Published online before print October 6, 2008, doi: 10.1161/HYPERTENSIONAHA.108.116731
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(Hypertension. 2008;52:960.)
© 2008 American Heart Association, Inc.
Original Articles |
ADMA Impairs Nitric Oxide–Mediated Arteriolar Function Due to Increased Superoxide Production by Angiotensin II–NAD(P)H Oxidase Pathway
From the Department of Pathophysiology (Z.V., A.R., A.K.) and II Department of Pathology (G.L.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Pathophysiology and Gerontology (A.K.), Faculty of Medicine, University of Pécs, Pécs, Hungary; and the Department of Physiology (A.K.), New York Medical College, Valhalla, New York.
Correspondence to Akos Koller, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail koller{at}nymc.edu
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Abstract |
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Asymmetrical dimethylarginine (ADMA) is thought to be an endogenous regulator of arteriolar tone by inhibiting NO synthase. However, our previous studies showed that, in isolated arterioles, ADMA induced superoxide production as well. Thus, the mechanisms by which ADMA affects arteriolar tone remain obscure. We hypothesized that ADMA, by activating NAD(P)H oxidase, increases superoxide production, interfering with NO mediation of flow-induced dilation. In the presence of indomethacin, isolated arterioles from rat gracilis muscle (
160 µm at 80 mm Hg) were incubated with ADMA (10–4 mol/L), which elicited significant constriction (from 162±4 to 143±4 µm) and eliminated the dilations to increases in intraluminal flow (from a maximum 31±2% to 3±1%; P<0.05). In the presence of ADMA, superoxide dismutase plus catalase restored dilations to flow (from a maximum 3±1% to 28±2%). Endothelial denudation or incubation of arterioles with the NAD(P)H oxidase inhibitor apocynin or the angiotensin-converting enzyme inhibitor quinapril inhibited ADMA-induced constriction. In addition, apocynin, quinapril, or the angiotensin type 1 receptor blocker losartan restored flow-induced dilations reduced by ADMA. Furthermore, inhibition of NO synthase abolished the "superoxide dismutase/catalase-restored" flow-induced dilation in the presence of ADMA. ADMA-induced increased production of superoxide, assessed by dihydroethidium fluorescence, was inhibited by apocynin, quinapril, or losartan. We suggest that ADMA activates the local renin-angiotensin system, and the angiotensin II released activates NAD(P)H oxidase; superoxide produced interferes with the bioavailability of NO, resulting in diminished flow-induced dilation, a mechanism that may contribute to the development of arteriolar dysfunction and increased tone associated with elevated ADMA levels.
Key Words: ADMA • regional blood flow • flow-dependent dilation • NO • oxidative stress • ACE
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Introduction |
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Asymmetrical dimethylarginine (ADMA) is a naturally occurring L-arginine analogue derived from the proteolysis of proteins containing methylated arginine residues.1–3 By now, numerous studies suggest that an elevated plasma level of ADMA is associated with endothelial dysfunction and is a risk factor for several human diseases,4 such as hyperhomocysteinanemia,5 hypertension,6 coronary artery disease,7 peripheral arterial occlusive disease,8 pulmonary hypertension,9 and preeclampsia.10
In our previous studies in isolated arterioles we have found that elevated levels of exogenous ADMA impair the regulation of arteriolar resistance by interfering with the NO mediation of flow/shear stress–induced dilation.11 Previous studies have found that ADMA inhibits purified NO synthase (NOS) catalytic activity, thus, release of NO and NO-mediated vascular responses.12,13 In addition, however, we have also found that ADMA elicits the release of reactive oxygen species, primarily superoxide, because superoxide dismutase reversed the ADMA-elicited reduction in basal diameter and ethidium bromide (EB) fluorescence used to detect oxidative stress.11 Thus, the exact mechanism(s) by which ADMA regulates vasomotor function and elicits increased superoxide production in arterioles remains obscure.
