Published online before print October 16, 2008, doi: 10.1161/ATVBAHA.108.171298
© 2009 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Interaction Between P450 Eicosanoids and Nitric Oxide in the Control of Arterial Tone in Mice
From the Charité Campus Buch, Franz Volhard Clinic/ECRC and HELIOS Klinikum-Berlin, Nephrology/Intensive Care Section, Charité Campus Virchow (H.C.A., J.S., M.G.), and Max Delbrück Center for Molecular Medicine, Berlin, Germany (W.-H.S., V.G., A.Ch.daC.G.); the Department of Physiology, the Chinese University of Hong Kong, China (P.L., Y.H.); and Cardiovascular Disease, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Conn (S.M.W.).
Correspondence to Maik Gollasch, MD, PhD, Charité University Medicine, Campus Virchow, Nephrology/Intensive Care Section, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail maik.gollasch{at}charite.de
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Abstract |
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Objective— Epoxyeicosatrienoic acids (EETs) serve as endothelial-derived hyperpolarizing factors (EDHF), but may also affect vascular function by other mechanisms. We identified a novel interaction between EETs and endothelial NO release using soluble epoxide hydrolase (sEH) –/– and +/+ mice.
Methods and Results— EDHF responses to acetylcholine in pressurized isolated mesenteric arteries were neither affected by the sEH inhibitor, N-adamantyl-N'-dodecylurea (ADU), nor by sEH gene deletion. However, the EDHF responses were abolished by catalase and by apamin/charybdotoxin (ChTx), but not by iberiotoxin, nor by the cytochrome P450 inhibitor PPOH. All four EETs (order of potency: 8,9-EET >14,15-EET
5,6-EET >11,12-EET) and all 4 dihydroxy derivatives (14,15-DHET8,9-DHET11,12-DHET >5,6-DHET) produced dose-dependent vasodilation. Endothelial removal or L-NAME blocked 8,9-EET and 14,15-DHET-dependent dilations. The effects of apamin/ChTx were minimal. 8,9-EET and 14,15-DHET induced NO production in endothelial cells. ADU (100 µg/mL in drinking water) lowered blood pressure in angiotensin II–infused hypertension, but not in L-NAME–induced hypertension. Blood pressure and EDHF responses were similar in L-NAME–treated sEH +/+ and –/– mice.
Conclusions— Our data indicate that the EDHF response in mice is caused by hydrogen peroxide, but not by P450 eicosanoids. Moreover, P450 eicosanoids are vasodilatory, largely through their ability to activate endothelial NO synthase (eNOS) and NO release.
Key Words: eicosanoids • soluble epoxide hydrolase • NO synthase • L-NAME • EDRF
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Introduction |
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The endothelium releases nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF).1,2 Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase (CYP)-derived metabolites of arachidonic acid (AA) that may be EDHFs.3,4 Other candidates include K+ ions and hydrogen peroxide (H2O2).5–7 Endothelial cell hyperpolarization spreads to adjacent vascular smooth muscle cells (VSMCs) through myo-endothelial gap junctions.8,9 Calcium-activated potassium channels, most probably the SK4 (IKCa) and SK3 (SKCa) expressed on the endothelium, are the end-cellular gateway mediating hyperpolarization, and subsequent EDHF relaxation.2,4,10–13 EETs convincingly cause hyperpolarization.14–16 They can induce vasodilation in certain vascular beds by increasing the open-state probability of calcium-activated potassium (BK) channels.4,15,17 The soluble epoxide hydrolase (sEH) metabolizes EETs to dihydroxy derivatives (DHET). sEH inhibition could enhance EET activity.18 Blood pressure decreased in spontaneously hypertensive rats (SHR) given an sEH inhibitor.19 sEH inhibition also lowered blood pressure in rats given angiotensin II (Ang II).20 Thus, sEH could contribute to Ang II–induced hypertension21 and salt-sensitivity.22 Even desoxycorticosterone acetate (DOCA)-salt hypertension was ameliorated with sEH inhibition.23 Finally, male sEH gene-deleted (–/–) mice had lower blood pressures than sEH +/+ mice.24 EETs could also affect vascular function by other mechanisms. A novel inhibitory interaction between CYPs and H2O2 was recently identified.25 CYP epoxygenases were directly inhibited by H2O2, an interaction that could modulate EET bioavailability. We studied interactions between P450 eicosanoids, EDHF, and NO using sEH –/– and +/+ mice. Our findings may have important implications for the development and use of pharmacological sEH inhibitors.
