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

Yumei Ye, Kyle T. Keyes, Chong F. Zhang, Jose R. Perez-Polo, Yu Lin, Yochai Birnbaum

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Purpose: 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 -1d-1), PIO (1.0 or 2.5 mgkg-1d-1), or PIO 2.5 mgkg-1d-1 with TAK-491 (1 or 3 mgkg -1d-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-1d-1), PIO (1.0 to 2.5 mgkg-1d -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.

Original languageEnglish (US)
Pages (from-to)107-120
Number of pages14
JournalCardiovascular Drugs and Therapy
Volume24
Issue number2
DOIs
StatePublished - Apr 2010

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pioglitazone
Angiotensin Receptor Antagonists
Myocardial Infarction
Left Ventricular Function
azilsartan medoxomil
Infarction

Keywords

  • Angiotensin receptor blocker
  • Infarct size
  • Ischemia-reperfusion injury
  • PPAR-Υ agonist

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Additive effect of TAK-491, a new angiotensin receptor blocker, and pioglitazone, in reducing myocardial infarct size. / Ye, Yumei; Keyes, Kyle T.; Zhang, Chong F.; Perez-Polo, Jose R.; Lin, Yu; Birnbaum, Yochai.

In: Cardiovascular Drugs and Therapy, Vol. 24, No. 2, 04.2010, p. 107-120.

Research output: Contribution to journalArticle

Ye, Yumei ; Keyes, Kyle T. ; Zhang, Chong F. ; Perez-Polo, Jose R. ; Lin, Yu ; Birnbaum, Yochai. / Additive effect of TAK-491, a new angiotensin receptor blocker, and pioglitazone, in reducing myocardial infarct size. In: Cardiovascular Drugs and Therapy. 2010 ; Vol. 24, No. 2. pp. 107-120.
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abstract = "Purpose: 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 -1d-1), PIO (1.0 or 2.5 mgkg-1d-1), or PIO 2.5 mgkg-1d-1 with TAK-491 (1 or 3 mgkg -1d-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-1d-1), PIO (1.0 to 2.5 mgkg-1d -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.",
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AU - Keyes, Kyle T.

AU - Zhang, Chong F.

AU - Perez-Polo, Jose R.

AU - Lin, Yu

AU - Birnbaum, Yochai

PY - 2010/4

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N2 - Purpose: 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 -1d-1), PIO (1.0 or 2.5 mgkg-1d-1), or PIO 2.5 mgkg-1d-1 with TAK-491 (1 or 3 mgkg -1d-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-1d-1), PIO (1.0 to 2.5 mgkg-1d -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.

AB - Purpose: 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 -1d-1), PIO (1.0 or 2.5 mgkg-1d-1), or PIO 2.5 mgkg-1d-1 with TAK-491 (1 or 3 mgkg -1d-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-1d-1), PIO (1.0 to 2.5 mgkg-1d -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.

KW - Angiotensin receptor blocker

KW - Infarct size

KW - Ischemia-reperfusion injury

KW - PPAR-Υ agonist

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