Role of 20-hydroxyeicosatetraenoic acid in mediating hypertension in response to chronic renal medullary endothelin type B receptor blockade.
ABSTRACT The renal medullary endothelin (ET-1) system plays an important role in the control of sodium excretion and arterial pressure (AP) through the activation of renal medullary ET-B receptors. We have previously shown that blockade of endothelin type B receptors (ET-B) leads to salt-sensitive hypertension through mechanisms that are not fully understood. One possible mechanism is through a reduction in renal medullary production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a metabolite of arachidonic acid, has natriuretic properties similar to ET-B activation. While these findings suggest a possible interaction between ET-B receptor activation and 20-HETE production, it is unknown whether blockade of medullary ET-B receptors in rats maintained on a high sodium intake leads to reductions in 20-HETE production.
The effect of increasing sodium intake from low (NS = .8%) to high (HS = 8%) on renal medullary production of 20-HETE in the presence and absence of renal medullary ET-B receptor antagonism was examined. Renal medullary blockade of ET-B receptors resulted in salt sensitive hypertension. In control rats, blood pressure rose from 112.8±2.4 mmHg (NS) to 120.7±9.3 mmHg (HS). In contrast, when treated with an ET-B receptor blocker, blood pressure was significantly elevated from 123.7±3.2 (NS) to 164.2±7.1 (HS). Furthermore, increasing sodium intake was associated with elevated medullary 20-HETE (5.6±.8 in NS vs. 14.3±3.7 pg/mg in HS), an effect that was completely abolished by renal medullary ET-B receptor blockade (4.9±.8 for NS and 4.5±.6 pg/mg for HS). Finally, the hypertensive response to intramedullary ET-B receptor blockade was blunted in rats pretreated with a specific 20-HETE synthesis inhibitor.
These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt intake may be, in part, due to ET-B receptor activation within the renal medulla.
- [Show abstract] [Hide abstract]
ABSTRACT: Endothelin-1 (ET-1) is a major regulator of vascular function, acting via both endothelin receptor type A (ET(A)R) and type B (ET(B)R). Although the role of ET(A)R in vascular smooth muscle (VSM) contraction has been studied, little is known about ET(B)R. ET(B)R is a G-protein coupled receptor with a molecular mass of ~50 kDa and 442 amino acids arranged in seven transmembrane domains. Alternative splice variants of ET(B)R and heterodimerization and cross-talk with ET(A)R may affect the receptor function. ET(B)R has been identified in numerous blood vessels with substantial effects in the systemic, renal, pulmonary, coronary and cerebral circulation. ET(B)R in the endothelium mediates the release of relaxing factors such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor, and could also play a role in ET-1 clearance. ET(B)R in VSM mediates increases in [Ca(2+)](i), protein kinase C, mitogen-activated protein kinase and other pathways of VSM contraction and cell growth. ET-1/ET(A)R signaling has been associated with salt-sensitive hypertension (HTN) and pulmonary arterial hypertension (PAH), and ET(A)R antagonists have shown some benefits in these conditions. In search for other pathogenetic factors and more effective approaches, the role of alterations in endothelial ET(B)R and VSM ET(B)R in vascular dysfunction, and the potential benefits of modulators of ET(B)R in treatment of HTN and PAH are being examined. Combined ET(A)R/ET(B)R antagonists could be more efficacious in the management of conditions involving upregulation of ET(A)R and ET(B)R in VSM. Combined ET(A)R antagonist with ET(B)R agonist may need to be evaluated in conditions associated with decreased endothelial ET(B)R expression/activity.Biochemical pharmacology 03/2012; 84(2):147-62. · 4.25 Impact Factor
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ABSTRACT: With rising rates of obesity, research continues to explore the contributions of homeostatic and hedonic mechanisms related to eating behaviour. In this Review, we synthesize the existing information on select biological mechanisms associated with reward-related food intake, dealing primarily with consumption of highly palatable foods. In addition to their established functions in normal feeding, three primary peripheral hormones (leptin, ghrelin and insulin) play important parts in food reward. Studies in laboratory animals and humans also show relationships between hyperphagia or obesity and neural pathways involved in reward. These findings have prompted questions regarding the possibility of addictive-like aspects in food consumption. Further exploration of this topic may help to explain aberrant eating patterns, such as binge eating, and provide insight into the current rates of overweight and obesity.Nature Reviews Endocrinology 06/2014; · 11.03 Impact Factor
Role of 20-Hydroxyeicosatetraenoic Acid in Mediating
Hypertension in Response to Chronic Renal Medullary
Endothelin Type B Receptor Blockade
Joshua S. Speed1,2, Eric M. George1,2, Marietta Arany1,2, Kathy Cockrell1,2, Joey P. Granger1,2*
1Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America, 2Center for Excellence in
Cardiovascular–Renal Research, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
Background: The renal medullary endothelin (ET-1) system plays an important role in the control of sodium excretion and
arterial pressure (AP) through the activation of renal medullary ET-B receptors. We have previously shown that blockade of
endothelin type B receptors (ET-B) leads to salt-sensitive hypertension through mechanisms that are not fully understood.