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Methods |
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Animals and Blood Pressure Measurements
The local council on animal care (American Physiological Society criteria) approved all protocols in FVB/N mice. We performed radiotelemetry, Ang II osmotic minipump infusion (1.44 mg/kg/d), and N(omega)-nitro-L-arginine methyl ester via the drinking water (L-NAME; 5 mg L-NAME per 10 mL tap water) as outlined elsewhere.26,27 After a 7- to 10-day recovery, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), and heart rate (HR) recordings were obtained for 3 days (baseline values) and continued thereafter. Mice received N-adamantyl-N'-dodecylurea (ADU 100 µg/mL) via the drinking water over 7 days. In additional experiments, we studied the effects of L-NAME on blood pressure in male sEH +/+ and sEH –/– mice backcrossed over 6 generations to FVB/N.
sEH Activity
We prepared renal microsomes using 1.5 kidney per male adult FVB/N +/+ animal. The sEH activities were determined using the 100 000g supernatants obtained during the preparation of renal microsomes and using [1-14C]-14,15-epoxyeicosatetraenoic acid (EET). [1-14C]-14,15-EET was prepared by chemical oxidation of radiolabeled AA according to Falck et al.28 To measure the sEH activity in blood vessels, mesenteric arteries were isolated and cleaned from fatty tissue. Vessels were incubated with [1-14C]-14,15-EET, and the 14,15-DHET produced and the remaining 14.15-EET were extracted with ethylacetate and analyzed by RP–high-performance liquid chromatography (HPLC).
Vessel Experiments
Intact 2nd or 3rd order branches of mesenteric arteries of adult male sEH +/+ or –/– mice were obtained. Thereafter, we carefully removed the connective tissue with scissors. The arteries then were mounted onto two glass cannulas in an arteriograph with continuous superfusion (3 to 5 mL/min) of oxygenated physiological salt solution (PSS) at 37°C.29,30 Dose-response curves for 5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET, 5,6-DHET, 8,9-DHET, 11,12-DHET, and 14,15-DHET were performed using vessels isolated from male +/+ mice preconstricted with U46619 (100 nmol/L). In some experiments, the endothelium was removed by intraluminal application of an air bubble mice. Mice background crossed onto C57BL/6ByJ or FVB/N were used.
Determination of EET and DHET-Levels
EET and DHET levels were determined in red blood cells, plasma samples, and isolated mesenteric arteries from male +/+ FVB/N mice (n=5) using liquid chromatography- tandem mass spectrometry.
Statistics
We used analysis of variance (repeated measures where indicated), Duncan multiple range tests, Bonferonni-corrected t tests, and Student t tests as indicated. A probability value <0.05 was accepted as significant. Fiducial limits are given in mean±SEM.
Methodological details are given in the supplemental materials (available online at http://atvb.ahajournals.org).
