06 September 2016
Hypertension: releasing the pressure at its source
Researchers at the University of Bristol and Afferent
Pharmaceuticals (a wholly-owned subsidiary of Merck & Co.,
Inc., Kenilworth, NJ, USA) have identified a potential new way of
treating high blood pressure, or hypertension by targeting aberrant
nerve signals in the carotid bodies, which sit on the common
carotid arteries on each side of the neck.
The research study, entitled"Purinergic receptors in the carotid
body as a new drug target for controlling hypertension,"was led by
Julian Paton, professor of physiology at the University of Bristol,
and was published in the 5 September online edition ofNature
Medicine.
Instead of treating high blood pressure by targeting directly
the functions within end organs such as the heart, kidneys and
vasculature, this novel approach aims to reduce nervous system
activity from a sensory organ, the carotid body, that when
activated can cause blood pressure to rise
uncontrollably.
Such a treatment may offer superiority over existing
medications, principally by lowering blood pressure directly at a
common source. Beneficial outcomes may also extend to other
cardiometabolic disorders, such as heart failure and sleep apnoea,
in which the carotid bodies are known to be sensitized. In
preclinical models, researchers were able to block this carotid
body aberrant signaling activity with an investigational drug
candidate, MK-7624 (also known as AF-219), demonstrating a
significant reduction in blood pressure.
"With this research, we've validated P2X3 receptors as a novel
drug target for the treatment of cardiovascular disease by
demonstrating that blockade of these receptors with a selective
antagonist controls carotid body activity," said Dr Angus
Nightingale, a cardiology consultant who runs the specialist
hypertensive clinic at the Bristol Heart Institute and is a
co-author of the study.
"The question now is whether blocking these P2X3 receptors in
humans will lower elevated blood pressure, and how we can best
identify those patients with carotid body hyperactivity who are
most likely to respond to treatment."
"The carotid bodies lie at the bifurcation (fork) of the
common carotid artery on each side of the neck and are the body's
smallest organs, each about the size of a rice grain," said
Professor Paton, who co-led the research with Dr Anthony Ford,
founder and chief scientific officer of Afferent
Pharmaceuticals.
"These organs sense chemicals such as oxygen in the blood. When
oxygen levels fall, the carotid bodies become active and send
signals to the brain that trigger increases in breathing and blood
pressure."
The researchers collaborated to test whether MK-7624/AF-219, a
highly selective and potent orally available P2X3 receptor
antagonist, can stop this nervous activity from occurring, thereby
lowering blood pressure.
"In healthy individuals, the carotid bodies have very low levels
of activity," said Professor Paton. "We discovered that these tiny
organs become hyperactive in conditions of hypertension, generating
what we have called aberrant or tonic discharge, which is sent into
the brain regions controlling cardiovascular activity. In this way,
changes within the carotid body may be a cause of high blood
pressure and therefore represent a novel target for controlling
blood pressure."
Previous research by Professor Paton and collaborators,
published in The
Journal of the American College of Cardiology, showed that
removing one carotid body was effective in lowering blood pressure
in human patients with drug-resistant hypertension. The next step
was to find out why the carotid body can become hyperactive in
hypertension, and to develop a pharmacological approach to
normalise its activity.
To carry out this research, the team utilized an established
animal model of human hypertension. They discovered that the energy
molecule ATP (adenosine triphosphate), a recognized common
signaling nucleotide, was able to persistently activate the P2X3
receptor, and that this protein was upregulated by almost 5 fold in
the carotid body in hypertension. By blocking this receptor in the
carotid body with MK-7264/AF-219, blood pressure fell significantly
in hypertensive rats.
"Crucially, unlike carotid body removal, the drug did not render
the carotid body inoperable," said Professor Paton. "Instead, it
normalized its activity levels to those found in a normotensive
state. Think of it in terms of a domestic fire alarm - it switches
off after the smoke disappears, but the battery remains in place,
meaning it can still respond in an emergency."
"We have developed some unique tests to assess the activity
state of the carotid body in human hypertensive patients," said Dr.
Nightingale. "We are hoping to initiate a clinical trial to test
P2X3 receptor antagonism in hypertensive patients who exhibit
hyperactive carotid bodies in the near future."
High blood pressure is the world's leading contributor to
mortality. In the UK, its cost to the National Health Service is
around £2 billion per year, and it remains poorly controlled,
triggering heart and renal failure, and strokes. The World Health
Organization has identified high blood pressure as the single most
important risk factor for the global burden of disease and
death.
"This approach may be the first novel anti-hypertensive
treatment strategy in more than 15 years, and perhaps the first
directed at a root cause of excessive sympathetic discharge to
cardiovascular end-organs," said Professor Paton.
"This research was translational from molecule to medicine, and
reflects the critical importance of integrative physiology as a
subject. Our study was an inter-disciplinary team effort, and would
not have been possible without close working with colleagues from
the University of Bristol, University Hospital Trust Bristol, the
University of Sao Paulo, Brazil, the University of Auckland, New
Zealand, and Afferent Pharmaceuticals. Nor would it have been
possible without funding from The British Heart Foundation and
Afferent Pharmaceuticals."
Paper
'Purinergic receptors in the carotid body as a new drug target
for controlling hypertension' by Julian Paton et al in Nature
Medicine.
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