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Dear all --

My old roommate and Cornell MD-PhD trainee Ankit Patel shared this
interesting article via Nature entitled
'high salt taste recruits aversive taste pathways' @ the link below.
Abstract is also below. I was struck by
this: '...salty taste is unique in that increasing salt concentration
fundamentally transforms an
innately appetitive stimulus into a powerfully aversive one. This
appetite-aversive
balance helps to maintain appropriate salt consumption...' The authors
highlight a new mechanism
that underlies appetite-AVERSION to salt and take a deep dive into a richer
understanding of taste
(and how to manipulate it) --

http://www.ncbi.nlm.nih.gov/m/pubmed/23407495/

Ankit has spent much of his research career (starting with how mosquitoes
pee) studying sodium/salt channels including the epithelial sodium channel
and its links with blood pressure, stroke & kidney disease. I've asked him
to kindly translate what this new basic science research
means -- what is the breakthrough? And provide any thoughts its potential
applications in the NCD policy/ public health context --

I'd be keen to hear from Clare and those at the World Action on Salt &
Health as well on whether this
research affects your work (or not?); as well as any other folks studying
Taste who might provide thoughts?


Abstract:

In the tongue, distinct classes of taste receptor cells detect the five
basic tastes; sweet, sour, bitter, sodium salt and umami. Among these
qualities, bitter and sour stimuli are innately aversive, whereas sweet and
umami are appetitive and generally attractive to animals. By contrast,
salty taste is unique in that increasing salt concentration fundamentally
transforms an innately appetitive stimulus into a powerfully aversive one.
This appetitive-aversive balance helps to maintain appropriate salt
consumption, and represents an important part of fluid and electrolyte
homeostasis. We have shown previously that the appetitive responses to NaCl
are mediated by taste receptor cells expressing the epithelial sodium
channel, ENaC, but the cellular substrate for salt aversion was unknown.
Here we examine the cellular and molecular basis for the rejection of high
concentrations of salts. We show that high salt recruits the two primary
aversive taste pathways by activating the sour- and bitter-taste-sensing
cells. We also demonstrate that genetic silencing of these pathways
abolishes behavioural aversion to concentrated salt, without impairing salt
attraction. Notably, mice devoid of salt-aversion pathways show unimpeded,
continuous attraction even to very high concentrations of NaCl. We propose
that the 'co-opting' of sour and bitter neural pathways evolved as a means
to ensure that high levels of salt reliably trigger robust behavioural
rejection, thus preventing its potentially detrimental effects on health.

--
Sandeep P. Kishore, Ph.D.

Chair, Advisory Council
Young Professionals Chronic Disease Network

Weill Cornell/ The Rockefeller University/ Sloan-Kettering Institute
Tri-Institutional MD-PhD Program

1230 York Avenue, Box 292
New York, NY 10065
email:
tel: (917) 733 -1973

 
Drsunil kumar
Replied at 10:29 PM, 16 Feb 2013

a post full of information

Ankit Patel
Replied at 3:27 PM, 17 Feb 2013

Dear all,

First off, thank you for introducing me to this group Sunny. I look
forward to hearing this group's thoughts and comments with their diverse
expertise.

As Sunny mentioned, my interest lies in sodium homeostasis in the kidney
and the mechanisms utilized to regulate sodium transport. A primary driver
of my interest in sodium homeostasis came from an idea put forth by a
famous physiologist named Arthur Guyton. He proposed the "infinite gain"
theory which essentially noted that all essential hypertension is a
consequence of a defect in the kidneys to maintain sodium homeostasis (
http://www.ncbi.nlm.nih.gov/pubmed/2063193). Inherent in that assumption,
is that the kidneys have an infinite gain system through changes in GFR and
subsequent regulation of sodium homeostasis to combat changes in blood
pressure by regulating blood volume.

The problem lies in understanding the defect (more realistically the slew
of defects) in regulation of sodium homeostasis that leads to essential
hypertension. There has been some nice work recently identifying some
genetic defects in sodium homeostasis presenting as hypertension but the
mechanism by which essential hypertension presents still remains unclear.
Since we can't directly target the molecular entities responsible for the
dysregulation in sodium homeostasis, another way of approaching the problem
is to decrease sodium intake. This is not a novel strategy and has been
shown to be an effective intervention for decades. Interesting data in a
paper published in NEJM in 2010 by Bibbins-Domingo et al. (
http://www.ncbi.nlm.nih.gov/pubmed/20089957) along with a slew of
subsequent papers utilized a computer model that reflected the consequence
of a population-wide reduction in salt to 3 grams/day/person on not only
mortality and cardiovascular morbidity but also healthcare costs. Though
these are computer simulations, the numbers are striking.

Though it seems evident that low sodium diets could provide provide
significant improvement, knowledge that has been known for sometime,
adherence seems to be an issue. A primary deterrent is the fact that salt
taste so good! As the authors mention in the article, salt can be
attractive at low concentrations and aversive at high concentrations, as
mechanism to regulate sodium intake in hopes of maintaining sodium
homeostasis. However, the role of evolution in tuning the
attractive-aversive axis is humans is unclear. Do you humans have a higher
set point to activate the aversive response from salt taste? This could be
one explanation why humans have salt intakes that are out of proportion to
their needs.