Previous studies also propose a potential interaction between ADMA and the renin-angiotensin system (RAS). For example, it has been shown that angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT1) receptor blockers decrease the plasma level of ADMA.14,15 Furthermore, Suda et al16 demonstrated that chronic treatment with ADMA caused vascular lesions and superoxide production in both wild-type and endothelial NOS-deficient mice, and these changes were prevented by either ACE inhibitor or AT1 receptor blocker treatment. Recently, Hasegawa et al17 have also found that chronic administration of ADMA induced ACE protein upregulation in mice cardiac tissues. These studies suggest a potential link between ADMA and RAS, yet its functional consequence on the regulation of arteriolar resistance is not known. Angiotensin II produced locally in the vessel wall has important autocrine and paracrine effects, even in the presence of normal or low circulating renin/angiotensin II levels.18 Also, it has been well established that angiotensin II plays an important role in the activation of the vascular NAD(P)H oxidases and, thus, superoxide production,19 whereas recent studies have also shown that exogenous ADMA elicits superoxide generation.16,20–23
Thus, one can suppose that ADMA, apart from the inhibitory effect of NO synthase, may activate other mechanisms contributing to the dysfunction of microvessels, known to be involved in the regulation of tissue blood flow and peripheral vascular resistance. Thus, on the basis of the aforementioned, we hypothesized that ADMA, by activating the arteriolar RAS, activates NAD(P)H oxidase and, thus, elicits oxidative stress, which interferes with NO released to increases in flow/shear stress resulting in vasomotor dysfunction of skeletal muscle arterioles.
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Methods |
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Animals
Experiments were carried out in isolated arterioles of male Wistar rats (n=55; weight:
350 g). Animals were housed in an animal care facility, were fed standard rat chow, and had free access to tap water. All of the protocols were approved by the institutional animal care and use committee. Rats were anesthetized with an intraperitoneal injection of pentobarbital sodium (50 mg/kg), and segments of gracilis muscle were removed; animals were then euthanized by an additional injection of pentobarbital sodium (150 mg/kg), followed by a bilateral pneumothorax.
Isolation of Gracilis Skeletal Muscle Arterioles
Using microsurgery instruments and an operating microscope, a segment (1.5 to 2.0 mm in length) of the gracilis arteriole was isolated, as described in details previously,24 and transferred into an organ chamber containing 2 glass micropipettes filled with calcium containing physiological salt solution (PSS) composed of (in mmol/L) 110.0 NaCl, 5.0 KCl, 2.5 CaCl2, 1.0 MgSO4, 1.0 KH2PO4, 5.5 glucose, and 24.0 NaHCO3 equilibrated with a gas mixture of 10% O2 and 5% CO2, balanced with nitrogen at pH 7.4. Both perfusate and bath solutions were continuously saturated with this gas mixture to mimic the in vivo level of pO2. After the vessel had been cannulated by the proximal micropipette and was fixed with suture, the inflow pressure was increased to 20 mm Hg to clear the lumen from blood. Finally, the other end of the vessel was fixed to the distal micropipette. Micropipettes were connected with silicone tubing to an adjustable physiological salt solution (PSS) reservoir. Resistance of micropipettes was equal. Inflow and outflow pressures were set to 80 mm Hg and measured by a pressure servo control system (Living System Instrumentation). Temperature was set at 37°C. Perfusate flow was measured with a ball flowmeter (Omega Inc).11
Agonists were added into the organ chamber, and at each concentration the peak arteriolar response was registered. All of the salts and chemicals were obtained from Sigma-Aldrich Co, except as otherwise mentioned. Solutions were prepared on the day of the experiment. The internal arteriolar diameter was measured by videomicroscopy with a microangiometer (Texas A&M University System). Changes in arteriolar diameter were continuously recorded with a chart recorder (Cole Parmer) and in digital form with a PowerLab system (ADInstruments Ltd) connected to a computer and analyzed with PowerLab and Sigma Plot software.