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Results |
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sEH Activity in Mesenteric Arteries
All four EETs (5,6-EET, 8,9-EET, 11,12-EET, 14,15-EET; total 243±56 ng/g, ratio 52:16:11:21) were present in the vessel wall of mesenteric arteries (see supplemental Table I). EETs were also detected in red blood cells (total 542±79 ng/g) and blood plasma (see supplemental Table I). The functional expression of sEH in the mesenteric artery was tested with the sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (ADU). Figure 1A shows the dose-response curve with an IC50 value for ADU of
10 nmol/L. ADU efficiently inhibited the sEH activity present in the cytosolic fraction of mouse renal homogenates. Using 10 µmol/L 14,15-EET as the substrate, ADU produced significant inhibition already in the low nmol/L range and almost completely abolished the hydrolysis at a concentration of 1 µmol/L. We analyzed the effect of ADU on the sEH activity in vessels derived from the mesenteric artery tree, as shown in Figure 1B. sEH protein expression was detected by Western blotting in arteries from sEH +/+ mice, but not from –/– mice (inset). Vessels isolated from male sEH +/+ mice, but not from male sEH –/– mice, hydrolyzed 14C-labeled 14,15-EET within 30 minutes. DHET production by the wild-type vessels was significantly reduced by preincubation with ADU at concentrations of 1 and 10 µmol/L. Thus, sEH is present and metabolically active in mesenteric and possibly other arteries of mice, and can be effectively blocked by ADU.
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EDHF Response Is Most Probably Caused by H2O2, but not by P450 Eicosanoids
We next examined whether or not EDHF-dependent vasodilation is affected by inhibiting sEH. Under basal conditions, vasorelaxation by acetylcholine (ACh) was equipotent between sEH +/+ and –/– arteries, as shown in Figure 2A and 2B. Vasoconstriction by 60 mmol/L KCl and vascular reactivity to U46619 expressed as % of KCl showed no differences. Similar results were obtained in isolated mesenteric arteries and isolated perfused mesenteric beds of female sEH +/+ and –/– mice (not shown). Next, we studied EDHF-dependent relaxation in vessels by treatment of the vessels with L-NAME plus indomethacin. ACh-dependent relaxation was significantly reduced in vessels treated with L-NAME alone or L-NAME plus indomethacin, as shown for male vessels in Figure 2B. However, the relaxation was not different between sEH +/+ and –/– mice. Similar results were obtained in female vessels (n=5, not shown). Note that this relaxation was completely abolished by apamin/ChTx, suggesting that activation of both endothelial small and intermediate-conductance Ca2+-activated K+ channels (SK3, SK4) is crucial in EDHF-dependent signaling and relaxation in mouse mesenteric arteries.7,31 In contrast, iberiotoxin was not effective in inhibiting EDHF-dependent relaxation, indicating that large-conductance Ca2+-activated K+ (BK) channels in arterial smooth muscle cells play no role in the EDHF response in this vascular preparation. EDHF-dependent dilation was completely inhibited by catalase 1000 U/mL (30 minutes preincubation) or carbenoxolone 100 µmol/L (30 to 45 minutes preincubation; Figure 2A and 2B right bar), but not by 6-(2-propargyloxyphenyl)hexanoic acid (PPOH, 10 µmol/L, 30 minutes), a selective CYP inhibitor, or by 14,15-epoxyeicosa-5(Z)-enoic acid (EEZE) at 10 µmol/L for 20 minutes, an EET antagonist (Figure 2A, n=4 in each group; Figure 2B, n=4 to 10 in each group). We next measured H2O2 production in endothelial cells of intact mesenteric arterioles using a laser confocal microscope with CM-H2DCFDA, a peroxide-sensitive fluorescence dye. In these experiments, the endothelial monolayer was loaded with CM-H2DCFDA, which can be clearly distinguished from underlying smooth muscle cells, as shown in supplemental Figure IIA and IIB. All experiments were performed in the presence of indomethacin 5 µmol/L and L-NAME 100 µmol/L (n=4 in each group). A significant increase in the dichlorofluorescein fluorescence was observed in endothelial cells stimulated by acetylcholine (ACh 1 µmol/L) as compared with controls or tissues treated with catalase (1000 U/mL). Removal of endothelial cells (-E) abolished the dichlorofluorescein signal in response to acetylcholine. Only smooth muscle layer was observed in (Figure IIA, images D and D'). Taken together, these results suggest that H2O2, but not EETs, significantly contributes to EDHF-mediated dilation in mouse mesenteric arteries, which is in line with previous findings.7,32,33
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Vasodilatory Effects of EETs and DHETs
Vasodilator responses were tested in the U46619-preconstricted pressurized (60 mm Hg) arteries. As shown in Figure 3, all 4 EETs (order of potency: 8,9-EET >14,15-EET5,6-EET >11,12-EET) and all 4 DHETs (14,15-DHET8,9-DHET11,12-DHET >5,6-DHET) produced dose-dependent vasodilation. 8,9-EET was the most potent EET, with 50% dilation at 3 µmol/L. 14,15-DHET, 8,9-DHET, and 11,12-DHET were the most potent DHET, with 50% dilation at 0.3 µmol/L.