A previous article by the same group initially identified the molecular
identity of the salt taster to be the epithelial sodium channel (ENaC)
which was found a subset of taste receptor-cells (TRCs) to provide the
unique salty taste: http://www.ncbi.nlm.nih.gov/pubmed/20107438. However,
they noticed that these TRCs were only specific for sodium and sodium at
low concentrations. They found another subset of TRCs that were activated
by high sodium concentrations (above 150 mM) as well as other salts such as
KCL or NMDG-Cl. Activation of TRCs by high salt concentrations were found
to be independent of ENaC.

It seems that attractive response of salt taste is mediated by ENaC while
aversive salt taste is mediated by another unknown target which is
inhibited by AITC (mustard oil). One approach that could be taken to limit
sodium intake would be to inhibit or block the attractive response to salt
taste. There is a well established inhibitor of ENaC called amiloride that
can inhibit the channel at micromolar concentrations. However, ENaC is
found in a number of epithelia in the body. It plays a particular
important role in the connecting tubule and cortical collecting duct of the
kidney in maintaining sodium homeostasis by regulating sodium transport in
the final site of sodium reabsorption in the nephron to help match sodium
intake with sodium excretion. One could envision that amiloride could be
used not only to increase sodium excretion and water similar to other
diuretics but also inhibit the attractive nature of salt taste and
hopefully decrease sodium intake. However, ENaC plays a key role in
exchanging sodium for potassium in the distal nephron and thus an important
side effect of systemic amiloride administration would be hyperkalemia.

If there was a way of selectively applying amiloride to the salt taste
receptors on the tongue, that could be one way to limit salt intake. In
this scenario, salt would only be able to elicit the aversive reaction
through activation of the TRC responsible for bitter taste or sour taste
thus limiting sodium intake.

The final paragraph in the paper eludes to their interest in modulating
these molecular targets to regulate salt intake in humans.

"Future studies using specific inhibitors and activators of each path- way
should help to address the contributions of the ENaC-, T2R- and
PKD2L1-expressing taste cells to human salt-taste perception, and may serve
as a springboard for the development of selective receptor-cell modulators
to help to control (and even satisfy) our strong appetite for high salt,
but without the potential ill effects of too much sodium."

The promise of these selective receptor-cell modulators gives hope for a
new mechanism of combating hypertension and cardiovascular morbidity
through regulating salt intake.

Any thoughts and comments would be welcome. Does anyone have
expertise/familiarity in this research?

Cheers,
Ankit

On Sat, Feb 16, 2013 at 12:23 PM, Sandeep Kishore
<:

> Dear all --
>
> My old roommate and Cornell MD-PhD trainee Ankit Patel shared this
> interesting article via Nature entitled
> 'high salt taste recruits aversive taste pathways' @ the link below.
> Abstract is also below. I was struck by
> this: '...salty taste is unique in that increasing salt concentration
> fundamentally transforms an
> innately appetitive stimulus into a powerfully aversive one. This
> appetite-aversive
> balance helps to maintain appropriate salt consumption...' The authors
> highlight a new mechanism
> that underlies appetite-AVERSION to salt and take a deep dive into a
> richer understanding of taste
> (and how to manipulate it) --
>
> http://www.ncbi.nlm.nih.gov/m/pubmed/23407495/
>
> Ankit has spent much of his research career (starting with how mosquitoes
> pee) studying sodium/salt channels including the epithelial sodium channel
> and its links with blood pressure, stroke & kidney disease. I've asked him
> to kindly translate what this new basic science research
> means -- what is the breakthrough? And provide any thoughts its potential
> applications in the NCD policy/ public health context --
>
> I'd be keen to hear from Clare and those at the World Action on Salt &
> Health as well on whether this
> research affects your work (or not?); as well as any other folks studying
> Taste who might provide thoughts?
>
>
> Abstract:
>
> In the tongue, distinct classes of taste receptor cells detect the five
> basic tastes; sweet, sour, bitter, sodium salt and umami. Among these
> qualities, bitter and sour stimuli are innately aversive, whereas sweet and
> umami are appetitive and generally attractive to animals. By contrast,
> salty taste is unique in that increasing salt concentration fundamentally
> transforms an innately appetitive stimulus into a powerfully aversive one.
> This appetitive-aversive balance helps to maintain appropriate salt
> consumption, and represents an important part of fluid and electrolyte
> homeostasis. We have shown previously that the appetitive responses to NaCl
> are mediated by taste receptor cells expressing the epithelial sodium
> channel, ENaC, but the cellular substrate for salt aversion was unknown.
> Here we examine the cellular and molecular basis for the rejection of high
> concentrations of salts. We show that high salt recruits the two primary
> aversive taste pathways by activating the sour- and bitter-taste-sensing
> cells. We also demonstrate that genetic silencing of these pathways
> abolishes behavioural aversion to concentrated salt, without impairing salt
> attraction. Notably, mice devoid of salt-aversion pathways show unimpeded,
> continuous attraction even to very high concentrations of NaCl. We propose
> that the 'co-opting' of sour and bitter neural pathways evolved as a means
> to ensure that high levels of salt reliably trigger robust behavioural
> rejection, thus preventing its potentially detrimental effects on health.
>
> --
> Sandeep P. Kishore, Ph.D.
>
> Chair, Advisory Council
> Young Professionals Chronic Disease Network
>
> Weill Cornell/ The Rockefeller University/ Sloan-Kettering Institute
> Tri-Institutional MD-PhD Program
>
> 1230 York Avenue, Box 292
> New York, NY 10065
> email:
> tel: (917) 733 -1973
>



--
Ankit B. Patel

Tri-Institutional MD-PhD Program
Weill Cornell/Rockefeller/Sloan-Kettering
1230 York Avenue, Box 218
New York, NY 10065

Phone #: (845)709-4976
Email:

Maryam Shafaee
Replied at 4:28 PM, 17 Feb 2013

Thank you Ankit for this super interesting analysis.