One possible mechanism is through a reduction in renal medullary production of 20-hydroxyeicosatetraenoic acid (20-
HETE). 20-HETE, a metabolite of arachidonic acid, has natriuretic properties similar to ET-B activation. While these findings
suggest a possible interaction between ET-B receptor activation and 20-HETE production, it is unknown whether blockade
of medullary ET-B receptors in rats maintained on a high sodium intake leads to reductions in 20-HETE production.
Methodology/Principal Findings: The effect of increasing sodium intake from low (NS=.8%) to high (HS=8%) on renal
medullary production of 20-HETE in the presence and absence of renal medullary ET-B receptor antagonism was examined.
Renal medullary blockade of ET-B receptors resulted in salt sensitive hypertension. In control rats, blood pressure rose from
112.862.4 mmHg (NS) to 120.769.3 mmHg (HS). In contrast, when treated with an ET-B receptor blocker, blood pressure
was significantly elevated from 123.763.2 (NS) to 164.267.1 (HS). Furthermore, increasing sodium intake was associated
with elevated medullary 20-HETE (5.66.8 in NS vs. 14.363.7 pg/mg in HS), an effect that was completely abolished by renal
medullary ET-B receptor blockade (4.96.8 for NS and 4.56.6 pg/mg for HS). Finally, the hypertensive response to
intramedullary ET-B receptor blockade was blunted in rats pretreated with a specific 20-HETE synthesis inhibitor.
Conclusion: These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt
intake may be, in part, due to ET-B receptor activation within the renal medulla.
Citation: Speed JS, George EM, Arany M, Cockrell K, Granger JP (2011) Role of 20-Hydroxyeicosatetraenoic Acid in Mediating Hypertension in Response to
Chronic Renal Medullary Endothelin Type B Receptor Blockade. PLoS ONE 6(10): e26063. doi:10.1371/journal.pone.0026063
Editor: Jean-Claude Dussaule, INSERM, France
Received April 20, 2011; Accepted September 19, 2011; Published October 7, 2011
Copyright: ? 2011 Speed et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported in part by National Institutes of Health (NIH) grant HL51971 (www.nih.gov) and American Heart Association (AHA) grant
09PRE2250470 (http://www.heart.org/HEARTORG/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
Endothelin (ET-1) was first isolated and characterized in 1988
as a very potent vasoconstrictor produced by vascular endothelial
cells . Two receptor subtypes were later identified: ET-A and
ET-B. ET-A receptors are responsible for the vasoconstrictor
properties of ET-1, and chronic activation results in hypertension
. Their role in blood pressure regulation has been extensively
researched. In contrast, ET-B receptors are located on the
vascular endothelium and activation results in vasodilation;
however, renal ET-B receptors have been found to be important
in many facets of renal function including renal blood flow and
electrolyte transport . In fact, the renal medulla produces more
ET-1 than any other site in the body , and activation of ET-B
receptors located here causes natriuresis through a reduction in
Na+reabsorption in the collecting duct and thick ascending loop of
Henle [5,6,7]. Furthermore, several studies indicate that renal
medullary endothelin is important in the maintenance of fluid and
electrolyte homeostasis, and this system becomes increasingly
important as Na+intake is elevated [8,9]. Moreover, a reduction in
renal production of ET-1 may be important in the pathogenesis of
essential salt sensitive hypertension [10,11], however the mecha-
nisms by which renal medullary ET-1 enhances pressure
natriuresis have yet to be fully elucidated.
