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Received for publication April 7, 2004.
Revised June 22, 2004.
Accepted for publication June 22, 2004.
Increased production of reactive oxygen and nitrogen species has recently been implicated in the pathogenesis of cardiac and endothelial dysfunction associated with atherosclerosis, hypertension and aging. Oxidant induced cell injury triggers the activation of nuclear enzyme poly(ADP-ribose) polymerase (PARP), which in turn contributes to cardiac and vascular dysfunction in various pathophysiological conditions including diabetes, reperfusion injury, circulatory shock and aging. Here we investigated the effect of a new PARP inhibitor, INO-1001, on cardiac and endothelial dysfunction associated with advanced aging using Millar's new Aria pressure-volume conductance system and isolated aortic rings. Young adult(3 months old) and aging (24 months old) Fisher rats were treated for 2 months with vehicle or the potent PARP inhibitor INO-1001. In the vehicle-treated aging animals there was a marked reduction of both systolic and diastolic cardiac function and loss of endothelial relaxant responsiveness of aortic rings to acetylcholine. Treatment with INO-1001 remarkably improved cardiac performance in aging animals and also ACh-induced, nitric oxide-mediated vascular relaxation. Thus, pharmacological inhibition of PARP may represent a novel approach to improve cardiac and vascular dysfunction associated with aging.
Key words:
aging, contractility, diastolic dysfunction, endothelial dysfunction, poly(ADP-ribose) polymerase, systolic dysfunction
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