Nitric oxide may be the key to why specific drugs for heart failure or asthma lose their effectiveness over time

A naturally occurring molecule in the body appears to control whether certain medications, such as beta adrenergic receptor agonists used in acute heart failure or in inhalers for asthma, lose their effectiveness over time.

Nitric oxide is a molecule produced by the body that controls many functions, including the contraction or dilation of blood vessels.

New experiments conducted by Duke University Medical Center and Howard Hughes Medical Institute researchers have shown that specialized forms of nitric oxide called SNOs may be the key to a problem that has stumped physicians for years -- why specific drugs for such diseases as heart failure or asthma lose their effectiveness over time.

Almost half of all drugs on the market today, as well as many hormone and neurotransmitters, target a specific family of cell surface receptors known as G-protein coupled receptors. The researchers believe that the presence or absence of nitric oxide or SNOs determines whether these receptors continue to function properly. This action is controlled by the ability of nitric oxide to inhibit a key regulatory system which ordinarily shuts the receptors off after they are stimulated

The researchers reported their latest findings on Friday, May 4, in the journal Cell.

"This work is significant in that it demonstrates how two of the most pervasive physiological systems -- G-protein coupled receptors and nitric oxide -- come together to influence one another," said Erin Whalen, Ph.D., who spent six years focusing on the link between the two biological systems. Whalen is a postdoctoral fellow in the laboratory of Robert Lefkowitz, M.D., a Howard Hughes Medical Institute investigator at Duke who first cloned these receptors in 1986. The link was cemented through a collaboration with Matt Foster, a post-doctoral fellow in the laboratory of Jonathan Stamler M.D.

G-protein coupled receptors reside on the cell surface where they interact with all manner of stimuli, including circulating factors such as adrenaline, as well such diverse sensory signals as odorants and light. The activation of these receptors leads to the propagation of intracellular signals. Once activated the receptors are quickly turned-off by an enzyme called a G protein-coupled receptor kinase. This process is called desensitization and can limit the effectiveness of many drugs, such as opiates for pain and adrenaline for asthma, and is further associated with numerous diseases including those of the cardiovascular and pulmonary systems. If activated for a long period of time the receptors are carried into the cell and are "turned off."

In animal, cellular and biochemical experiments, the researchers found that a lack of nitric oxide leads to a decrease in beta adrenergic receptor number and function. Also, the researchers found that when SNO compounds were administered to mice they could prevent the receptors from being "turned off" by the drugs.

The researchers said these findings, if confirmed in humans, open up new avenues for the development of non-desensitizing drugs not only for heart failure and asthma but also for other conditions such as pain and high blood pressure.

"We demonstrated that when one of the systems goes awry, so does the other," said Stamler, whose laboratory has made many fundamental discoveries about the role of nitric oxide in human biology, including the discovery of SNOs' ubiquitous role in human health and disease. "When nitric oxide function is impaired by disease, therapeutic agents like beta-agonists in asthma and adrenergic stimulants in heart failure will work less well. The key now is to determine how best to manipulate these ubiquitous receptors, together with nitric oxide for the treatment of human diseases."

"In broad terms, the results of these experiments present a novel role for nitric oxide in regulating the activity of G-protein coupled receptors," Lefkowitz said. "Also, the findings point to the possibility that deficiencies in the activity of nitric oxide, which occurs in common disorders such as high blood pressure, diabetes, atherosclerosis, cystic fibrosis and neurodegenerative conditions, as well as in aging, may interfere with the G-protein coupled receptor signaling."

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