One important mechanism of ET-1 induced natriuresis is
through increases in nitric oxide (NO) production. For instance,
increasing dietary Na+
enhances eNOS expression in the
medullary thick ascending loop of Henle, however this is
attenuated by ET receptor blockade . Furthermore, knockout
of ET-1 production by the collecting duct results in salt sensitive
hypertension associated with reductions in urinary nitrate/nitrite
and renal medullary expression of nitric oxide synthase (NOS) I
and III . Finally, the acute, natriuretic response to intramed-
ullary ET-B activation can be attenuated by a NOSI inhibitor
. While substantial evidence implicates NO in mediating
the renal effects of ET-1, growing evidence suggest that 20-
PLoS ONE | www.plosone.org1October 2011 | Volume 6 | Issue 10 | e26063
Hydroxyeicosatetraenoic Acid (20-HETE) may also play an
20-HETE is a metabolite of arachidonic acid metabolism
though the cytochrome p-450 pathway, specifically the CYP4A
family in rats and CYP4F in humans. 20-HETE has actions
similar to those of ET-1 both in the vasculature and the renal
medulla . Chronic blockade of 20-HETE production results in
salt sensitive hypertension [15,16], as does chronic, systemic ET-B
blockade . Within the kidney, both 20-HETE and ET-B
receptor activation inhibit Na+reabsorption by the proximal
tubule and the medullary thick ascending loop of Henle [6,17,18].
While chronic ET-B blockade is associated with a reduction in
renal medullary CYP4A protein expression , the functional
significance of this interaction in the control of blood pressure has
yet to be determined. Therefore, the specific goal of our study was
to determine if chronic increases in salt intake lead to enhanced
formation of 20-HETE by the renal medulla and to determine if
this relationship is altered during chronic intramedullary infusion
of an ET-B antagonist. Finally, we wanted to determine if the
increase in blood pressure in response to chronic intramedullary
ET-B blockade is blunted when 20-HETE production is inhibited.
In order to determine if chronic intramedullary blockade of ET-
B receptors causes a reduction in pressure natriuresis and salt
sensitive hypertension, we examined the sodium excretion and
blood pressure relationship in rats treated with an ET-B receptor
antagonist, specifically delivered to the renal medulla. Our data
indicates that in response to intramedullary blockade, rats on a
normal salt diet had only a slight elevation in blood pressure;
however, rats placed on a high salt diet had a significant elevation
in pressure (Figure 1). We also indicate that under steady state
conditions, the pressure natriuresis relationship is shifted right-
ward, with a reduction in slope (Figure 2), in response to chronic
intramedullary blockade of ET-B receptors, suggesting a reduction
in the kidneys’ ability to excrete salt and water.
Our data also indicates that rats placed on a high salt diet have
a significant increase in renal medullary 20-HETE levels. When
treated with an ET-B receptor blocker, this increase is completely
abolished (Figure 3). Our data shows that only part of the blood
pressure effects of ET-B receptor blockade is related to 20-HETE.
In fact when we blocked 20-HETE production alone we report
that blood pressure increased by approximately 10 mmHg and
when we blocked the ET-B receptor in the presence of a 20-HETE
inhibitor, the blood pressure response was about 10–12 mmHg
lower than the group of rats receiving 20-HETE inhibitor alone.
Thus, the blood pressure effect of the ET-B receptor blockade is
attenuated when 20-HETE levels are clamped by a 20-HETE
inhibitor. (Figure 4)
Figure 1. Mean arterial pressure in response to chronic
intramedullary blockade of ET-B receptors. Chronic intramedul-
lary blockade of ET-B receptors causes a slight increase in MAP in rats
on a normal salt diet (112.862.4 in vehicle vs. 120.769.3). However, rats
placed on high salt diet had a much greater elevation in MAP in
response to IM ET-B blockade (123.763.2 vs. 164.267.1). * denotes
p,.05 vs. all other groups.
