previous studies have demonstrated that increased blood glucose concentrations attenuate activation of cardiac KATP channels21 and that hyperglycemia attenuates the myocardial protection produced by isoflurane.22 Thus, hyperglycemia predicts mortality after myocardial infarction and may contribute to perioperative risk by impairing volatile anesthetic-induced cardiovascular protective mechanisms via activation of both cardiac and vascular KATP channels.
In the present study, the inhibitory effect of HG on isoflurane-induced KATP channel activity was almost completely reversed by pretreatment with selective PKC inhibitors, calphostin C and PKC inhibitor 20–28. These results indicate that HG suppresses isoflurane-induced vascular KATP channel activation via PKC activation. Hyperglycemia has been shown to increase levels of diacylglycerol, leading to increased activation of PKC,19,23 and it has been suggested that abnormal activation of PKC mediates hyperglycemic events in VSMCs.23 Recent studies have shown that KATP channels in VSMCs are regulated by direct phosphorylation with PKA and PKC and that KATP channel activity is dependent on a balance between phosphorylation by PKA and PKC.24 Some smooth-muscle constrictors (e.g., angiotensin II, serotonin, and acetylcholine) that stimulate PKC inhibit vascular KATP channels, whereas vasodilators (e.g., calcitonin gene-related peptide and adenosine) that stimulate PKA activate these channels.24 Our previous study demonstrated that isoflurane activated vascular KATP channels mediated by activation of PKA.14 It is therefore possible that predominant PKC activation by hyperglycemia prevents isoflurane-induced vascular KATP channel activation via the PKA pathway.
Oxidative damage has been proposed as a possible mechanism by which excess glucose results in tissue damage.25 Hyperglycemia leads to glucose auto-oxidation, increased flux through the polyol pathway, prostanoid synthesis, and protein glycation, all of which lead to increased free-radical generation.25 Previous studies have suggested that superoxide-impaired KATP channel function in VSMCs is important pathophysiology. It has been reported that the cerebral artery dilation induced by the KATP channel opener (KCO), cromakalim, is reduced by exposure to excessive superoxide.26 Furthermore, Kinoshita et al. reported that superoxide produced by acute exposure to high glucose attenuates human omental artery vasodilation mediated by the KCO levocromakalim.8 In the present study, however, pretreatment of arteries with a free-radical scavenger, which abolished HG-induced increase of superoxide, failed to relieve HG-induced inhibition of isoflurane-induced KATP channel activity. These results indicate that superoxide production by HG is not involved in the isoflurane–KATP channel interaction in VSMCs. Our previous study demonstrated that isoflurane activated vascular KATP channels via a cell-signaling pathway,14 whereas a KATP channel opener directly activated the channels to bind channel molecules.24 The different mechanisms of isoflurane and KCOs may indicate different responses to oxidative stress.
The inherent limitations of this study must be addressed. First, in our experimental model, we evaluated hyperglycemia by incubating the VSMCs for 24 h in high glucose medium. However, we cannot exclude the possibility that more acute or subacute hyperglycemia may have a different influence on vascular KATP channel activity. Second, just one concentration (0.5 mM) of isoflurane was used. However, 0.5 mM isoflurane corresponds to 2.4 vol%, which is a clinically relevant concentration. Third, no direct data showing that HG increases PKC activity in VSMCs were presented. Previous studies reported that hyperglycemia could lead to increased activation of PKC in both cultured aortic smooth muscle cells and in fresh aortic tissue.27,28 Furthermore, our results demonstrated that a PKC activator, PMA, mimicked the effects of HG. These results suggest that the HG effect depends on PKC.
In conclusion, we have shown that hyperglycemia impairs isoflurane-induced KATP channel activity in freshly isolated rat VSMCs via activation of PKC. Our results suggest that hyperglycemia can impede the isoflurane-induced coronary vasodilation response, especially in ischemia or hypoxia, possibly contributing to increased myocardial ischemic injury in patients with perioperative hyperglycemia.
|
Footnotes |
|---|
Accepted for publication November 20, 2008.
Supported, in part, by a Grant-in-Aid for Scientific Research (C, 15591636) from the Japan Society for the Promotion of Science, Tokyo, Japan.
