Additive effect of TAK-491, a new angiotensin receptor blocker, and pioglitazone, in reducing myocardial infarct size.
OBJECTIVE
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Ye
Yumei
Y
The Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
Keyes
Kyle T
KT
Zhang
Chong F
CF
Perez-Polo
Jose R
JR
Lin
Yu
Y
Birnbaum
Yochai
Y
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000502:physiology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004359:Drug Therapy, Combination; D006339:Heart Rate / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; C494828:Bax protein, rat; D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D045162:Thiazolidinediones; D051028:bcl-2-Associated X Protein; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D000077205:Pioglitazone