Figure 2. Pressure natriuresis relationship in response to
intramedullary ET-B blockade. In response to chronic intramedul-
lary ET-B blockade, there is a rightward shift of the pressure natriuresis
relationship suggesting there is an impairment of the kidneys’ normal
ability to excrete salt and water.
Figure 3. Renal medullary tissue levels of 20-HETE in response
to blockade of medullary ET-B receptors. In response to
increasing salt intake in male SD rats, renal medullary 20-HETE levels
are significantly elevated (5.660.75 vs. 14.363.7, n=4 and n=7
respectively). With chronic intramedullary blockade of ET-B receptors,
this response is completely abolished (4.960.79 vs. 4.560.55, n=5 and
n=6 respectively). * denotes p,.05 vs. NS + VEH.
Endothelin and Salt Sensitive Hypertension
PLoS ONE | www.plosone.org2October 2011 | Volume 6 | Issue 10 | e26063
Previous studies indicate that ET-B receptors are important in
the renal response to an increase in salt intake, and loss of function
of these receptors results in hypertension [8,20]. While blockade of
ET-B receptors throughout the entire body causes salt-sensitive
hypertension, the importance of renal medullary ET-B receptors
in mediating the chronic blood pressure response should be
considered. Our data indicates that the hypertension caused by
ET-B receptor blockade is very closely associated with renal
medullary ET-B receptors. As shown in Figure 1, chronic blockade
of ET-B receptors, specifically in the renal medulla, results in
hypertension very similar to that seen in systemic ET-B blockade
. This is a consequence of a reduction in the kidneys’ ability to
excrete salt and water as evidenced by the rightward shift and
reduced slope of the pressure natriuresis relationship after 7 days
of ET-B blockade (Figure 2). Therefore, we can conclude that
activation of renal medullary ET-B receptors is a necessary
response to increasing salt intake and is important in the
maintenance of water and electrolyte homeostasis.
We next wanted to determine if there is an important
interaction between endothelin and 20-HETE in the regulation
of blood pressure during chronic elevations in salt intake. It is well
established that multiple components of the ET-1 system are
upregulated within the renal medulla in response to increasing salt
intake , and this contributes to the kidneys’ function in
maintaining salt homeostasis and blood pressure. Because it has
become increasingly apparent that 20-HETE has natriuretic
properties, we hypothesized that increasing salt intake would lead
to an elevation in renal medullary production of 20-HETE, and
that this response would be attenuated with chronic intramedul-
lary ET-B blockade. Indeed, rats placed on a HS diet had almost
3-fold higher renal medullary tissue levels of 20-HETE than rats
on a NS diet. This response was completely abolished in rats with
chronic intramedullary ET-B blockade (Figure 3) suggesting that
increases in 20-HETE production in response to high salt is a
result of ET-B receptor activation.
Since we saw a significant reduction in 20-HETE production in
rats chronically treated with an ET-B receptor antagonist, we next
wanted to test the functional significance of this observation by
comparing the hypertensive response to intramedullary ET-B
receptor antagonism in the presence and absence of a 20-HETE
inhibitor. We proposed that if 20-HETE plays an important role
in mediating the chronic effects of renal medullary ET-1 on
pressure natriuresis and blood pressure regulation during increases
in sodium intake, the blood pressure response to medullary ET-B
receptor blockade would be attenuated in the presence of a 20-
HETE inhibitor. In the present study, we found that chronic
intramedullary infusion of the ET-B receptor antagonist increased
blood pressure by 40 mmHg. In contrast, intramedullary infusion
of a 20-HETE inhibitor alone increased blood pressure by only
10 mmHg, thus, the maximum role for 20-HETE in mediating
the blood pressure response to ET-B receptor blockade is about
10 mmHg. Consistent with this is our finding that in the presence
of a 20-HETE inhibitor, chronic intramedullary infusion of the
ET-B receptor antagonist increased blood pressure by only
25 mmHg or about 15 mmHg lower than when we infused ET-
B receptor antagonist alone into the renal medulla. While these
data suggest that 20-HETE may, in part, play an important role in
mediating ET-B receptor function in response to a high salt intake,
we cannot rule out an important interaction between ET-B
receptor blockade, 20-HETE, and nitric oxide. As pointed out in
the introduction, there is substantial evidence implicating NO in
mediating some of the renal effects of ET-1, especially the
collecting duct actions of ET-1. However, our data also implicates
an important interaction between 20-HETE and ET-1, an
interaction that may occur at nephron sites such as the medullary
thick ascending limb where 20-HETE is produced.
