Abstract
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) Fischer 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 improved cardiac performance in aging animals and also acetylcholine-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.
Footnotes
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This work was supported by Grant 1R03 AG21206-01 from the National Institutes of Health.
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doi:10.1124/jpet.104.069658.
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ABBREVIATIONS: PARP, poly(ADP-ribose) polymerase; LV, left ventricle; LVSP, left ventricular systolic pressure; LVEDP, left ventricular end-diastolic pressure; MAP, mean arterial pressure; +dP/dt, maximal slope of systolic pressure increment; –dP/dt, maximal slope of diastolic decrement; EF, ejection fraction; SV, stroke volume; SW, stroke work; CI, cardiac index; SWI, SW index; TPRI, total peripheral resistance index; PRSW, preload recruitable SW; EDV, end-diastolic volume; PV, pressure volume; ESPVR, end-systolic pressure-volume relation; EDPVR, end-diastolic pressure-volume relation; A, aging; ACh, acetylcholine.
- Received April 7, 2004.
- Accepted June 22, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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