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, or 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
Johns Hopkins have developed a new class of NO-based
compounds called nitroxyl precursors, which produce
nitroxyl. 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
announced their results at the American Chemical Society's
annual summer meeting, held recently 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. "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
Toscano's research partner, Nazareno Paolocci,
assistant professor in the
Department of Cardiology at the 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
"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 on dogs 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 — 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."