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For 60 years, scientists have puzzled over the possibility of a hepatic
osmoreceptor that influences blood pressure regulation. Now,
researchers of the Max Delbrück Center for Molecular Medicine (MDC)
Berlin-Buch, the Experimental and Clinical Research Center (ECRC)
of the MDC and Charité and the Hannover Medical School (MHH)
appear to have made a breakthrough discovery. Dr. Stefan Lechner
and Prof. Gary R. Lewin (both of MDC), Professor Friedrich C. Luft
(ECRC) and Professor Jens Jordan (ECRC; now MHH) have
discovered a new group of sensory neurons in the mouse liver
which mediates the regulation of blood pressure and metabolism.
This peripheral control center outside of the brain is triggered simply
by drinking water and leads to an elevation of blood pressure in sick
and elderly people. (Neuron, Vol. No. 69 (2) pp. 332-344).
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More than ten years ago Professor Jens Jordan, MD, then a research
fellow at Vanderbilt University in Nashville, Tennessee, observed a
phenomenon together with his colleagues, more or less by accident.
Later, at the former Franz Volhard Clinic of the Charité in Berlin-Buch,
Jens Jordan again observed that in patients with a damaged nervous
system, blood pressure readings rose by as much as 50 mm Hg if
the patients drank a half liter of water all at once. “In young people
whose sympathetic nervous system was stimulated by drugs, water
intake also caused blood pressure levels to rise,” said Professor
Friedrich C. Luft of the ECRC. “Even in healthy older people, water
drinking triggers a regulator for blood pressure.” The two clinicians
invited neuroscientists at MDC to collaborate with them and started
a joint research project.
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For 60 years researchers have suspected that there must also be a
control center for the body’s self-regulation located outside of the brain.
Motivated by findings of recent studies, the researchers in Berlin-Buch
therefore looked for sensory neurons specifically in organs peripheral
to the central nervous system that would detect body changes caused
by water intake and would thus be able to activate a regulator which
in old and sick people causes blood pressure to rise and which stimulates
metabolism in healthy young people.
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Pressor Reflex Triggered by Water Intake In humans, a pressor reflex is
triggered simply by drinking tap water. After passing through the esophagus
and stomach, the water is absorbed by the small intestine and is then swept
on towards the liver in portal vein blood. MDC-scientists and their clinical
partners have now found a new population of osmoreceptors in the liver,
which detect the slightest physiological shifts in blood osmolality, a specific
measure of the human water balance. If the osmolality decreases below its
set point, the osmoreceptors send an electrical signal. This signal triggers
an action potential, which in turn stimulates the hepatic vessels to raise
blood pressure. (Graphic: Dr. Stefan Lechner/ Copyright: MDC)
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“In this entire process, osmolality plays a key role,” explained Dr. Stefan
Lechner, a member of Professor Lewin’s research group. “It is the
measure of the body’s water balance. And it indicates how many
molecules are dissolved in a liter of fluid. Each species has a characteristic
set point for osmolality, which depends to a great extent on the immediate
living conditions. We wanted to know how deviations of osmolality are
able to activate a regulator.”
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The researchers observed in the mouse model that specific neurons in the
liver react actively to water intake. The water the mice drink is absorbed
in the small intestine and reaches the blood system via the liver. Due to
the sudden water intake, the osmolality in the blood vessels of the liver
falls under its set-point value. This deviation is registered by sensory neurons
in the liver, the so-called osmoreceptors, as the researchers could
now demonstrate. They found that the osmoreceptors transform the information
into an electrical signal, which in turn triggers a reflex and stimulates the
hepatic blood vessels to raise blood pressure.
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Ion Currents Help to Elucidate the Mechanisms
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To study the activation of the osmoreceptors under realistic physiological
conditions, the researchers stained this newly discovered group of
osmoreceptors in the liver with a dye. In their experiments they could
thus show that after drinking water, even the slightest shifts of osmolality
in the blood flowing through the liver activate nerve fibers in the liver and
cause ion currents to flow. The ion currents were similar to those that
can be measured in an ion channel located both in the central nervous
system and in the internal organs (heart, liver, kidney, testicles, pancreas).
This ion channel, abbreviated TRPV4, reacts very sensitively to changes
and functions quasi as an osmoreceptor.
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“The TRPV4 ion channel opens in just a few hundred milliseconds like the
lens of a camera, letting the electrical signal through and thus activating a
regulator,” explained Dr. Stefan Lechner. “We were now interested in
whether the TRPV4 ion channel is acting alone or whether it needs subunits
to aid it, and we wanted to know how the whole thing works mechanically.”
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In further experiments, to elucidate the role and function of TRPV4 in this
regulation process, the researchers studied mice in which the gene for the
TRPV4 ion channel had been inactivated. After giving these knockout mice
water to drink, they did not observe any activation of the osmoreceptors
in the liver. No ion currents flowed and as a consequence, no reflex was
triggered. The researchers concluded that the elevation of the blood
pressure due to water intake must be associated with the presence of the
TRPV4 ion channel.
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Consequences for therapy
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“We are now able to describe the characteristics of a completely new
group of hepatic osmoreceptors on the molecular level, which in humans
are possibly an extension of a very important regulating reflex,” said
Professor Lewin. “The research findings not only improve our understanding
of the physiological role of osmoreceptors in mediating blood pressure,
metabolism and osmolalic self-regulation, over the long term they could
also lead to new strategies in the treatment of diseases caused by the
absence of the gene encoding the TRPV4 channel protein.”
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“The effect of drinking water on blood pressure regulation is already
leading to therapeutic consequences in the daily routine of the hospital,”
Professor Jordan added. "We tell patients to drink water who, due to blood
pressure regulation disorders, suffer from fainting attacks when standing.
This alleviates the symptoms and at the same time we are able to reduce
the amount of medication. Healthy people can also suffer fainting attacks
when they stand for a long time or are otherwise under strain, e.g.
when they donate blood. In many cases these can be avoided by drinking
water. Our decade-long persistence in investigating osmolalic self-regulation
has really paid off!”
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Pressor Reflex Triggered by Water Intake In humans, a pressor reflex is
triggered simply by drinking tap water. After passing through the esophagus
and stomach, the water is absorbed by the small intestine and is then swept
on towards the liver in portal vein blood. MDC-scientists and their clinical
partners have now found a new population of osmoreceptors in the liver,
which detect the slightest physiological shifts in blood osmolality, a specific
measure of the human water balance. If the osmolality decreases below its
set point, the osmoreceptors send an electrical signal. This signal triggers
an action potential, which in turn stimulates the hepatic vessels to raise
blood pressure. (Graphic: Dr. Stefan Lechner/ Copyright: MDC)
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