In conclusion, we have found that renal medullary production
of 20-HETE is elevated in response to a high salt intake, and this
response is completely abolished in rats treated with an ET-B
receptor antagonist directly in the renal medulla. Finally, we found
that the elevation in blood pressure in response to intramedullary
ET-B receptor blockade was significantly blunted in the presence
of a 20-HETE inhibitor, suggesting that 20-HETE may play a role
in mediating the natriuretic effects of ET-1 during a high salt
intake. Therefore, in response to a high salt diet, renal medullary
production of endothelin-1 is enhanced, thus activating mainly
ET-B receptors located on the medullary thick ascending loop of
Henle and collecting ducts. When activated, it is believed that
production of NO and 20-HETE lead to a reduction in Na uptake
by these tubule segments and, ultimately, an increase in Na+
Figure 4. Mean arterial pressure in rats with intramedullary
blockade of ET-B receptors in the presence and absence of a
20-HETE inhibitor. A) This figure illustrates the changes in blood
pressure in response to chronic intramedullary infusion of the ET-B
antagonist, A-192621, the 20-HETE inhibitor, HET0016, and rats
pretreated with HET0016, and then administered A-192621. B)
Illustrates that the increase in blood pressure in response to
intramedullary blockade of ET-B receptors is blunted when the rats
are pretreated with a 20-HETE inhibitor. *indicates that p,0.05 vs. A-
192621 treated group.
Endothelin and Salt Sensitive Hypertension
PLoS ONE | www.plosone.org3October 2011 | Volume 6 | Issue 10 | e26063
excretion, therefore, providing a mechanism for the kidney to
increase Na+and water excretion, without elevations in blood
Materials and Methods
All studies were performed using age matched Sprague Dawley
rats purchased from Harlan, Inc. (Indianapolis, IN). Animals were
housed ina temperature-controlled
12:12 hour light/dark cycle. All surgeries were performed under
isoflurane anesthesia. All experimental procedures executed in this
study were in accordance with National Institutes of Health
guidelines for use and care of animals and approved by the
Institutional Animal Care and Use Committee (IACUC) at
UMMC (Protocol number 0258D)
For specific intramedullary blockade of the ET-B receptor,
1 mg/kg/day of A-192621 was used. This dose was based on the
ED50observed in systemic administration of the drug , as well
as unpublished data from our laboratory in which we found that
intravenous infusion of 1 mg/kg/day had minimal effects on
blood pressure. For blockade of 20-HETE production, HET0016
was used at a dose of 1 mg/kg. This dose was determined from
previous reports that IV infusion of HET0016 at 10 mg/kg
significantly reduced urinary levels of 20-HETE, but not EET’s,
which would suggest that HET0016 is a highly specific inhibitor of
CYP4A proteins . This dose was then extrapolated to fit
regional blood flow of the kidney.