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The 8,9-EET-dependent vasodilations were slightly inhibited by the SK3/SK4 channel blockers apamin/ChTx, as shown in Figure 4 (n=6 in each group). In contrast, dilations by the less potent EETs (ie, 5,6-EET, 11,12-EET, and 14,15-EET) were not affected by apamin/ChTx (not shown). Apamin/ChTx slightly inhibited 14,15-DHET– (Figure 5, n=6 in each group), 8,9-DHET–, and 11,12-DHET–dependent dilations, but had no effect on 5,6-DHET–dependent dilations (supplemental Figure I). Together, these results demonstrate that DHETs are up to 10-fold more potent vasodilators in mouse mesenteric arteries than EETs. EETs/DHETs exhibit their vasodilatory properties without any, or with very little, involvement of SK3/SK4 channels.
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EET/DHET-Dependent Dilation Is Mediated by eNOS Activation
To study the mechanisms of P450 eicosanoid-induced vasodilation, we used the most potent metabolites, namely 8,9-EET and 14,15-DHET. As shown in Figures 4 and 5
, 8,9-EET– and 14,15-DHET–induced vasodilations were dependent on intact endothelium (panels A and C, n=6 in each group). In the presence of SK3/SK4 channel blockers, a prominent residual dilation to 8,9-EETs and 14,15-DHETs occurred (panels D). This response indicates the presence of a major additional endothelial vasodilator mechanism. To determine whether or not EETs/DHETs activate eNOS to produce vasodilation, N(omega)-nitro-L-arginine methyl ester (L-NAME) was coadministered with apamin/ChTx. Figures 4 and 5 panels B and D show that the dilation in response to both 8,9-EET and 14,15-DHET was completely inhibited by L-NAME/Apamin/ChTx; n=6 in each group). Indomethacin (5 µmol/L, 30 minutes preincubation) had no effect. Figures 4 and 5 panels E show that both 8,9-EET and 14,15-DHET are able to induce NO production in primary mouse aortic endothelial cells. These effects were inhibited by L-NAME (100 µmol/L, n=4 experiments in each group). Thus, our results suggest that EETs/DHETs can modulate the bioavailability and/or action of NO to produce vasodilation.
L-NAME–Induced Hypertension Is Resistant to sEH Inhibition
Figure 6A shows the telemetric blood pressure values of mice given L-NAME (panel A, n=6) for 7 days followed by ADU. Depicted are baseline values, the days 5 to 7 under L-NAME treatment, and the days 5 to 7 given L-NAME with ADU. Mice given L-NAME exhibited a prompt increase in mean arterial blood pressure (MAP) from 103±1 mm Hg to 112±2 mm Hg (panel A). The combination of L-NAME with ADU increased blood pressure slightly to 114±2 mm Hg. In addition, L-NAME induced elevated blood pressure in sEH –/– mice that was not different compared to +/+ mice (Figure 6B, n=6 each). In contrast, ADU reduced blood pressure in Ang II–induced hypertension. Mice were given Ang II for 7 days followed by 7 days with additional ADU treatment. Ang II infusion increased blood pressure (MAP) from 100±1 mm Hg to 132±5 mm Hg. After ADU, MAP in these mice was reduced to 114±3 mm Hg. These values did not reach initial blood pressures; however, the blood pressure reduction was highly significant (supplemental Figure I, n=6).