Sandeep Kishore
Replied at 2:09 PM, 18 Feb 2013

Ah, Sorry everyone -- was hoping to relay this to the Global Steering
Committee members of YP, but actually would love to see more replies and
thoughts on this discussion (and all discussions in this community!) - even
if you haven't posted before (I know it can sometimes be daunting to an
anonymous group; but we won't bite!) please don't hesitate to jump in and
share your thoughts so we can get some dialogue, imagination and
translation to real-world applications - we're all here to learn from one
another!

Ankit, 2 quick questions for you --

1 -- are there any known amiloride analogues that are specific to the
tongue (and/or is it known whether there are any differences specific to
tongue receptors that could be exploited).

2 -- Taking the long view, I could see how these neurobiological axes could
be co-opted chemically for + and - to nudge towards appetite/aversion. Do
you think there has been a recalibration of the 'set point' for salt
aversion/attraction you speak of (how fast could that transpire? and dare
we try to manipulate it!?)

Would agree that one approach is simply to say let us agree to mandate or
voluntarily reduce salt by industry and or leverage public policies to
reduce salt in processed foods, etc...but this provides a richer
understanding of taste that i'm still mulling on, perhaps an alternative
food biology approach to reformulation....?

On Mon, Feb 18, 2013 at 1:37 PM, GHDonline (Sandeep Kishore) <
> wrote:

