Additive Effect of TAK-491, a New Angiotensin Receptor Blocker, and Pioglitazone, in Reducing Myocardial Infarct Size

We assessed the effects of TAK-491 (a newly designed potent and selective ARB) alone and in combination with pioglitazone (PIO) on myocardial infarct size (IS). Rats received TAK-491 (0.3, 1, 3, or 10 mgkg(-1)d(-1)), PIO (1.0 or 2.5 mgkg(-1)d(-1)), or PIO 2.5 mgkg(-1)d(-1) with TAK-491 (1 or 3 mgkg(-1)d(-1)) for 4 days. On day 5 rats underwent 30-minute coronary artery occlusion and 4-hour reperfusion. Area at risk (AR) was assessed by blue dye and IS by TTC. Left ventricular (LV) dimensions and function was assessed by echocardiography 35 days after infarction. TAK (1.0-10 mgkg(-1)d(-1)), PIO (1.0 to 2.5 mgkg(-1)d(-1)), PIO2.5+TAK1.0, and PIO2.5+TAK3.0 significantly reduced IS. IS was the smallest in the TAK 10.0, followed by PIO+TAK 3.0. The protective effects of TAK and PIO were additive, as IS was smaller in the PIO2.5+TAK1.0 than in PIO 2.5 alone (p = 0.008) or TAK1.0 alone (p = 0.002); and in PIO2.5+TAK3.0 than in PIO alone (p < 0.001) or TAK3.0 alone (p < 0.001). TAK, PIO and their combination tended to attenuate LV remodeling and improved LV function 35 days after infarction; however, the differences among individual groups were not statistically significant. Both TAK-491 and PIO increased calcium-dependent nitric oxide synthase activity, whereas only PIO increased COX2 expression and activity. Both PIO and TAK-491 increased Akt, ERK 1/2 and eNOS phosphorylation and inhibited BAX activation. TAK-491 and PIO independently limited myocardial IS in a dose-dependent fashion; and the effects were additive. The mechanism of protection and the role of TAK-491 in this clinical setting should be further investigated.