Experiment 1: Effect of Na+intake on renal medullary 20-
HETE production and the effect of ET-B blockade on this
increases in dietary sodium intake, we first determined if renal
medullary production of 20-HETE is elevated in response to
increases in dietary sodium intake in normal SD rats. Then we
examined the effect of increases in dietary sodium intake on renal
medullary production of 20-HETE during chronic ET-B receptor
blockade. Male SD rats (300–350 g) were randomly distributed
among 4 groups including a control on Normal Sodium (NS, 0.8%
NaCl) diet (n=4), control on High sodium diet (HS, 8% NaCl)
(n=7), Endothelin type B receptor (ET-B) blockade on NS (n=5),
and ET-B receptor blockade on HS (n=6). Next, one kidney was
removed and the other was instrumented with a chronic
indwelling catheter placed into the interstitium of the renal
medulla. The catheters were made of V-1 tubing connected to V-3
tubing with superglue. A round piece of alliedsil (Allied
Biomedical, Paso Robles, CA) sheeting was placed between the
two portions in order to secure the catheter to the kidney. The V-1
portion was inserted 4–5 mm into the kidney and secured to the
renal capsule with vetbond. The rats were given 7 days to recover
International, St. Paul, MN) for 24-hour collection of blood
pressure and placed on respective diets. After pressure normalized
post surgery, the rats were tethered, placed in metabolic cages, and
infusion of vehicle (70% ethanol, 0.6 ml/min) to the medullary
interstitium was began. Control pressure was taken for 3 days and
urine was collected on ice for 24 hours on the final day for
measurement of 20-HETE. Next, vehicle or the ET-B antagonist
A-192621(Abbott Laboratories, Abbott Park, IL) (1 mg/kg/day)
was infused for seven days, and urine was collected on the final
day. The rats were euthanized and tissues were harvested for
measurements of 20-HETE production. Kidneys were dissected to
ensure proper placement. Urinary Na+
measured using an EasyLyte Na+/K+analyzer (Medica Corp.),
and Na+excretion was calculated by multiplying the urinary Na+
concentration by the urine flow per 24 hours.
Measurement of 20-HETE.
renal homogenates using <50 mg of tissue by the following
protocol. First, samples were homogenized in a.1 M potassium
phosphate buffer (.1 M monobasic KPO, 1 M dibasic KPO,
250 mM sucrose, 1 mM ETDA, and 1 mL/mL PMSF). The
samples were acidified with 1 M formic acid to bring the pH
between 3.5 and 4.0. 2 ng of 20-hydroxyeicosa-6(Z), 15(Z)-dienoic
acid was added to each sample as an internal standard to account
for loss during extraction. Next, three mL of ethyl acetate were
added and the samples were vortexed for 2 minutes. They were
then centrifuged for 3 minutes at 2200 rpm. The upper organic
layer was transferred to another glass tube and 1 mL of distilled
water was added to the samples, and they were vortexed again for
2 minutes. Once again, the upper organic layer was transferred to
another glass vial and the ethyl acetate was evaporated under
nitrogen until samples were dry. They were quickly capped and
stored at 280uC until assayed by mass spectrometry. 20-HETE
was measured by liquid chromatography mass spectrometry
(LCMS) as previously described .
Lipids were separated from
Experiment 2: Functional significance of 20-HETE in
chronic, intramedullary ET-B blockade
To determine the role of 20-HETE in mediating the long-term
blood pressure response to chronic ET-B receptor blockade, we
examined the effect of IM blockade of 20-HETE production on
the blood pressure response to chronic ET-B receptor blockade.
Male SD rats were uninephrectomized and chronic renal
medullary interstitial catheter was placed in the opposite kidney,
as previously described. The rats were then instrumented with
telemetry probes (Data Science International, St. Paul, MN) for
24 hr measurement of blood pressure. The rats were then placed
on a high Na+diet and allowed to heal for one week. Baseline
pressure was measured for 3 days. Next, a 20-HETE inhibitor
(HET0016, 1 mg/kg/day) was administered IM for five days. The
rats were then placed in metabolism cages on the last two days for
urine collection. Finally, an ET-B antagonist (A-192621, 1 mg/
kg/day IM) was administered via IM infusion for five days and rats
were placed in metabolic cages on the final day for 24 hour urine
collection. Blood pressure was monitored daily and recorded as
24 hour average. The doses used were extrapolations from
systemic blockade studies based on regional blood flow [8,15].
All data is presented as mean 6 standard error of the mean. In
experiment 1, blood pressure was averaged over the last 3 days of
chronic intramedullary infusion of A-192621. Blood pressure
averages and 20-HETE data were analyzed by one-way analysis of
variance, and Tukey’s post hoc test was used for comparison
between groups. In experiment 2 (Figure 4), the change in blood
pressure between groups was analyzed by Student’s t-test.
Conceived and designed the experiments: JSS JPG. Performed the
experiments: JSS MA KLC. Analyzed the data: JSS EMG. Contributed
reagents/materials/analysis tools: JPG. Wrote the paper: JSS JPG.
Endothelin and Salt Sensitive Hypertension
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PLoS ONE | www.plosone.org5October 2011 | Volume 6 | Issue 10 | e26063