Cardiovascular system holds a key to circadian clock

June 28, 2001

Blood pressure varies in all of us throughout the day. This pattern, circadian variability, is exaggerated in patients who have high blood pressure, suggesting that the mechanisms which control this rhythm are disturbed.

Indeed, this altered biorhythm seems to have clinical consequences. Heart attacks and strokes occur most commonly early in the morning when blood pressure is at its highest point in its 24 hour cycle. Scientists at the University of Pennsylvania School of Medicine have discovered another key to the body's circadian clock that may begin to explain these observations and lead to new treatments based on the body's timing mechanism.

Their discovery, which provides the first evidence for how hormones and vitamins can reset the human circadian clock, shows in detail how activation of vitamin A receptors can regulate the rhythm of the clock. This provides an important clue to how the master clock, which lies deep in the brain, can regulate distal organs, such as the liver, kidney and muscle by controlling clocks throughout the body.

The Penn study establishes that blood vessels contain their own peripheral circadian system, similar to clocks in other organs.

Also, significantly, it links hormonal and vitamin control for the first time to the circadian rhythms that control body temperature, sleep and wakefulness , pain sensitivity, and the response to drugs.

"We know that the responseto certain drugs used in the treatment of cancer vary substantially depending on the time of day that they are administered," said Garret FitzGerald, MD, chairman of Penn's Department of Pharmacology and author of the study. "However, this work elucidates a molecular mechanism which permits a refinement of such chronopharmacology. Resetting the clock might have obvious application in the treatment of jet lag, but could also combine with existing knowledge to adjust circadian variability in drug response to the needs of a particular patient."

The findings will be published June 29 in the Journal Cell.

"If one understands exactly which component needs to be regulated to reset the biological clock, one can target just that component with drugs" said Peter McNamara, Ph.D, who is the lead author with FitzGerald on the project. "Circadian oscillations may respond more directly to the environment. The central clock responds to changes in light intensity whereas in a vascular clock, this signal may be blood borne hormones or metabolic signals." McNamara was using a genetic screen to identify new proteins that interact with a retinoic acid receptor (the RXR receptor) when he found that it bound with MOP4 -- a protein very similar to one that had been previously identified as a switch for the brain's master clock (the protein CLOCK) and the clock protein's partner, BMAL1. He showed that MOP4 protein cycled in a circadian pattern and that the retinoic acid receptors, when bound with vitamin A, modulated the rhythm of the clock in blood vessels.

"In the particular case of the cardiovascular system " added FitzGerald, " clocks probably evolved to protect the blood supply to individual organs from large shifts in blood pressure, such as might be caused by the adrenaline rush of danger or exercise. We realized 20 years ago that this system was disturbed in people with high blood pressure. This work provides the first molecular opportunity to address this problem."
Also collaborating in the research were Sang-beom Seo, PhD, of Penn's Center for Experimental Therapeutics; Radu Daniel Rudic, PhD, of Penn's Department of Pharmocology; Amita Sehgal, PhD, of the Howard Hughes Medical Institute and the Department of Neuroscience at Penn, and Debabrata Chakravarti, PhD, also of the Department of Pharmacology.

The Study was funded by the National Institutes of Health.

Editor's note: Dr. FitzGerald may also be contacted directly at: 215-898-1184.
His email is:
Dr. McNamara may be reached at 215-898-0255.
His email is

University of Pennsylvania School of Medicine

Related Blood Pressure Articles from Brightsurf:

Children who take steroids at increased risk for diabetes, high blood pressure, blood clots
Children who take oral steroids to treat asthma or autoimmune diseases have an increased risk of diabetes, high blood pressure, and blood clots, according to Rutgers researchers.

High blood pressure treatment linked to less risk for drop in blood pressure upon standing
Treatment to lower blood pressure did not increase and may decrease the risk of extreme drops in blood pressure upon standing from a sitting position.

Changes in blood pressure control over 2 decades among US adults with high blood pressure
National survey data were used to examine how blood pressure control changed overall among U.S. adults with high blood pressure between 1999-2000 and 2017-2018 and by age, race, insurance type and access to health care.

Transient increase in blood pressure promotes some blood vessel growth
Blood vessels are the body's transportation system, carrying oxygen and nutrients to cells and whisking away waste.

Effect of reducing blood pressure medications on blood pressure control in older adults
Whether the amount of blood pressure medications taken by older adults could be reduced safely and without a significant change in short-term blood pressure control was the objective of this randomized clinical trial that included 534 adults 80 and older.

Brain blood flow sensor discovery could aid treatments for high blood pressure & dementia
A study led by researchers at UCL has discovered the mechanism that allows the brain to monitor its own blood supply, a finding in rats which may help to find new treatments for human conditions including hypertension (high blood pressure) and dementia.

Here's something that will raise your blood pressure
The apelin receptor (APJ) has been presumed to play an important role in the contraction of blood vessels involved in blood pressure regulation.

New strategy for treating high blood pressure
The key to treating blood pressure might lie in people who are 'resistant' to developing high blood pressure even when they eat high salt diets, shows new research published today in Experimental Physiology.

Arm cuff blood pressure measurements may fall short for predicting heart disease risk in some people with resistant high blood pressure
A measurement of central blood pressure in people with difficult-to-treat high blood pressure could help reduce risk of heart disease better than traditional arm cuff readings for some patients, according to preliminary research presented at the American Heart Association's Hypertension 2019 Scientific Sessions.

Heating pads may lower blood pressure in people with high blood pressure when lying down
In people with supine hypertension due to autonomic failure, a condition that increases blood pressure when lying down, overnight heat therapy significantly decreased systolic blood pressure compared to a placebo.

Read More: Blood Pressure News and Blood Pressure Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to