Nitroxyl-releasing drugs promise to revive failing hearts

Half a million Americans are diagnosed each year with heart failure, a progressively debilitating condition characterized by the heart's declining ability to pump blood efficiently. The condition causes about 50,000 deaths annually and accounts for 1 million hospitalizations – more than for all forms of cancer combined.

Since the 1980s, nitroglycerin and other medications that release nitric oxide (NO) into the bloodstream have been the usual approach to treating this condition. Though these drugs benefit the ailing heart by improving its ability to relax, they also have a negative flipside: they leave the heart with a diminished capacity for pumping.

Hoping to improve on that formula, researchers at The Johns Hopkins University have developed a new class of NO-based compounds called nitroxyl (HNO) precursors that produce HNO. In early studies, these compounds seem to play a role in protecting the cardiovascular system from further damage during heart failure and in restoring function to organs affected by the debilitating condition. Scientists will announce their results in late August at the American Chemical Society's annual summer meeting, held this year in Philadelphia.

"Our results are preliminary, but very promising," said John P. Toscano, professor in the Chemistry Department in the Krieger School of Arts and Sciences at Johns Hopkins. "Our goal is not only to develop new classes of nitroxyl precursors, but also to figure out the mechanisms by which they seem to affect heart function. This has the potential to lead to alternative treatments for cardiac failure in humans. But we are still in the very early testing stage."

Toscano's research partner, Nazareno Paolocci, assistant professor in the Department of Cardiology at The Johns Hopkins School of Medicine, administered normal, conscious dogs and those with heart failure with a compound called Angeli's salt, which generates HNO. It turned out that this treatment doubled the dogs' hearts' ability to pump and enhanced their ability to relax between contractions -- a promising development.

"Our previous work in collaboration with Dr. David A Kass (of Johns Hopkins) and Dr. David A Wink (of the National Cancer Institute) has shown that nitroxyl donors appear to be very good candidates to treat failing hearts that are characterized by pressure overload, poor contractile function and delayed relaxation. Moreover, these compounds can be successfully combined with other drugs used in heart failure patients, namely, beta-blockers," Paolocci said.

Essentially all physiological studies probing the effects of nitroxyl have used Angeli's salt as a donor of that substance, prompting Toscano's team to set to work to develop new sources. New nitroxyl donors not only would confirm that the physiological effects seen with Angeli's salt are truly due to HNO, but they also would help researchers determine if the rate of HNO release had any effect on the resulting physiological response.

"One of the main reactions of nitroxyl is dimerization – that is, the reaction of one HNO molecule with another – which is dependent on the local concentration," Toscano said. "So, compounds that release HNO at faster rates generate higher initial concentrations of it and therefore may result in HNO being consumed by the dimerization reaction, rather than being available to elicit the desired physiologic response."

So far, Toscano's team has cultivated one class of compounds based on the reaction of certain secondary amines with nitric oxide to form compounds called diazeniumdiolates, which traditionally are NO donors, but have been turned into HNO donors by Toscano's team.

Paolocci and his team have tested two of these derivatives – one a pure HNO donor, which behaves similarly to Angeli's salt and one a pure NO donor, which behaves analogously to standard NO donors – on dogs to assess their cardiovascular action.

"We're very optimistic with what we have seen so far," Toscano said. "This looks promising. We know that NO is an important biological molecule, and we are just beginning to learn that HNO may, in potentially very different ways, be just as important."

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