>
> Sandeep Kishore replied to the discussion "Nature: High salt taste
> recruits aversive taste pathways | What does this mean for public health?"
> in the Young Professionals Chronic Disease Network community.
>
> Reply contents:
> "Hi team --
>
> Was wondering if someone on Team GSC could respond to Ankit's post with
> questions or dialogue
>
> Benn pointed out that 70% of our membership has not posted a single time;
> and that on the other hand we have high utilizers/posters
>
> In order to get the community engaged, they must participate digitally as
> well and feedback and feedforward on each others' ideas esp
> when a new member has taken the time to seriously put together a
> translation/discussion brief for this group.
>
> Would someone be willing to respond with thoughts -- big or small, to keep
> discussion going? All it takes is 1 first follower/reply
> and that usually lowers the barrier to entry for other folks and gets
> discussion (Rather than just posting information/articles) really
> going!?
>
> Who's up for it -- the GSC can/should/must step up to lead and minimize
> 'orphan' posts :))
>
> spk
>
> ---------- Forwarded message ----------
> From: GHDonline (Ankit Patel) <>
> Date: Sun, Feb 17, 2013 at 3:27 PM
> Subject: Re: [Young Professionals Chronic Disease Network] Nature: High
> salt taste recruits aversive taste pathways | What does this mean for
> public health?
> To: Sandeep Kishore <>
>
>
>
> Ankit Patel replied to the discussion "Nature: High salt taste recruits
> aversive taste pathways | What does this mean for public health?" in the
> Young Professionals Chronic Disease Network community.
>
> Reply contents:
> "Dear all,
>
> First off, thank you for introducing me to this group Sunny. I look
> forward to hearing this group's thoughts and comments with their diverse
> expertise.
>
> As Sunny mentioned, my interest lies in sodium homeostasis in the kidney
> and the mechanisms utilized to regulate sodium transport. A primary driver
> of my interest in sodium homeostasis came from an idea put forth by a
> famous physiologist named Arthur Guyton. He proposed the "infinite gain"
> theory which essentially noted that all essential hypertension is a
> consequence of a defect in the kidneys to maintain sodium homeostasis (
> http://www.ncbi.nlm.nih.gov/pubmed/2063193). Inherent in that assumption,
> is that the kidneys have an infinite gain system through changes in GFR and
> subsequent regulation of sodium homeostasis to combat changes in blood
> pressure by regulating blood volume.
>
> The problem lies in understanding the defect (more realistically the slew
> of defects) in regulation of sodium homeostasis that leads to essential
> hypertension. There has been some nice work recently identifying some
> genetic defects in sodium homeostasis presenting as hypertension but the
> mechanism by which essential hypertension presents still remains unclear.
> Since we can't directly target the molecular entities responsible for the
> dysregulation in sodium homeostasis, another way of approaching the problem
> is to decrease sodium intake. This is not a novel strategy and has been
> shown to be an effective intervention for decades. Interesting data in a
> paper published in NEJM in 2010 by Bibbins-Domingo et al. (
> http://www.ncbi.nlm.nih.gov/pubmed/20089957) along with a slew of
> subsequent papers utilized a computer model that reflected the consequence
> of a population-wide reduction in salt to 3 grams/day/person on not only
> mortality and cardiovascular morbidity but also healthcare costs. Though
> these are computer simulations, the numbers are striking.
>
> Though it seems evident that low sodium diets could provide provide
> significant improvement, knowledge that has been known for sometime,
> adherence seems to be an issue. A primary deterrent is the fact that salt
> taste so good! As the authors mention in the article, salt can be
> attractive at low concentrations and aversive at high concentrations, as
> mechanism to regulate sodium intake in hopes of maintaining sodium
> homeostasis. However, the role of evolution in tuning the
> attractive-aversive axis is humans is unclear. Do you humans have a higher
> set point to activate the aversive response from salt taste? This could be
> one explanation why humans have salt intakes that are out of proportion to
> their needs.
>
> A previous article by the same group initially identified the molecular
> identity of the salt taster to be the epithelial sodium channel (ENaC)
> which was found a subset of taste receptor-cells (TRCs) to provide the
> unique salty taste: http://www.ncbi.nlm.nih.gov/pubmed/20107438. However,
> they noticed that these TRCs were only specific for sodium and sodium at
> low concentrations. They found another subset of TRCs that were activated
> by high sodium concentrations (above 150 mM) as well as other salts such as
> KCL or NMDG-Cl. Activation of TRCs by high salt concentrations were found
> to be independent of ENaC.
>
> It seems that attractive response of salt taste is mediated by ENaC while
> aversive salt taste is mediated by another unknown target which is
> inhibited by AITC (mustard oil). One approach that could be taken to limit
> sodium intake would be to inhibit or block the attractive response to salt
> taste. There is a well established inhibitor of ENaC called amiloride that
> can inhibit the channel at micromolar concentrations. However, ENaC is
> found in a number of epithelia in the body. It plays a particular
> important role in the connecting tubule and cortical collecting duct of the
> kidney in maintaining sodium homeostasis by regulating sodium transport in
> the final site of sodium reabsorption in the nephron to help match sodium
> intake with sodium excretion. One could envision that amiloride could be
> used not only to increase sodium excretion and water similar to other
> diuretics but also inhibit the attractive nature of salt taste and
> hopefully decrease sodium intake. However, ENaC plays a key role in
> exchanging sodium for potassium in the distal nephron and thus an important
> side effect of systemic amiloride administration would be hyperkalemia.
>
> If there was a way of selectively applying amiloride to the salt taste
> receptors on the tongue, that could be one way to limit salt intake. In
> this scenario, salt would only be able to elicit the aversive reaction
> through activation of the TRC responsible for bitter taste or sour taste
> thus limiting sodium intake.
>
> The final paragraph in the paper eludes to their interest in modulating
> these molecular targets to regulate salt intake in humans.
>
> "Future studies using specific inhibitors and activators of each path- way
> should help to address the contributions of the ENaC-, T2R- and
> PKD2L1-expressing taste cells to human salt-taste perception, and may serve
> as a springboard for the development of selective receptor-cell modulators
> to help to control (and even satisfy) our strong appetite for high salt,
> but without the potential ill effects of too much sodium."
>
> The promise of these selective receptor-cell modulators gives hope for a
> new mechanism of combating hypertension and cardiovascular morbidity
> through regulating salt intake.
>
> Any thoughts and comments would be welcome. Does anyone have
> expertise/familiarity in this research?
>
> Cheers,
> Ankit
>
> On Sat, Feb 16, 2013 at 12:23 PM, Sandeep Kishore
> <:
>
> > Dear all --
> >
> > My old roommate and Cornell MD-PhD trainee Ankit Patel shared this
> > interesting article via Nature entitled
> > 'high salt taste recruits aversive taste pathways' @ the link below.
> > Abstract is also below. I was struck by
> > this: '...salty taste is unique in that increasing salt concentration
> > fundamentally transforms an
> > innately appetitive stimulus into a powerfully aversive one. This
> > appetite-aversive
> > balance helps to maintain appropriate salt consumption...' The authors
> > highlight a new mechanism
> > that underlies appetite-AVERSION to salt and take a deep dive into a
> > richer understanding of taste
> > (and how to manipulate it) --
> >
> > http://www.ncbi.nlm.nih.gov/m/pubmed/23407495/
> >
> > Ankit has spent much of his research career (starting with how mosquitoes
> > pee) studying sodium/salt channels including the epithelial sodium
> channel
> > and its links with blood pressure, stroke & kidney disease. I've asked
> him
> > to kindly translate what this new basic science research
> > means -- what is the breakthrough? And provide any thoughts its potential
> > applications in the NCD policy/ public health context --
> >
> > I'd be keen to hear from Clare and those at the World Action on Salt &
> > Health as well on whether this
> > research affects your work (or not?); as well as any other folks studying
> > Taste who might provide thoughts?
> >
> >
> > Abstract:
> >
> > In the tongue, distinct classes of taste receptor cells detect the five
> > basic tastes; sweet, sour, bitter, sodium salt and umami. Among these
> > qualities, bitter and sour stimuli are innately aversive, whereas sweet
> and
> > umami are appetitive and generally attractive to animals. By contrast,
> > salty taste is unique in that increasing salt concentration fundamentally
> > transforms an innately appetitive stimulus into a powerfully aversive
> one.
> > This appetitive-aversive balance helps to maintain appropriate salt
> > consumption, and represents an important part of fluid and electrolyte
> > homeostasis. We have shown previously that the appetitive responses to
> NaCl
> > are mediated by taste receptor cells expressing the epithelial sodium
> > channel, ENaC, but the cellular substrate for salt aversion was unknown.
> > Here we examine the cellular and molecular basis for the rejection of
> high
> > concentrations of salts. We show that high salt recruits the two primary
> > aversive taste pathways by activating the sour- and bitter-taste-sensing
> > cells. We also demonstrate that genetic silencing of these pathways
> > abolishes behavioural aversion to concentrated salt, without impairing
> salt
> > attraction. Notably, mice devoid of salt-aversion pathways show
> unimpeded,
> > continuous attraction even to very high concentrations of NaCl. We
> propose
> > that the 'co-opting' of sour and bitter neural pathways evolved as a
> means
> > to ensure that high levels of salt reliably trigger robust behavioural
> > rejection, thus preventing its potentially detrimental effects on health.
> >
> > --
> > Sandeep P. Kishore, Ph.D.
> >
> > Chair, Advisory Council
> > Young Professionals Chronic Disease Network
> >
> > Weill Cornell/ The Rockefeller University/ Sloan-Kettering Institute
> > Tri-Institutional MD-PhD Program
> >
> > 1230 York Avenue, Box 292
> > New York, NY 10065
> > email:
> > tel: (917) 733 -1973
> >
>
>
>
> --
> Ankit B. Patel
>
> Tri-Institutional MD-PhD Program
> Weill Cornell/Rockefeller/Sloan-Kettering
> 1230 York Avenue, Box 218
> New York, NY 10065
>
> Phone #: (845)709-4976
> Email:
>
> --
> View this post online:
> <
>
> http://www.ghdonline.org/yp-chronic/discussion/nature-high-salt-taste-recruit...
> >
>
> Unsubscribe or change your email notification settings:
> <http://www.ghdonline.org/users/sandeep-kishore/edit/>
>
> Contact the GHDonline team:
> <http://www.ghdonline.org/contact/>
>
> You can reply to this discussion by responding directly to this e-mail; it
> will be shared with all community members and posted as is. Files cannot be
> added via email attachment and must be uploaded directly to GHDonline.
>
>
>
> --
> Sandeep P. Kishore, Ph.D.
>
> Chair, Advisory Council
> Young Professionals Chronic Disease Network
>
> Weill Cornell/ The Rockefeller University/ Sloan-Kettering Institute
> Tri-Institutional MD-PhD Program
>
> 1230 York Avenue, Box 292
> New York, NY 10065
> email:
> tel: (917) 733 -1973"
>
> --
> View this post online:
> <
> http://www.ghdonline.org/yp-chronic/discussion/nature-high-salt-taste-recruit...
> >
>
> Unsubscribe or change your email notification settings:
> <http://www.ghdonline.org/users/sandeep-kishore/edit/>
>
> Contact the GHDonline team:
> <http://www.ghdonline.org/contact/>
>
> You can reply to this discussion by responding directly to this e-mail; it
> will be shared with all community members and posted as is. Files cannot be
> added via email attachment and must be uploaded directly to GHDonline.
>



