Improvement of Aging-Associated Cardiovascular Dysfunction by the Orally Administered Copper(II)-Aspirinate Complex

Abstract

Background:

Aging-associated nitro-oxidative stress causes tissue injury and activates proinflammatory pathways that play an important role in the pathogenesis of aging-associated cardiovascular dysfunction. It has been recently reported, that the copper(II)–aspirinate complex (CuAsp) exerts not only the well-known anti-inflammatory and platelet antiaggregating effects of aspirin, but, due to its superoxide dismutase mimetic activity, it acts as a potent antioxidant as well. In this study we investigated the effects of CuAsp on aging-associated myocardial and endothelial dysfunction.

Methods and Results:

Aging and young rats were treated for 3 weeks with vehicle, or with CuAsp (200 mg/kg per day per os). Left ventricular pressure–volume relations were measured by using a microtip pressure–volume conductance catheter, and indexes of contractility (e.g., slope of end-systolic pressure–volume relationships [ESPVR] [E_es], and dP/dt _max − end-diastolic volume [EDV]) were calculated. In organ bath experiments for isometric tension with isolated aortic rings, endothelium-dependent and -independent vasorelaxation were investigated by using acetylcholine and sodium nitroprusside. When compared to the young controls, aging rats showed impaired left ventricular contractility (E_es, 0.51 ± 0.04 vs. 2.16 ± 0.28 mmHg/μL; dP/dt _max − EDV, 10.71 ± 2.02 vs. 37.23 ± 4.18 mmHg/sec per μL; p < 0.05) and a marked endothelial dysfunction (maximal relaxation to acetylcholine: 66.66 ± 1.30 vs. 87.09 ± 1.35%; p < 0.05). Treatment with CuAsp resulted in reduced nitro-oxidative stress, improved cardiac function (E_es, 1.21 ± 0.17 vs. 0.51 ± 0.04 mmHg/μL; dP/dt _max − EDV, 23.40 ± 3.34 vs. 10.71 ± 2.02 mmHg/sec per μL; p < 0.05) and higher vasorelaxation to acetylcholine in aging animals (94.83 ± 0.73 vs. 66.66 ± 1.30%; p < 0.05). The treatment did not influence the cardiovascular functions of young rats.

Conclusions:

Our results demonstrate that oxidative stress and inflammatory pathways contribute to the pathogenesis of cardiovascular dysfunction in the aging organism, which can be reversed by CuAsp.