Nitric Oxide-like Drug Could Revive A Failing Heart

The 5 million or so heart failure patients in this country traditionally have been treated with nitroglycerin or other drugs that release nitric oxide into the bloodstream. While these medicines increase the heart's ability to contract, they also blunt chemical signals allowing the heart to fully relax and pump most effectively.

Now, animal research directed by Johns Hopkins researchers suggests that a chemical relative of nitric oxide could better restore normal function to failing hearts.

Studying normal dogs and those with heart failure, researchers gave the animals an infusion of the compound Angelis' salt, which generates a form of nitric oxide called nitroxyl anion. Nitroxyl anion is closely related to nitric oxide, but with an extra electron, or negative charge. This small change doubled the hearts' ability to contract, enhanced their ability to relax and stimulated the release of calcitonin gene-related peptide (CGRP), a native protein that dilates blood vessels. A report on the work is published in the April 15 issue of the Proceedings of the National Academy of Sciences.

"This is a truly novel pathway for stabilizing a failing heart," says David A. Kass, M.D., senior author of the study and professor of medicine and biomedical engineering at Johns Hopkins. "In our study, a single infusion produced a substantial improvement in both the contraction and relaxation components of heart function — and this was particularly notable in failing hearts. There did not appear to be any toxicity associated with these effects. This could prove to be a useful alternative to traditional nitric oxide treatments that only enhance part of the pumping cycle."

Heart failure, which prevents the heart from pumping enough blood to the body, strikes an estimated 550,000 Americans each year. Heart attack, high blood pressure and heart valve disease all contribute to the condition. Although the failing heart keeps working, people with the condition become increasingly short of breath and tired, even with minimal exertion.

Kass and colleagues studied 11 dogs with heart failure and nine without, comparing the effects of nitroxyl anion, nitric oxide and nitroglycerin on the heart.

Nitroxyl anion worked well in both failing and normal hearts. Furthermore, it greatly enhanced the influence of dobutamine, another stimulator of heart function. When combined with nitroglycerin, dobutamine's effects are stifled, but added to nitroxyl anion the effectiveness is doubled. Nitroxyl anion also increased calcitonin gene-related peptide by 100 percent in healthy animals, and nearly 200 percent in heart failure dogs, supporting a proposed role of this compound to assist the failing heart. Neither nitric oxide nor nitroglycerin affected CGRP.

The research was supported by the American Heart Association, the University of Tokyo and the National Institutes of Health.

Study co-authors were Nazareno Paolocci, Tatsuo Katori, Hunter C. Champion and Marcus E. St. John of Johns Hopkins; Katrina M. Miranda and David A. Wink of the National Cancer Institute; and Jon M. Fukoto of the University of California-Los Angeles.

Paolocci, N. et al, "Positive Inotropic and Lusitropic Effects of HNO/NO- in Failing Hearts: Independence from Beta-Adrenergic Signaling," Proceedings of the National Academy of Sciences, April 15, 2003; Vol. 100.