--
Sandeep P. Kishore, Ph.D.

Chair, Advisory Council
Young Professionals Chronic Disease Network

Weill Cornell/ The Rockefeller University/ Sloan-Kettering Institute
Tri-Institutional MD-PhD Program

1230 York Avenue, Box 292
New York, NY 10065
email:
tel: (917) 733 -1973

JOSEPH LUNYERA
Replied at 2:21 PM, 18 Feb 2013

Hi team!

I'll start with a brief introduction. I'm an intern doctor attached to
Mulago National Referal Hospital in Kampala, Uganda. I've been a silent
member for quiet a while now, since October last year. I was introduced to
the team by Dr. Jeremy Schwartz, who happened to be my former lecturer
while at Makerere University Medical School. He is also a great friend of
mine.

I have a lot of interest in Nephrology, so reading this post was fun for
me. I'm also excited about the WASH campaign, I think it's timely,
especially in LMICs where the majority of the population are not aware of
the dangers of high salt intake. I strongly believe that through such
campaigns, we can achieve a similar awareness about the dangers of
increased salt intake as has been achieved with sugar.

Finally, I'm excited to inform the team that Uganda is on the verge of
getting a Kidney Foundation, for which I'm very much a part of the founding
committee. We are working around the clock to have it launched on World
Kidney Day, March 14th! We also intend to do screening for kidney disease
and DM/HTN for our participants on that day.

Contributions from the team is highly appreciated, especially in terms of
ideas and collaborations.

Cheers!

Joseph Lunyera
Intern Doctor,
Mulago National Referral Hospital,
Kampala, Uganda.

Sandeep Saluja
Replied at 3:08 PM, 18 Feb 2013

Any effective salt substitutes available(not just KCL)?
What role for mustard oi?

Sandeep Saluja M.D.

Katherine Ellington
Replied at 3:51 PM, 18 Feb 2013

Thinking about salt in the context of public health research:
Reducing salt does have cardiovascular benefit for some (but how many in the population?) discussed in the Bibbins-Domingo NEJM study:

"The cardiovascular benefits of reduced salt intake are on par with the benefits of population-wide reductions in tobacco use, obesity, and cholesterol levels. A regulatory intervention designed to achieve a reduction in salt intake of 3 g per day would save 194,000 to 392,000 quality-adjusted life-years and $10 billion to $24 billion in health care costs annually. Such an intervention would be cost-saving even if only a modest reduction of 1 g per day were achieved gradually between 2010 and 2019 and would be more cost-effective than using medications to lower blood pressure in all persons with hypertension."
It's brain, heart and kidney function.

Your research may be helpful in teaching about the taste for salt and the challenge to disrupt the taste-intake relationship. Furthermore, the connection between salt and kidney (dys)function should be more widely discussed. This may also be another ENaC paradigm for genetics and personalized medicine as some patients to have aversive salt pathways turned on reduce salt intake.

It's not the same opportunity like the trans-fat campaign in NYC.

Jo Jewell
Replied at 4:36 AM, 19 Feb 2013

Hi Ankit,

It was extremely interesting to read about your work on salt, especially the biomedical aspects. Thanks for posting. It was particularly timely as I'm doing some work with colleagues at the moment on food preferences that seems to be somehow linked in, but we have more of a focus on policy implications. We touch on innate preferences (including for sweetness, energy-dense foods), but are also looking at preference/habit formation - 'liking of foods' (including through repeated exposure to food products/marketing messages). The idea being to identify possible entry points for effective policies.