Change in Basal Arteriolar Diameter to ADMA
During a 1-hour equilibration period the vessel was allowed to reach a stable active diameter in the presence of 80 mm Hg of perfusion pressure. To exclude the potential contribution of prostaglandins, all of the experiments were performed in the presence of indomethacin (2.5x10–5 mol/L). The basal arteriolar diameter was measured as a function of time after the administration of ADMA. ADMA-induced change in basal diameter was also assessed in the presence of apocynin or quinapril or in the absence of the endothelium. The endothelium of the arteriole was removed by perfusion of air for 1 minute at a low perfusion pressure.24 The arteriole was then perfused with PSS to clear the debris. The intraluminal pressure was then raised to 80 mm Hg for 15 minutes to reestablish a stable arteriolar tone. The efficacy of endothelial denudation was ascertained by a single dose (10–7 mol/L) of acetylcholine.
Flow-Induced Responses of Arterioles
In the next series of experiments, changes in the diameter of arterioles were obtained in response to step increases in intraluminal flow (from 0 to 20 µL/min, in 5-µL/min steps) at constant intravascular pressure (80 mm Hg) and in the presence of indomethacin as well.24 Each flow rate was maintained for 5 to 10 minutes to allow the vessel to reach a steady-state diameter. First, flow-induced changes in arteriolar diameter were measured in control conditions. Then, arterioles were incubated with ADMA (10–4 mol/L) for 30 minutes. After incubation, arteriolar responses to step increases in intraluminal flow were obtained again in the continuous presence of ADMA in the absence or presence of 120 U/mL of superoxide dismutase (SOD) and 80 U/mL of catalase (CAT; a method that was shown to effectively scavenge superoxide25,26) or NO synthase inhibitor N
-nitro-L-arginine methyl ester (L-NAME; 10–4 mol/L for 30 minutes) to assess the role of reactive oxygen species and NO contributing to flow-induced responses. In other experiments, in the presence of ADMA apocynin (3x10–4 mol/L), an inhibitor of NAD(P)H oxidases27,28 (although recent findings question its specificity),29 or quinapril (10–5 mol/L), an inhibitor of ACE or losartan (10–5 mol/L), an AT1 receptor blocker was administered, and flow-induced responses were obtained.
Detection of Superoxide Formation
Superoxide production was assessed in arterial samples by the dihydroethidium fluorescence method. Dihydroethidium is a cell-permeable compound that can undergo a 2-electron oxidation to form the DNA-binding fluorophore EB.30 The reaction is relatively specific for superoxide, with minimal oxidation induced by H2O2 or hypochlorous acid.31 Femoral arteries were removed from rats and were immersed in PSS or 10–4 mol/L of ADMA-containing PSS, 10–4 mol/L of ADMA and 3x10–4 mol/L of apocynin-containing PSS, 10–4 mol/L of ADMA and 10–5 mol/L of quinapril-containing PSS, or 10–4 mol/L of ADMA and 10–5 mol/L of losartan-containing PSS for 30 minutes. Then, dihydroethidium (5x10–6 mol/L) was added to the vials and incubated for a further 10 minutes. After the incubation period, arteries were washed out with ice-cold PSS and immersed in an embedding medium. Frozen sections of femoral arteries were visualized by a digital camera attached to a fluorescence microscope. Intensity of EB fluorescence of the arteriolar wall was measured and quantified by Image J software. Relative EB fluorescence intensity was counted by extracting the intensity of the background from a standard size of the arterial wall. Measurement was repeated 5 times, and relative intensity of EB fluorescence was presented as the percentage of control.
Statistical Analysis of Data
Constrictions of arterioles in response to ADMA were expressed as a percentage of the baseline diameter at an intraluminal pressure of 80 mm Hg and plotted as a function of time. Peak dilations of arterioles were expressed as changes in arteriolar diameter as a percentage of the maximal dilation of the vessel, defined as the difference of the passive diameter (at 80-mm Hg intraluminal pressure in a Ca2+-free physiological salt solution containing 10–3 mol/L of EGTA and 10–4 mol/L of sodium nitroprusside) and the initial basal diameter of the arterioles (at 0 flow condition, at 80 mm Hg). Statistical analyses were performed by 2-way ANOVA for repeated measures followed by the Tukey’s posthoc test or Student t test, as appropriate. P<0.05 was considered statistically significant. All of the data are expressed as mean±SE.
