Fight-or-flight hormone suspected in diseases

Everyone is pretty familiar with adrenaline and the fight-or-flight response. It's that rush you get when the roller coaster drops for the first time, and what helps you scribble down that last proof on the midterm with two minutes to spare.

However, long-term elevation of these aptly-named stress hormones can have many negative effects. In fact, norepinephrine, a compound closely related to adrenaline, might be an underlying cause of conditions as seemingly dissimilar as glaucoma and asthma.

A paper published Sept. 9 by a former doctorate student at Hopkins theorizes that constantly elevated levels of norepinephrine put people at risk for diabetes mellitus, open-angle glaucoma, osteoarthritis, rheumatoid arthritis and asthma.

"Having too much norepinephrine places people in an elevated fight-or-flight mode, wherein the body is not devoting sufficient resources to the rest and digest homeostatic processes. I believe this makes people vulnerable to developing a broad range of diseases," Paul Fitzgerald, who authored the paper, said.

These five diseases have at least two things in common; drugs used to treat them often interfere with norepinephrine signaling, and they often develop in people with pre-existing conditions that are also related to high norepinephrine levels.

For example, osteoarthritis and rheumatoid arthritis are associated with elevated stress, bipolar disorder, increased body weight and hypertension, which in turn are related to elevated norepinephrine levels.

Some studies have shown that arthritis patients who take norepinephrine-lowering antidepressants experience reduced pain.

Asthma rates are also higher in those with bipolar disorder and who are overweight. Drugs that interfere with norepinephrine signaling have been shown to reduce the symptoms of asthama.

One component of the fight-or-flight response is to suppress insulin. Insulin tells cells to remove glucose from the blood and store it, but during an emergency, sugar is broken down and released into the blood for muscles to use. Diabetes is characterized by low insulin levels and high blood sugar.

Studies with mice have shown that when norepinephrine is prevented from interacting with pancreatic cells, mice are resistant to developing diabetes.

Conversely, elevated norepinephrine suppressed insulin production in isolated pancreatic cells. In humans with diabetes, evidence exists that antidepressants which raise norepinephrine levels cause decreased insulin sensitivity.

Additionally, bipolar disorder, obesity and hypertension all involve higher levels of norepinephrine, and people with one of these three conditions are also more likely to develop diabetes.

Another condition that Fitzgerald believes is affected by norepinephrine is glaucoma, which causes blindness through irreversible damage to the optic nerve and is the second leading cause of blindness worldwide.

Drugs that lower norepinephrine levels have been shown in mice to lower fluid pressure in the eye, one of the main risk factors for glaucoma. Two drugs effective in treating glaucoma act by interfering with norepinephrine. A correlation has also been found between glaucoma and elevated stress levels.

Much work remains to be done. Norepinephrine initiates a cell response by binding to receptor proteins on the cell's surface, but the unique chemical reactions and signaling pathways that occur inside the cell as a result of norepinephrine have not been determined for these diseases.

Further research might uncover links between norepinephrine and other diseases, including Parkinson's, Alzheimer's and even some cancers.

"What I'd really like to have happen is that some clinical epidemiologists examine the effects of norepinephrine weakening drugs, such as clonidine and propranolol, on the prevalence of these diseases," Fitzgerald said.

"My belief is that blocking norepinephrine transmission should help prevent or treat a broad range of diseases."

Fitzgerald received a Ph.D. degree in neuroscience from Hopkins and is now doing postdoctoral work at the National Institutes of Health in Washington D.C. He has previously studied the possibility of using noradrenaline to treat for mental illnesses, and the correlation between noradrenaline and certain types of cancer.

The paper was published in Autonomic and Autocoid Pharmacology.