Beneficial Effects of Long-Term Use of the Antioxidant Probucol in Heart Failure in the Rat

Abstract

Background — Congestive heart failure (CHF) is a disease that is characterized by progressive left ventricular (LV) dysfunction and dilatation. Oxidative stress is thought to contribute to the progression of CHF, and antioxidants have been shown to have beneficial effects when started early after myocardial infarction (MI). In this study, we tested whether the powerful antioxidant probucol would attenuate progression of CHF once it was established after MI in the rat. Methods and Results — Ligation of a coronary artery was used to create an MI in rats (n=266). Survivors were then randomized 20 days after MI to either probucol 61 mg · kg −1 · d −1 or vehicle and followed up for a total of 100 days after MI. Studies of cardiac hemodynamics, LV remodeling, cardiac apoptosis and morphology, systemic neurohumoral activation, oxidative stress, and renal function were then evaluated. Probucol improved LV function (LV maximum rate of pressure rise from 3103 to 4250 mm Hg/s, P <0.05, and LV end-diastolic pressure decrease from 28 to 24 mm Hg, P <0.05), reduced pulmonary weights, prevented right ventricular systolic hypertension, and preserved renal function compared with vehicle. Probucol also prevented LV dilatation, prevented wall thinning (1.70 versus 1.42 mm, P <0.05), reduced cardiac fibrosis and cardiac apoptosis, attenuated increased myocardial cell cross-sectional area, and increased scar thickness. Conclusions — In chronic CHF, probucol exerts multiple beneficial morphological effects that result in better LV remodeling and function, reduced neurohumoral activation, and preserved renal function.