Do keep us updated!

Jo

Jaime Miranda
Replied at 10:36 AM, 19 Feb 2013

Folks, we are getting onto this issue from the other angle, pragmatism. We know low-sodium salt reduces blood pressure, much so in hypertensive people.

So, why not aiming to move the (BP) curve to the left (for everybody). Yeah, what an idiot you may call me... but we are trying. We are launching a pragmatic community stepped-wedge intervention trial in a semi-urban setting with a baseline prevalence of hypertension of ~26-30%. The intervention package is a complex one, to provide the low-sodium salt substitute together with a social marketing campaign. The intervention targets the whole community, not only people with hypertension.

You can find more about this on:
http://www.gacd.org/projects/current-projects/hypertension/project-pages/proj...

All this year we are in planning/development mode. Next March 2014 we will start deploying this intervention.

If you think this structure can serve to try/test some of this exciting ideas about taste, on the ground, get in touch.



www.cronicas.pe
http://www.cronicas.pe/cronicasweb/en

Abrazos a todos,

Jaime

Slim Slama
Replied at 11:59 AM, 19 Feb 2013

Hi Jaime,

It is not a fool idea at the contrary, a very useful and pragmatic one indeed. You might also be interested to look at other diet related links with blood pressure and include a good dietary history while recruiting your villagers.

See the abstract of an Swiss article entitled "Food and Hypertension: Beyond table salt" (sorry the full abstract is in French): http://bit.ly/XmN4QQ


Abstract:
The role of dietary sodium intake in the development, and its impact on the treatment, of hypertension are well recognized. However, many other nutritional compounds have been shown, or are believed, to influence blood pressure. Some compounds, such as caffeine and fructose, may raise arterial blood pressure, whereas others might lower arterial blood pressure, for example garlic, dark chocolate, fibers and potassium. In this article, we review several alimentary compounds and their (hypothesized) mechanisms of action, as well as the available evidence supporting a role of these compounds in the «non pharmacological» treatment and prevention of hypertension.


Good luck!

Abrazo!!

Slim Slama


Dr Slim Slama, MD, MPH
FMH Internal Medicine
Geneva Health Forum Programme Director
Assistant Professor
Division of International and Humanitarian Medicine
Department of Community Medicine, Primary Care and Emergency
Geneva University Hospitals
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Jeremy Schwartz
Replied at 6:04 AM, 20 Feb 2013

Hi all,
I've enjoyed this conversation so far. I'm gearing up to study dietary salt intake and cardiovascular disease (CVD) in the Eastern Caribbean so I've become quite familiar of late with the ongoing debates on the issue. As Jaime said, we know dietary salt restriction lowers BP. This is on a population level. On an individual level, it's a bit more complicated as the effect is really only seen in salt-sensitive people. Unfortunately, at this time, determining whether or not an individual is salt sensitive is complicated and not generally applicable. But, yes, on a population level, the data are pretty convincing that if a population consumes less salt, its average BP will drop. Where it gets complicated is over the question of whether this translates into improved CVD outcomes. I won't get into the details but would recommend a few recent papers (of which there have been many) that delve into it:
http://www.ncbi.nlm.nih.gov/pubmed/23124030
http://www.ncbi.nlm.nih.gov/pubmed/22639013
Very briefly, the question that, I beileve, still remains unresolved (due to differences in methodologies in sodium measurement/estimation, type of study, populations studied, etc)
is whether getting all populations' dietary sodium intake down to the level currently recommended by WHO (1.5gms/day; http://www.who.int/nutrition/publications/guidelines/sodium_intake/en/index.html) actually translates into CVD benefit or if it actually confers increased CVD risk- the paradoxical or J-curve relationship- as suggested by a few recent studies.

But, I wanted to weigh in on this fascinating article that Sunny shared at the beginning of this thread. Thanks, Ankit, for the great summary of the article and the evidence on the topic. It's fairly well established that increasing dietary potassium intake and lower sodium to potassium ratio confers CVD benefits, especially decreased stroke risk. WHO just released its new potassium intake guidelines (http://www.who.int/nutrition/publications/guidelines/potassium_intake/en/inde...) at the same time as the sodium guidelines linked to above. A few hypotheses as to why potassium might do this: 1. that high potassium diets are associated with overall healthier diets (http://www.ncbi.nlm.nih.gov/pubmed/19211830); 2. that potassium has a BP-lowering effect (http://www.ncbi.nlm.nih.gov/pubmed/9168293); and 3. that potassium serves as a modifier between sodium and CVD (http://www.ncbi.nlm.nih.gov/pubmed/16772638).
Potassium chloride tastes a lot like sodium chloride- this is why salt substitutes are largely made of potassium chloride.
So, my question is this: If potassium and sodium have opposite effects on CVD risk, why would we (or at least mice, as described in this article) have evolved to have taste-aversive responses to both that work via the same mechanism? Figure 4 illustrates how, as the authors gave wild type mice increasing amounts of potassium chloride, they licked less and less. Knock out both genes and they kept licking. For sodium chloride, the wild types seemed to enjoy more until a certain level, beyond which they licked less. Knock out the same 2 genes and they just kept on licking. So, from an evolutionary perspective, this doesn't make sense to me. Does anyone have any thoughts?