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Results |
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Effect of ADMA on Basal Arteriolar Diameter
In the present experiments, an active arteriolar tone developed in response to the presence of intraluminal pressure of 80 mm Hg, without the use of any vasoactive agent (active: 153±4 µm; passive: 235±3 µm; P<0.05). Summary data show that, in control conditions, ADMA elicited a significant decrease in the basal diameter of isolated gracilis muscle arteriole as a function of time. The maximum decrease in diameter occurred at
15 minutes (11±1%). The presence of apocynin, quinapril, or endothelium removal abolished the constrictor effect of ADMA on basal diameter (Figure 1).
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Effect of ADMA on Flow-Induced Responses of Arterioles
In control conditions, increases in intraluminal flow (5, 10, 15, and 20 µL/min) elicited substantial dilations of isolated arterioles. However, in the presence of ADMA (10–4 mol/L), step increases in flow did not elicit dilations (maximum from 31±2% to 3±1%; Figure 2). Flow-induced dilations were restored to the control level by the presence of SOD/CAT, and the restored dilations were abolished by the presence of L-NAME (maximum from 3±1% to 28±2% and 1±1%; Figure 2).
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Also, original records (Figure 3A) and summary data (Figure 3B) show that the presence of apocynin significantly restored dilations to increases in flow in ADMA-treated arterioles (maximum from 4±1% to 25±3%), the magnitude of which reached the control levels (control, maximum of 28±2%). We have also found that the presence of quinapril or losartan also restored flow-induced dilations to the control level (maximum of 32±2% and 23±2%, respectively; Figures 4 and 5
).
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Assessment of Oxidative Stress in the Presence of ADMA
Representative fluorescent photomicrographs of EB fluorescence in control and ADMA-incubated arterial sections (Figure 6A) indicate an increased EB fluorescence in ADMA-incubated vessels as compared with the control. Simultaneous incubation of ADMA with apocynin decreased the fluorescence in the arterial wall. Summary data show (Figure 6B) that EB staining was significantly higher in vessels incubated with ADMA as compared with the control, whereas in the simultaneous presence of ADMA and apocynin, quinapril, or losartan arterial fluorescence intensity was significantly decreased, close to the control levels.
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Discussion |
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The main findings of the present study are that, in isolated gracilis muscle arterioles, ADMA reduced basal diameter, which was reversed by apocynin and ACE inhibitor quinapril, and ADMA inhibited flow/shear stress–induced dilation and elicited vascular oxidative stress (indicated by increased EB fluorescence), both of which were normalized by SOD, apocynin, ACE inhibitor quinapril, or AT1 receptor blocker losartan.
It has been shown that L-arginine is the substrate of NOS and that methylated L-arginines, such as N-nitro-L-arginine, N-monomethyl-L-arginine, and N-nitro-L-arginine-methyl-ester, inhibit NOS, with the consequent elimination of NO-mediated dilations of vessels.32,33 These forms of methylated L-arginine, however, are not readily available in vivo. Methylations of L-arginine in proteins, however, do occur in vivo, which then released from proteins during proteolysis.3 ADMA is one of the most important endogenously produced methylated L-arginines.13 In vitro biochemical studies show that ADMA inhibits NOS and likely enhances superoxide production via "uncoupling of NOS activity" in endothelial cells.20 There are, however, effects of ADMA seemingly unrelated to NOS, which have not yet been clarified. For example, Suda et al16 have found in wild-type and endothelial NOS-knockout mice that long-term treatment with ADMA induced coronary microvascular lesions. These changes were not because of the developed hypertension and were not antagonized by administration of L-arginine. Other studies revealed an increased superoxide production in epithelial, endothelial, and even in cardiac cells after ADMA incubation.20–23 However, the mechanisms responsible for the enhanced superoxide production by ADMA remain unclear. Previous studies also reported an increased NAD(P)H oxidase activity in most peripheral vascular beds of animals with various forms of hypertension,34,35 diabetes,36–38 or hyperhomocysteinanemia.39 Interestingly, in these human diseases, the serum levels of methylated L-arginines such as ADMA are increased.4–6,40 Thus, it was logical to hypothesize that the presence of ADMA, in addition to inhibiting NOS, may leads to increased release of superoxide, which is due to activation of NAD(P)H oxidase. Because angiotensin II is a known activator of NADP(H) oxidase, the potential role of RAS in ADMA-induced arteriolar dysfunction could be hypothesized as well. To test these hypotheses, we have used isolated gracilis arterioles to elucidate the effect of ADMA on NO-mediated dilator responses elicited by increasing flow/shear stress. Previous studies showed that, in gracilis arterioles, increases in intraluminal flow elicit the release of prostaglandins in addition to NO.24 In addition, in certain conditions, cyclooxygenases produce reactive oxygen species. Thus, to exclude the potential contribution of these pathways, which may interfere with the interpretation of results, we performed our experiments in the presence of indomethacin, an inhibitor of cyclooxygenases involved in the production of prostaglandins.