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To determine whether or not endothelial relaxation is modulated by L-NAME, endothelial-dependent dilation of isolated mesenteric arteries of FVB/N +/+ and –/– mice was examined. Figure 6C shows the results. L-NAME–treated animals showed reduced ACh-dependent vasodilation. Noteworthy, this dilation was not affected by the presence of L-NAME in the bath chamber. This response was neither affected by ADU nor by genetic sEH deletion (n=6 in each group). Thus, chronic treatment of mice with L-NAME leads to EDHF responses that cannot be modified by sEH inhibition in the vessel wall in L-NAME–induced hypertension.
In an additional experimental series, we studied the effects of catalase on EDHF-dependent vasodilation of L-NAME treated mice. Vasorelaxation by acetylcholine (ACh) in the presence of L-NAME was equipotent between sEH +/+ and –/– arteries of L-NAME treated animals, as shown in Figure 6D. Catalase 1000 U/mL inhibited this EDHF response. However, the effects of catalase were not different between sEH +/+ and –/– mice. Indomethacin 5 µmol/L had no additional effects (n=4 to 7 in each group).
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Discussion |
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This study is the first to investigate the vascular interaction between P450 eicosanoids, SEH, and NO in mice. The novel findings are 3-fold. First, both EETs and DHETs are vasodilatory in mesenteric arteries largely through their ability to activate eNOS and NO release. Second, the ACh-induced EDHF response is predominantly caused by H2O2, but not by P450 eicosanoids. Thus, the effect is not related to sEH inhibition. Third, in contrast to Ang II–infused hypertension, L-NAME hypertension is not affected by sEH inhibition.
EDHF in Mouse Mesenteric Arteries
Little is known about the contribution of EETs and DHETs to vascular tone in mice, although these epoxides have been implicated in EDHF-mediated relaxation of certain vascular beds in other species.34–38 Thus far, we are not aware of any study showing vasomotor effects of EETs/DHETs in the vasculature of mice. We found that all four EETs and all four DHETs produced dose-dependent vasodilation of mouse mesenteric arteries. The effects were endothelium-dependent, but not or only slightly inhibited by apamin/ChTx. In contrast, apamin/ChTx completely blocked the EDHF response. These results suggest that EETs/DHETs (alone or in combination) do not function as an EDHF in mice, which should be solely dependent on SK4/SK3 channels. Moreover, we observed that EDHF responses in mesenteric arteries were not affected by any measures that influence EET generation or action, including CYP inhibition by PPOH, sEH inhibition by ADU or by gene deletion, or EET antagonism by EEZE. Instead, our data show that the EDHF response is completely inhibited by catalase and accompanied by H2O2 production, which is in line with previous findings.7,32,33 Taken together, our results present evidence that P450 eicosanoids do not significantly contribute to EDHF-mediated dilation in mesenteric arteries of mice. Our data strongly support the notion that H2O2 is an EDHF in this vessel,7,32,33 which causes hyperpolarization, most probably via activation of endothelial SK3/SK4 channels in endothelial cells, which spreads to adjacent vascular smooth muscle cells (VSMC) through myo-endothelial gap junctions and produces subsequent EDHF relaxation.2,4,10–13 Specifically, the gap junction components Cx40, Cx43, and Cx37 have been recently implicated in the EDHF signal spread from endothelial to smooth muscle cells in mouse mesenteric arteries.39
Prominent Role of NO in Vasodilation by EETs/DHET