-Jeremy

Clare Farrand
Replied at 6:15 AM, 20 Feb 2013

Hello everyone.

I run the World Action on Salt and Health Group (WASH) under the leadership of Professor Graham Macgregor - an expert on salt. His research work has focused on the mechanisms underlying the rise in blood pressure in hypertension, the importance of the renin-angiotensin system, and the influence of salt and potassium intake on health.

WASH was set up, with the ambitious aim to improve the health of all populations around the world by reducing salt intake. I was particularly interested to read this paper, and the comments from members ,and in doing so to learn more about your intervention, Jaimie. - We do not have much experience in reducing salt intakes in developing countries, where most of the salt added is during cooking, from condiments, sauces, etc and at the table. I would be very interested to hear more - and welcome you to become a WASH member, and also anyone who also supports salt reduction - this does not require anything but to support salt reduction, and we will keep you updated with our activities. Joseph Lunyera we would certainly like to offer our support to you - we have recently developed some materials in reducing salt intakes in LMICs.

Salt Awareness Week fast approaches - 11th-17th March - please let me know if you would like more info.

I agree with Jaimie, let's move that curve to the left, for everybody!

Kind regards,
Clare

Steven van de Vijver
Replied at 6:39 AM, 20 Feb 2013

Hi everyone,

As high salt intake is the main risk factor for CVD in the slums of Nairobi
we have tried to implement an population intervention with salt substitutes
(high potassium, low sodium). Unfortunately it was difficult and relatively
expensive to have the salt imported on an acceptable price (including taxes
etc) as in some countries like Kenya the local produced salt from the sea
have a monopoly so we adjusted the intervention.

Indeed not many population studies on salt reduction/substitution in LMIC
have been published. Personally I found the studies in Ghana
http://www.ncbi.nlm.nih.gov/pubmed/16433927 and China
http://www.ncbi.nlm.nih.gov/pubmed/17885542 interesting, the last study
also published on the limited impact of taste
http://www.ncbi.nlm.nih.gov/pubmed/18710605

Regards, Steven

--
APHRC Campus
Kirawa Road, off Peponi Road
P.O. Box 10787-00100
Nairobi, Kenya

JOSEPH LUNYERA
Replied at 4:36 PM, 22 Feb 2013

Hello team.

Thank you for the great work!

Clare Farrand, thanks for your response. As I mentioned earlier, we are
launching the Uganda Kidney foundation on World Kidney day (WKD), March
14th, 2013 here in Kampala. In preparation for this, we have been holding
weekly meetings on Fridays. Today I shared with the organising committee
for the WKD celebrations your willingness to be of help to us. They noted
that your materials on salt reduction would be of great help to us in
passing our message to the community here in Kampala. We will be screening
participants for high blood pressure, diabetes, and kidney disease on that
day. Your materials will certainly fit in perfectly with our objectives. My
e-mail address is . Please send me your contact so
that I can send you our program for the WKD celebrations in Kampala..

Thanks.

Ankit Patel
Replied at 12:15 PM, 23 Feb 2013

Hello All,

Thank you for all your responses. Great to see some wonderful discussion
on this forum.

Sandeep K., the question regarding a "tongue-specific" form of amiloride is
a good one. I have yet to hear of any such forms. There are aerosolized
form of amiloride that have been used to try to limit amiloride in the
lungs for patients with Cystic Fibrosis (ENaC is thought to play a key role
in pathogenesis of CF) as well as aersolized forms of Camostat mestilate
which is thought to prevent activation of ENaC. Maybe be we can use
modulators of ENaC with less harmful effects to attenuate the response to
salt taste. In response to your second question, you might be better
suited to judge how fast a reset of the set point between
aversive/attractive salt taste based on your interest in evolutionary
biology. It seems to me that there is a certain degree of this that has
occurred on the populational level in different parts of the world (there
are particular groups in Tibet and others that are known to have high-salt
diets) but also believe this could occur on an individual level with
increased (or decreased) salt intake. This can be modulated over the
course of hours.

Joseph, I commend you on your efforts in Uganda. I hope you will be able
to make your announcement on March 14th. There maybe some opportunities
for collaboration for you with the National Kidney Foundation that runs a
program called KEEP (Kidney Early Evaluation Program). Is this the program
that you will be running in Uganda? KEEP has a well kept database of all
of the CKD screenings they have conducted. I'm currently using the database
to help develop a predictive model for CKD progression to ESRD. There are
also a set of KEEP biostatisticians that could be helpful in answering any
questions you wish to ask with the data you collect. Also, Li-Li Hsiao has
developed a really well run program at Harvard called KDSAP. Her program
has developed some informational material for patients that are being
screened and an infrastructure to use the CKD screenings as mentored
educational experience for medical students, undergraduates, and even high
school students. The ASN hopes to adopt the program and generate funding
for different centers to develop their own KDSAP affiliate site. This will
hopefully be announced soon.

Sandeep S., Other than NuSalt (a combination of NaCl and KCl) i'm not aware
of any other good salt substitutes. It seems mustard oil may have the
opposite effect we are looking for by inhibiting the aversive pathway for
salt intake. But as alluded by Jeremy, It's unclear why KCl can produce
some salty taste as ENaC has a high selectivity for Na over K.