ADMA Activates NAD(P)H Oxidase in Arterioles and Elicits Oxidative Stress
First, we confirmed our previous finding that ADMA elicits significant constriction of arterioles (Figure 1). This constriction was prevented by previous incubation of arterioles with SOD and CAT, suggesting that the decrease in the diameter of arterioles was because of increased oxidative stress. NAD(P)H oxidase has been shown to be a key oxidative enzyme involved in many diseases associated with arteriolar dysfunction.27,34,35 Thus, we have used apocynin, know to inhibit NAD(P)H oxidase, although recent findings question its specificity.29 We have found that, in the presence of ADMA, apocynin restored the basal diameter of arterioles. Furthermore, in endothelium-denuded vessels, additional administration of ADMA did not elicit a reduction in the diameter of arterioles. Collectively these findings suggest that ADMA activates NAD(P)H oxidase and that these mechanisms associate primarily with arteriolar endothelium.
Thus, it seems that the primary action of ADMA, in addition to inhibition of NOS, is the activation of this oxidative pathway, which then results in the reduction of NO bioavailability and, thus, flow-dependent dilation. Indeed, we found the scavenger of reactive oxygen species (SOD plus CAT) restored flow-induced dilation (Figure 2) in the presence of ADMA, confirming our previous findings.11 Furthermore, the NO synthase inhibitor L-NAME abolished the "SOD/CAT-restored" flow-induced dilation in the presence of ADMA. We interpret these findings to mean that the primary effect of ADMA is an increased production of reactive oxygen species, which then interferes with NO released by NOS and, thus, dilation. Collectively these findings suggest that the primary source of superoxide in the presence of ADMA is likely the NAD(P)H oxidase (Figures 3A, 3B, and 6
).
ADMA Activates RAS in Arterioles
Several in vitro and in vivo studies have established an important role for angiotensin II in the activation of NAD(P)H oxidase leading to oxidative stress.19,34,35 Also, previous studies proposed a potential interaction between ADMA and the RAS.14,17 Thus, we hypothesized that the arteriolar RAS is involved in the ADMA-induced oxidative stress. Indeed, we have found that the ACE inhibitor quinapril restored flow-induced dilations in arterioles in the presence of ADMA (Figure 4) and also inhibited a reduction of diameter by ADMA (Figure 1). In addition, we have also found that the AT1 receptor blocker losartan restored flow-mediated dilation of arterioles in the presence of ADMA (Figure 5). Collectively, it seems that ADMA, via as yet unknown mechanism(s), activates the microvascular RAS,41 which leads to an increased level of angiotensin II in the microvascular wall, and AT1 receptors are involved in the ADMA-angiotensin II pathway producing reactive oxygen species.
