SB-211475, A METABOLITE OF CARVEDILOL, A NOVEL ANTIHYPERTENSIVE AGENT, IS A POTENT ANTIOXIDANT

The antioxidant effects of SB 211475, a metabolite of carvedilol, a novel antihypertensive agent, were studied and compared with carvedilol and other antioxidants such as U78517F, U74500A and probucol. SB 211475 inhibited Fe2+-vitamin C-initiated lipid peroxidation, assessed as thiobarbituric acid reactive substance, in brain homogenate with an IC50 of 0.28 mu M. Under the same conditions, the IC(50)s of probucol, carvedilol, U74500A and U78517F were 50, 8.1, 0.71 and 0.16 mu M, respectively. SB 211475 inhibited oxidation of human low density lipoprotein by mouse macrophages with an IC50 of 0.043 mu M. In the same model, the IC(50)s Of carvedilol, U78517F and probucol were 3.8, 0.15 and 0.80 mu M, respectively. SB 211475 protected cultured bovine pulmonary artery endothelial cells against hydroxyl radical-initiated lipid peroxidation (IC50 = 0.15 mu M) and cell damage (lactate dehydrogenase release, IC50 = 0.16 mu M), and promoted cell survival with an EC(50) of 0.13 mu M. SB 211475 also protected endothelial cells against xanthine/xanthine oxidase-initiated cytotoxicity and protected rat cerebellar neurons from hydroxyl radical-mediated cell death (EC(50) = 0.19 mu M). Moreover, SB 211475 inhibited superoxide (O-2(-)) release from human neutrophils stimulated by phorbol myristate acetate. These observations indicate that SB 211475 is a potent antioxidant and may potentially contribute to the therapeutic effects of carvedilol in vivo.