|
REFERENCES |
|---|
|
TopAbstractIntroductionMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
- Noordzij PG, Boersma E, Schreiner F, Kertai MD, Feringa HH, Dunkelgrun M, Bax JJ, Klein J, Poldermans D. Increased preoperative glucose levels are associated with perioperative mortality in patients undergoing noncardiac, nonvascular surgery. Eur J Endocrinol 2007;156:137–42
[Abstract/Free Full Text] - Estrada CA, Young JA, Nifong LW, Chitwood WR. Outcomes and perioperative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting. Ann Thorac Surg 2003;75:1392–9
[Abstract/Free Full Text] - Gandhi GY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, Williams BA, Schrader LM, Rizza RA, McMahon MM. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc 2005;80:862–6
[Abstract/Free Full Text] - Gu W, Pagel PS, Warltier DC, Kersten JR. Modifying cardiovascular risk in diabetes mellitus. Anesthesiology 2003; 98:774–9[Web of Science][Medline]
- Kersten JR, Brooks LA, Dellsperger KC. Impaired microvascular response to graded coronary occlusion in diabetic and hyperglycemic dogs. Am J Physiol 1995;268:H1667–74[Web of Science][Medline]
- Daut J, Maier-Rudolph W, von Beckerath N, Mehrke G, Günther K, Goedel-Meinen L. Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels. Science 1990; 247:1341–4
[Abstract/Free Full Text] - Liu Q, Flavahan NA. Hypoxic dilatation of porcine small coronary arteries: role of endothelium and KATP-channels. Br J Pharmacol 1997;120:728–34[Web of Science][Medline]
- Kinoshita H, Azma T, Nakahata K, Iranami H, Kimoto Y, Dojo M, Yuge O, Hatano Y. Inhibitory effect of high concentration of glucose on relaxations to activation of ATP-sensitive K+ channels in human omental artery. Arterioscler Thromb Vasc Biol 2004;24:2290–5
[Abstract/Free Full Text] - Miura H, Wachtel RE, Loberiza FR, Saito T, Miura M, Nicolosi AC, Gutterman DD. Diabetes mellitus impairs vasodilation to hypoxia in human coronary arterioles: reduced activity of ATP-sensitive potassium channels. Circ Res 2003;92:151–8
[Abstract/Free Full Text] - Longnecker DE, Harris PD Microcirculation. In: G Kaley, B Altura, ed. Anesthesia. Baltimore: University Park Press, 1980: 333–69
- Clark SC, MacCannell KL. Vascular responses to anaesthetic agents. Can Anaesth Soc J 1975;22:20–33[Web of Science][Medline]
- Crystal GJ, Gurevicius J, Ramez Salem M, Zhou X. Role of adenosine triphosphate-sensitive potassium channels in coronary vasodilation by halothane, isoflurane and enflurane. Anesthesiology 1997;86:448–58[Web of Science][Medline]
- Zhou X, Abboud W, Manabat NC, Salem MR, Crystal GJ. Isoflurane-induced dilation of porcine coronary arterioles is mediated by ATP-sensitive potassium channels. Anesthesiology 1998;89:182–9[Web of Science][Medline]
- Tanaka K, Kawano T, Nakamura A, Nazari H, Kawahito S, Oshita S, Takahashi A, Nakaya Y. Isoflurane activates sarcolemmal adenosine triphosphate-sensitive potassium channels in vascular smooth muscle cells: a role for protein kinase A. Anesthesiology 2007;106:984–91[Web of Science][Medline]
- Jackson WF, Huebner JM, Rusch NJ. Enzymatic isolation and characterization of single vascular smooth muscle cells from cremasteric arterioles. Microcirculation 1997;4:35–50[Web of Science][Medline]
- Kawano T, Oshita S, Tsutsumi Y, Tomiyama Y, Kitahata H, Kuroda Y, Takahashi A, Nakaya Y. Clinically relevant concentrations of propofol have no effect on adenosine triphosphate-sensitive potassium channels in rat ventricular myocytes. Anesthesiology 2002;96:1472–7[Web of Science][Medline]
- Kawano T, Oshita S, Takahashi A, Tsutsumi Y, Tanaka K, Tomiyama Y, Kitahata H, Nakaya Y. Molecular mechanisms underlying ketamine-mediated inhibition of sarcolemmal adenosine triphosphate-sensitive potassium channels. Anesthesiology 2005;102:93–101[Web of Science][Medline]
- Skatchkov MP, Sperling D, Hink U, Mülsch A, Harrison DG, Sindermann I, Meinertz T, Münzel T. Validation of lucigenin as a chemiluminescent probe to monitor vascular superoxide as well as basal vascular nitric oxide production. Biochem Biophys Res Commun 1999;254:319–24[Web of Science][Medline]
- Way KJ, Katai N, King GL. Protein kinase C and the development of diabetic vascular complications. Diabet Med 2001;18:945–59[Web of Science][Medline]
- Tanaka K, Ludwig LM, Kersten JR, Pagel PS, Warltier DC. Mechanisms of cardioprotection by volatile anesthetics. Anesthesiology 2004;100:707–21[Web of Science][Medline]
- Kersten JR, Montgomery MW, Ghassemi T, Gross ER, Toller WG, Pagel PS, Warltier DC. Diabetes and hyperglycemia impair activation of mitochondrial KATP channels. Am J Physiol Heart Circ Physiol 2001;280:H1744–50
[Abstract/Free Full Text] - Kehl F, Krolikowski JG, Mraovic B, Pagel PS, Warltier DC, Kersten JR. Hyperglycemia prevents isoflurane-induced preconditioning against myocardial infarction. Anesthesiology 2002; 96:183–8[Web of Science][Medline]
- Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes 1998;47:859–66[Abstract]
- Brayden JE. Functional roles of KATP channels in vascular smooth muscle. Clin Exp Pharmacol Physiol 2002;29:312–6[Web of Science][Medline]
- Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 1996;19:257–67[Abstract]
- Armstead WM. Superoxide generation links protein kinase C activation to impaired ATP-sensitive K+ channel function after brain injury. Stroke 1999;30:153–9
[Abstract/Free Full Text] - Inoguchi T, Xia P, Kunisaki M, Higashi S, Feener EP, King GL. Insulin's effect on protein kinase C and diacylglycerol induced by diabetes and glucose in vascular tissues. Am J Physiol 1994;267:E369–79[Web of Science][Medline]
- Kunisaki M, Bursell SE, Umeda F, Nawata H, King GL. Normalization of diacylglycerol-protein kinase C activation by vitamin E in aorta of diabetic rats and cultured rat smooth muscle cells exposed to elevated glucose levels. Diabetes 1994;43:1372–7[Abstract]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
