Blocking Breakdown of Norepinephrine Protects Against Heart Failure
By BiotechDaily International staff writers
Posted on 14 Jan 2010
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The breakdown of the neurohormone norepinephrine by the mitochondrial enzyme monoamine oxidase-A (MAO-A) results in production of hydrogen peroxide and other dangerous chemical species that accumulate in the nerves and the heart muscle.
Investigators at Johns Hopkins University (Baltimore, MD, USA) recently studied the role of MAO-A in the enlargement of the heart muscle (hypertrophy) and in heart failure.
They reported in the November 12, 2009, online edition of the journal Circulation Research that MAO-A activity was triggered in cell cultures of neonatal and adult myocytes on stimulation with norepinephrine, followed by increase in cell size, reactive oxygen species production, and signs of maladaptive hypertrophy. These changes were prevented by the specific MAO-A inhibitor clorgyline. Clorgyline is an antidepressant, which is no longer in use in humans due to side effects such as insomnia, agitation, and hypertension.
In mice with left ventricular dilation and pump failure attributable to pressure overload, norepinephrine catabolism by MAO-A was increased accompanied by exacerbated oxidative stress. MAO-A inhibition prevented these changes.
"Our study helps describe heart failure as a vicious chemical circle of stimulant norepinephrine overload and breakdown, and it offers a disease blueprint with monoamine oxidase-A as the target for drugs similar to clorgyline to rein in the disease," said senior author Dr. Nazareno Paolocci, assistant professor of cardiology at Johns Hopkins University. "When norepinephrine is not properly stored and released from the nerves directed to the heart, monoamine oxidase-A breaks it down, generating dangerous chemical species in the nerves and the heart muscle. These toxic free radicals produce the same deleterious effects on heart muscle size and pumping function long observed in heart failure."
"Now that we know clorgyline works, we can focus future drug testing on newer, safer MAO-A inhibitors, such as moclobemide, whose chemical bindings are reversible, unlike those of clorgyline," said Dr. Paolocci.
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