The vasculature can be exposed not only to endogenously produced P450 eicosanoids, but also from nonvascular sources. For example, red blood cells have been suggested to serve as a potential reservoir for epoxides which on release may act in a vasoregulatory capacity.40–42 Recently, EETs have been demonstrated to influence eNOS activity and expression in cultured bovine aortic endothelial cells;43 however, the contribution of this pathway to vascular function was not examined. Our results are the first to demonstrate that EETs/DHETs can modulate the bioavailability of NO via eNOS to produce vasodilation. We observed that the vasodilatory effects of the most potent DHET (ie, 14,15-DHET) and EET (8,9-EET) in mouse mesenteric arteries are endothelium-dependent and inhibited by L-NAME. Moreover, both eicosanoids induced NO production in primary mouse aortic endothelial cells. Interestingly, 5,6-EET, but not 11,12- and 14,15-EET, produced relaxations in rabbit superior mesenteric arterial ring preparations, which were completely inhibited by removal of the endothelium and partially inhibited by L-NAME.44 Nitric oxide and prostaglandins have been suggested to mediate vasodilation by 5,6-EET in rabbit lung.45 Although we did not study the mechanism of eNOS activation in detail, we believe that eNOS phosphorylation plays an important role.46 EETs have been found to augment eNOS function by enhancing eNOS phosphorylation at its Ser1179 and Thr497 residues in cultured endothelial cells.46 An alternative explanation is that eNOS activation is induced by an increase in endothelial [Ca2+]i, because at least some EETs (5,6-EET, 8,9-EET) have been reported to elevate endothelial [Ca2+]i via TRPV4 channels.47
Thus far, two major pathways of interaction between endothelium-derived relaxing factors (EDRFs) have been described. First, an inhibitory interaction has been described between NO and EET, in which NO inhibits CYP-mediated production of EET from AA.48 Second, an inhibitory interaction between EETs and H2O2 has been identified, in which CYP epoxygenases are directly inhibited by H2O2.25 The present study reveals a third way of interaction among substances proposed as EDRFs, namely an interaction between EETs/DHETs and NO, in which EETs/DHETs can induce endothelial NO release to modulate vascular tone. Future studies should explore the intracellular signaling pathways of P450 eicosanoids leading to eNOS activation and whether this novel pathway can also occur in other vascular beds and species. Notably, similarly to the mouse, H2O2 has been revealed as EDHF in mesenteric arteries of man,6 but not in the rat.31,49
Role of sEH in Blood Pressure Regulation
sEH inhibition has been reported to lower blood pressure in several forms of hypertension. Our data confirm previous findings that Ang II–induced hypertension is reduced by pharmacological sEH inhibition.19–22 The novel finding of the present study is that L-NAME hypertension is insensitive to pharmacological or genetic sEH inhibition. These data suggest that the role of sEH in blood pressure regulation depends on the type of secondary hypertension. We propose that sEH inhibition is ineffective in lowering blood pressure in L-NAME hypertension for the following reasons: (1) L-NAME hypertension is primarily attributable to increased vascular tone and diminished NO release in vessels; (2) EETs and DHETs are both potent vasodilators which primarily rely on intact eNOS activity; (3) EDHF responses in L-NAME–treated mice are not modified by sEH inhibition, but remain sensitive to catalase. The mechanism of how sEH inhibition ameliorates Ang II–induced hypertension in mice is largely unclear, but may involve renal and cardiac mechanisms rather than changes in peripheral arterial resistance.21
In summary, our data demonstrate that P450 eicosanoids have an important impact on bioavailability of NO in the vasculature. This interaction between 2 EDRFs plays an important role in the modulation of vasomotor tone in the mesenteric microcirculation and has important implications for blood pressure regulation by sEH inhibition in mice and possibly other species. This pathway may increase in importance during cardiovascular disease, when NO production is reduced.
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Acknowledgments |
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We thank Yoland Anistan, Diana Herold, Ramona Zummach, Christel Andrée, and Ilona Kamer for excellent technical assistance. We are grateful to Dr John R. Falck for providing 14,15-EEZE and Dr M. Rothe (Lipidomix GmbH, Berlin) for help in metabolite analysis.
Sources of Funding
This study was supported by the Deutsche Forschungsgemeinschaft and Deutscher Akademischer Austauschdienst (DAAD).
Disclosures
None.
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Footnotes |
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Original received May 28, 2008; final version accepted October 2, 2008.
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