Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cells’ ability to open blood’s floodgates hinges on unexpected factors

08.01.2004


New insights may help brain scientists, diabetic patients, many others



A mystery of basic cell metabolism that has persisted for a century has come a major step closer to giving up its secrets.

Teams of scientists at Washington University School of Medicine in St. Louis have identified a mechanism that triggers increased blood flow to brain cells actively engaged in work. The findings appear in two papers in the Jan. 13 issue of the Proceedings of the National Academy of Sciences (PNAS) and are available online.


The researchers are hoping to apply the new insights to improve understanding of basic brain function and limit side effects of diabetes, but the new insights could have much wider ramifications.

"One can pick out any number of diseases where knowing how increased blood flow in the brain is activated will be very important and useful," says Marcus E. Raichle, M.D., professor of radiology, neurology and of anatomy and neurobiology. "Changes in blood circulation in the brain are linked, for example, to Alzheimer’s disease as well as stroke."

Scientists have known since the late 1800s that when a muscle cell contracts repeatedly or a nerve cell increases its activity, the circulatory system responds by increasing blood flow to the activated cells. They assumed this happens so the blood can supply the cells with more sugar and oxygen as fuel for the increased workload.

Over the past decade, a growing body of evidence has suggested that this idea, logical as it seems, is incorrect. The new Washington University studies, one conducted in animals and the other in humans, give scientists a sense for how blood flow increases in the context of cellular exertion. Why blood flow increases still remains elusive, but knowing how the increase is triggered will provide vital aid to answering that question.

Raichle, who led the human study in PNAS, also directed a 1988 study that found increased brain activity increased blood flow much more than brain cells’ consumption of oxygen. Later Washington University studies confirmed the surprising finding that the reason for increased blood flow wasn’t to bring in additional sugar or oxygen.

Joseph Williamson, M.D., a retired Washington University pathologist, read Raichle’s 1988 study and was intrigued. Williamson, lead investigator for the other Washington University study appearing in PNAS, specializes in the effects of diabetes. In addition to elevating sugar levels throughout the body, diabetes also increases blood flow and can cause damage to nerves, retinas and kidneys.

Williamson was struck by a similarity between working muscle cells and cells of diabetic patients in regions likely to be damaged by the disease: both experienced increases in the ratio of two forms of a key energy-producing compound, nicotinamide adenine dinucleotide (NAD).

"Because of its role as the major carrier of electrons and protons from fuels for energy metabolism, NAD is strategically positioned -- even uniquely positioned -- to coordinate blood flow with energy metabolism in the resting cell, in the working cell and in disease states like diabetes and hypoxia," Williamson says.

When in use as a carrier of electrons and protons, NAD is converted to NADH (NAD plus H, or one atom of hydrogen). Williamson thought the ratio between these two forms of the compound (NADH/NAD) might be modulating blood flow.

Two other compounds involved in energy production, pyruvate and lactate, can affects cells’ ratio of NADH to NAD. Williamson thought it might be possible to use this connection to test his theory. With colleagues at Washington University, he demonstrated in a 2001 rat study that blood flow to working skeletal muscle increased even more than normal after lactate injections, which increase the NADH/NAD ratio. Injections of pyruvate, which decrease the ratio, had the opposite effect. They also found the same results in brain regions that process sensory information from rat whiskers.

In the new paper, the same effects were detected in the rat retina and visual region of the brain during optical stimulation. Williamson and his co-authors have also revealed that the increased NADH/NAD ratio activates a signaling pathway that promotes the creation of nitric oxide, a compound widely recognized for its ability to dilate blood vessels.

"This was the evidence that Marc Raichle’s group needed to go ahead and look for this same effect in humans," Williamson says. "They needed some proof that the principle might be applicable to the visual region of the brain in humans, and they found that it is."

For the human research, seven subjects were studied using PET imaging scans. Participants were either asked to close their eyes during the scans or to fix their gaze on an unmoving central crosshair in an animated visual display.

Andrei Vlassenko, M.D., Ph.D., research associate in radiological sciences and an author of the human study, notes that without lactate injections, the blood flow increase to the visual cortex during the visual task was 19 percent. After lactate injections, it was 26 percent.

"That might not seem like a lot if you look strictly at the gain, but if you look at the gain as a percentage of original level of increase, that’s fully one-third more," Vlassenko says.

Mark A. Mintun, M.D., professor of radiology and psychiatry, was lead author of the human study. He points out that the mechanism under study isn’t the only way the brain controls blood flow. There are other mechanisms to respond to stress, hyperventilation, blood pressure alterations or other dramatic changes.

"What we’re doing is isolating the response in blood flow when the brain function itself changes and using that response as a window for investigating brain metabolism," Mintun explains.

Mintun, Raichle and Vlassenko already have a follow-up study using pyruvate injections underway.

Williamson is using the results of the studies to build his case for a new understanding of how diabetes causes damage to tissues. He believes the same signaling pathways activated by increased NADH/NAD ratios may also trigger the production of chemically reactive compounds that damage cells.


Ido Y, Chang K, Williamson JR. NADH augments blood flow in physiologically activated retina and visual cortex. Proceedings of the National Academy of Sciences, early online edition, Dec. 29, 2003.

Mintun MA, Vlassenko AG, Rundle MM, Raichle ME. Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain. Proceedings of the National Academy of Sciences, early online edition, Dec. 29, 2003.

Funding from the Kilo Foundation and the National Institutes of Health.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Michael C. Purdy | WUSTL
Further information:
http://mednews.wustl.edu/medadmin/PAnews.nsf/0/CC2D5DAAB382459486256E140052E567
http://medinfo.wustl.edu/

More articles from Health and Medicine:

nachricht Chronic stress induces fatal organ dysfunctions via a new neural circuit
21.08.2017 | Hokkaido University

nachricht New malaria analysis method reveals disease severity in minutes
14.08.2017 | University of British Columbia

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Nagoya physicists resolve long-standing mystery of structure-less transition

21.08.2017 | Materials Sciences

Chronic stress induces fatal organ dysfunctions via a new neural circuit

21.08.2017 | Health and Medicine

Scientists from the MSU studied new liquid-crystalline photochrom

21.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>