Katherine, thank you for your comments. You are right, not everyone is
salt-sensitive and there are certain people whose blood pressures do not
right with increases in sodium intake. However, it is found that increased
sodium intake can induce salt sensitivity thus it is hard to determine who
will be effected by reductions in salt intake. You make an interesting
point regarding genetics. There are number of genetic diseases re: ENaC,
Liddle's (ENaC hyperactivity) and PHA (reduced ENaC activity). I'm not
sure what effect these mutations have on salt taste in these patients. Are
Liddle's patients satiated with a small amount of sodium and do patients
with PHA have a higher salt intake because they require more sodium to
achieve a similar attractive response?

Jo, thanks for your comment. Your work on "liking of foods" is delves into
some more downstream processing of sensory neuroscience and would be a key
to understand in further informing policy implications that you are
interested. I hope there will be more work done on this realm and will be
good to keep an eye on.

Jaime, sounds like an interesting program you are initiating. I agree that
is important to apply the salt reduction to the whole community not just
hypertensives as Bibbins-Domingo's paper imply. Incorporating social
marketing campaign along with the lower salt intervention maybe a good way
to help increase the adherence to a low-salt diet. Wish you luck.

Slim, great point! There are other dietary modifications that have been
shown to reduce blood pressure. It is important to keep these in mind when
attempting intervention. Potassium seems to be a particularly important
way for which the mechanism is not entirely clear. Not that everything
revolves around garlic, but a recent article found that thiol reactive
compounds in garlic can inhibit ENaC and may serve as a mechanism for its
BP lowering effects.
http://www.ncbi.nlm.nih.gov/pubmed/?term=garlic+AND+ENaC

Jeremy, thanks for your thoughtful reply. I look forward to hearing about
your study. I agree there is some controversial data suggesting that
decreasing sodium intake is not always beneficial and that there is an
actual optimal sodium intake as suggested by the "J-shaped" curve. I will
be interesting to continue to follow the story and see what results. As you
mention, ideal sodium intake make just vary from population to population.
Also, individuals can develop salt-sensitivity later in life which is
thought to increase with sodium intake. If validated, it may again suggest
for more global measures in sodium restriction.

Also, thank you for discussion on the effects of potassium. I have
recently started reading a little regarding the effects of dietary
potassium and found it to be striking. Dietary potassium has been directly
shown to reduce stroke and CVD but not always found to have a decrease in
blood pressure. Interestingly, dietary potassium was shown early on to not
change total body sodium suggesting it doesn't have an effect on blood
pressure via blood volume. As stated in a paper you cited, the kidneys are
able to do a great job of excreting excess potassium but not necessarily
conserving potassium. Increases in [K+] are known to increase aldosterone
secretion, which in turns helps increase potassium secretion in the distal
nephron by absorbing sodium. Thus, pathophysiologically, one would think
excess potassium may have a detrimental effect on blood pressure. As you
mention, the beneficial effects of potassium still remain a mystery and are
suggested to potentially be through its effect on releasing of vasodilatory
substances in the vasculature. Increase investigations in this area would
be supremely helpful. The striking benefits of dietary potassium in early
studies makes me wonder what the impact of K-citrate supplementation may
have as an anti-hypertensive/anti-stroke/anti-CVD medication. The effects
of the DASH study have already shown some effects of increasing potassium
and citrate in the diet.

More specifically in regards to your question regarding taste perception of
KCl, I think KCl does seem to have a bit of a bitter taste compared to NaCl
and this paper may explain why. Evolutionarily, we may have developed the
attractive salt taste to be exclusively dependent on Na (ENaC has over a
100 fold selectivity for Na over K) since during the hunter gather period
of our evolution, increase sodium was necessary to help maintain
homeostasis while potassium was abundant in the diet. The evolution of our
taste has not kept up with the evolution of our diets. I presume we
developed the taste aversive mechanisms to both as to not overwhelm the
body's capacity to excrete either sodium or potassium or other cations and
maintain homeostasis. Interestingly, the aversive response seems to be
triggered around 300 mM when the osmolarity is approaching blood
osmolarity. This maybe a mechanism also to help prevent dehydration.
Therefore the aversive mechanism could be thought to be non-specific to
maintain hydration while the attractive mechanism was sodium specific since
sodium was generally deficient in the diets of primitive man.

Clare, thank you for your contribution and informing us on your work. It
is great to hear from experts in the field and the efforts being put in
place. I most certainly would be interested in hearing more about Salt
Awareness Week. My contact is .

Steven, thank you for sharing your experience. It seems that in Ghana, the
effect salt reduction did show a community-wide decrease in BP. I wish you
luck garnering support to carry out your intervention in Nairobi.

Thank you all for your comments. They were greatly appreciated.

Cheers,
Ankit
--
Ankit B. Patel

Tri-Institutional MD-PhD Program
Weill Cornell/Rockefeller/Sloan-Kettering
1230 York Avenue, Box 218
New York, NY 10065

Phone #: (845)709-4976
Email:

JOSEPH LUNYERA
Replied at 8:06 PM, 27 Feb 2013

Thank you Ankit Patel.
Our screening program for March 14th is not under the KEEP program. We
decided to do screening as part of our activities for the day (World Kidney
Day). Besides we hardly have local data on Kidney disease from this part of
the world, save a few, as yet, unpublished studies done just recently; so
we thought this could be a good beginning. We are still working on the
capture form for the screening, and our focus, as I mentioned earlier, is
on DM (RBS), HTN (Bp) and urinalysis for kidney disease. Any comments? You
could also share with us some of your screening materials, or from KEEP. We
intend to do more future screenings, when we make our announcement on March
14th. We would highly welcome opportunities for collaboration with the KEEP
& KDSAP programs. I will be the contact person for our program. Here is my
email: .

Cheers!

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