Dr. Calvert and Dr. Lefer's Study Concludes That Exercise Protects the Heart Via Nitric Oxide

May 2011

For years doctors haven't known exactly how exercise appeared to benefit the heart by protecting it from injury after a heart attack. "Exercise protects against myocardial ischemia reperfusion injury via stimulation of beta3-adrenergic receptors and increased nitric oxide signaling: Role of nitrite and nitrosothiols," published in Circulation Research, is making significant impact due to its new evidence that the heart's ability to store the nitric oxide generated during exercise appears to be an essential component to protecting the heart after a heart attack. Dr. John Calvert is the study's first author and Dr. David Lefer the senior author. Collaborators included scientists at University of Colorado, Boulder, and Johns Hopkins University.

"Our study provides new evidence that nitric oxide generated during physical exercise is actually stored in the bloodstream and heart in the form of nitrite and nitrosothiols. These more stable nitric oxide intermediates appear to be critical for the cardioprotection against a subsequent heart attack," Dr. Lefer says.

Nitric oxide, a short-lived gas generated within the body, turns on chemical pathways that relax blood vessels to increase blood flow and activate survival pathways. The study found that both the chemical nitrite and nitrosothiols, nitric oxide attached to proteins via sulfur, appear to act as convertible reservoirs for nitric oxide in critical situations such as a lack of blood flow or oxygen.

In experiments with mice, the researchers showed that four weeks of being able to run on a wheel protected the mice from having a blocked coronary artery; the amount of heart muscle damaged by the blockage was less after the exercise period. Importantly, the mice were still protected a week after the wheel was taken away.

The researchers found that voluntary exercise boosted endothelial nitric oxide synthase (eNOS, an enzyme that produces nitric oxide). Moreover, the levels of eNOS in heart tissue, and nitrite and nitrosothiols in the blood as well as heart tissue, stayed high for a week after exercise ceased unlike other heart enzymes stimulated by exercise. However, the study found that the protective effects of exercise did not extend beyond four weeks after exercise ended, when nitrite and nitrosothiols in the heart returned to baseline.

Another molecule that appears to be important  for the benefits of exercise is the beta-3-adrenergic receptor, which allows cells to respond to the hormones epinephrine and norepinephrine. All of the beneficial effects of voluntary exercise were lost in mice that were deficient in this receptor. One of the effects of stimulating the receptor appears to be activating eNOS. Additional animal studies are currently underway in Dr. Lefer's lab to determine the potential benefit of beta-3-adrenergic receptor activating drugs following a heart attack.

The research was supported by the American Diabetes Association, the National Institutes of Health and the Carlyle Fraser Heart Center at Emory University Hospital Midtown.

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