The relationship between ADMA and local RAS may also present in chronic conditions, as shown by Hasegawa et al17 that long-term ADMA administration caused upregulation of local ACE and increased the wall:lumen ratio and perivascular fibrosis in coronary microvessels in wild-type mice. Also, overexpression of dimethylarginine dimethylaminohydrolase-2, an ADMA-degrading enzyme, in transgenic mice prevented the development of ADMA-induced microvascular lesions and upregulation of ACE.17 Suda et al16 also suggested a role for the upregulation of local ACE and increased oxidative stress in the long-term vascular effects of ADMA in vivo.
ADMA Induces Oxidative Stress via Activating Vascular RAS
To provide further evidence for the idea that ADMA induces vascular oxidative stress and that NAD(P)H oxidase and RAS contribute to these processes, we have investigated the effect of ADMA on EB fluorescence, an indicator of oxidative stress, in sections of small branches of femoral artery. We have found that ADMA increased dihydroethidium fluorescence (Figure 6A and 6B),42 which was significantly reduced toward control levels in the presence of apocynin, quinapril, or losartan. Similar findings were reported recently, namely that treatment of isolated human umbilical vein endothelial cells with ADMA (30 µmol/L) increased reactive oxygen species generation, which was reversed by the AT1 receptor blocker losartan.22
In the present acute experiments we aimed to investigate the short-term functional effects of ADMA, thus, changes observed were unlikely due to the upregulation of various genes or protein synthesis. Nevertheless, it is likely that the chronic presence of elevated levels of ADMA upregulates several components of microvascular RAS, such as expression of ACE protein. This idea is supported by studies of Hasegawa et al17 showing that the chronic presence of ADMA enhanced the p38 mitogen-activated protein kinase activity in human coronary artery endothelial cells, which may provide a link between ADMA and RAS, because ACE protein expression has been show to be regulated by various mechanisms, including p38 mitogen-activated protein kinase.43 Nevertheless, further studies are needed to elucidate the exact mechanism of action by which ADMA activates RAS in the arteriolar wall.
In conclusion, our findings in isolated skeletal muscle arterioles suggest that elevated levels of ADMA activate the RAS in the arteriolar wall, leading to increased production of angiotensin II, which then activates NAD(P)H oxidase. The consequent increased level of reactive oxygen species interferes with the bioavailability of NO released to increases in flow/shear stress, resulting in inhibition of flow-induced dilation and enhanced arteriolar tone (Figure 7), both of which favor the development of increased peripheral resistance.
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Perspectives
Elevated levels of reactive oxygen species, activation of local RAS, and microvascular dysfunction are key factors in the development of cardiovascular diseases, such as hypertension, peripheral vascular diseases, and atherothrombosis.44 Thus, understanding the mechanisms responsible for the reduced bioavailability of NO and increased production of superoxide in the presence of elevated levels of ADMA, shown to be present in many of these diseases, has the potential to identify novel therapeutic targets and modalities aiming to improve the regulation of arteriolar resistance by local mechanisms. Our findings provide a theoretical base for the clinical use of antioxidants, inhibitors of the renin-angiotensin-aldosterone system, and possibly specific NAD(P)H oxidase inhibitors, which may correct the adverse effect of elevated levels of ADMA present in several pathophysiological conditions. In addition, a decrease in the level of methylated L-arginines could also be therapeutically targeted by enzymes regulating ADMA levels, such as protein arginine methyltransferase inhibitors or dimethylarginine dimethylaminohydrolase gene transfer.45 Importantly, further studies are necessary to elucidate the potential interaction of elected levels of ADMA with that of the arachidonic acid metabolism and enzymes involved in the production prostaglandins and the mechanisms by which ADMA activates the local RAS.
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Acknowledgments |
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Sources of Funding
This study was supported by the Hungarian National Scientific Research Fund (OTKA) T48376, K71591, T67984, and Health Science Council of Hungarian Ministry of Health (ETT-HMH) 364/2006; American Heart Association, Founders Aff. 0855910D; and National Institutes of Health grant HL-43023.
Disclosures
None.
Received May 21, 2008; first decision June 11, 2008; accepted August 29, 2008.
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