Role of Endogenous Endothelin in the Extension of Myocardial Infarct Size Studied with the Endothelin Receptor Antagonist, TAK-044

1995 ◽  
Vol 26 ◽  
pp. S365-368
Author(s):  
Masatoyo Kojima ◽  
Keiji Kusumoto ◽  
Shuji Fujiwara ◽  
Toshifumi Watanabe ◽  
Masahiko Fujino
Keyword(s):  
Infarct Size ◽  
Receptor Antagonist ◽  
Myocardial Infarct ◽  
Endothelin Receptor Antagonist ◽  
Myocardial Infarct Size ◽  
Endothelin Receptor

scholarly journals An Endothelin Receptor Antagonist, TAK- 044, Limits the Extension of Myocardial Infarct Size in Rats.

1994 ◽  
Vol 64 ◽  
pp. 261
Author(s):  
Toshifumi Watanabe ◽  
Yumiko Awane ◽  
Shota Ikeda ◽  
Shuji Fujiwara ◽  
Mitsuhiro Wakimasu ◽  
...  
Keyword(s):  
Infarct Size ◽  
Receptor Antagonist ◽  
Myocardial Infarct ◽  
Endothelin Receptor Antagonist ◽  
Myocardial Infarct Size ◽  
Endothelin Receptor

Role of kinins in chronic heart failure and in the therapeutic effect of ACE inhibitors in kininogen-deficient rats

2000 ◽  
Vol 278 (2) ◽  
pp. H507-H514 ◽  
Author(s):  
Yun-He Liu ◽  
Xiao-Ping Yang ◽  
Dharmesh Mehta ◽  
Manohar Bulagannawar ◽  
Gloria M. Scicli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Infarct Size ◽  
Receptor Antagonist ◽  
Cardiac Remodeling ◽  
Myocardial Infarct ◽  
Brown Norway ◽  
Myocardial Infarct Size ◽  
Normal Cardiac Function

Using Brown Norway Katholiek (BNK) rats, which are deficient in kininogen (kinin precursor) due to a mutation in the kininogen gene, we examined the role of endogenous kinins in 1) normal cardiac function; 2) myocardial infarction (MI) caused by coronary artery ligation; 3) cardiac remodeling in the development of heart failure (HF) after MI; and 4) the cardioprotective effect of angiotensin-converting enzyme inhibitors (ACEI) on HF after MI. Two months after MI, rats were randomly treated with vehicle or the ACEI ramipril for 2 mo. Brown Norway rats (BN), which have normal kininogen, were used as controls. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), end-diastolic pressure (EDP), and ejection fraction (EF) as well as myocardial infarct size (IS), interstitial collagen fraction (ICF), cardiomyocyte cross-sectional area (MCA), and oxygen diffusion distance (ODD) were measured. We found that 1) cardiac hemodynamics, function, and histology were the same in sham-ligated BN and BNK rats; 2) IS was similar in BN and BNK; 3) in rats with HF treated with vehicle, the decrease in LVEF and the increase in LVEDV, LVESV, LVEDP, ICF, MCA, and ODD did not differ between BNK and BN; and 4) ACEI increased EF, decreased LVEDV and LVESV, and improved cardiac remodeling in BN-HF rats, and these effects were partially blocked by the bradykinin B2 receptor antagonist icatibant (HOE-140). In BNK-HF rats, ACEI failed to produce these beneficial cardiac effects. We concluded that in rats, lack of kinins does not influence regulation of normal cardiac function, myocardial infarct size, or development of HF; however, kinins appear to play an important role in the cardioprotective effect of ACEI, since 1) this effect was significantly diminished in kininogen-deficient rats and 2) it was blocked by a B2 kinin receptor antagonist in BN rats.

scholarly journals Investigating the role of GSK3beta kinase as a molecular target for myocardial infarct size reduction by using novel pharmacological inhibitors

2013 ◽  
Vol 34 (suppl 1) ◽  
pp. 777-777
Author(s):  
I. Andreadou ◽  
A. Lazari ◽  
S. I. Bibli ◽  
N. Gaboriaud-Kolar ◽  
A. L. Skaltsounis ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Molecular Target ◽  
Size Reduction ◽  
Myocardial Infarct Size ◽  
Infarct Size Reduction

Abstract 2894: Essential Role of ERK 1/2 in Sildenafil-Induced Early and Delayed Cardioprotection in Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Anindita das ◽  
Lei Xi ◽  
Fadi N Salloum ◽  
Yuan J Rao ◽  
Rakesh C Kukreja
Keyword(s):  
South Carolina ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Heart Association ◽  
Myocardial Infarct Size ◽  
Western Blots ◽  
Delayed Cardioprotection

Background: Sildenafil (SIL), a potent inhibitor of phosphodiesterase-5 induces powerful protection against myocardial ischemia-reperfusion (I-R) injury through activation of protein kinase G (PKG). However, the downstream targets of PKG in SIL-induced cardioprotection remain unclear. We hypothesized that PKG-dependent activation of survival kinase, ERK may play a critical role in SIL-induced cardioprotection in mice. Methods & Results: Ventricular myocytes were isolated from adult male ICR mice and exposed to 40 min of simulated ischemia (SI) with/without 1 hr pre-incubation of SIL (1 μM). Myocyte necrosis and apoptosis were determined after 1 hr or 18 hrs of reoxygenation (RO) using trypan blue or TUNEL assay, respectively. Pretreatment with SIL protected cardiomyocytes after SI-RO (necrosis 18.5±0.5% and apoptosis 6.6±0.7%; n=4, p<0.001) as compared with controls (necrosis 42.1±1.8% and apoptosis 23.3±0.9%). Co-incubation of PD98059 (20 μM), a selective ERK1/2 inhibitor blocked both anti-necrotic and anti-apoptotic protection in cardiomyocytes. Furthermore, intra-coronary infusion of SIL (1 μM) in Langendorff isolated mouse hearts 10 min prior to zero-flow global I (20 min) and R (30 min) significantly reduced myocardial infarct size (from 29.4±2.4% to 16.0±3.0%; p<0.05, n=6). Co-treatment of PD98059 abrogated SIL-induced protection (33.0±5.9; n=4). To evaluate the role of ERK1/2 in delayed cardioprotection, mice were treated with saline or SIL (0.7 mg/kg i.p.) 24 hours before global I-R in Langendorff mode. PD98059 (1 mg/kg) was administered (i.p.) 30 min before the treatment of SIL. Infarct size was reduced from 27.6±3.3% in saline-treated controls to 6.9±1.2% in SIL-treated mice (P<0.05, n=6). The delayed protective effect of SIL was also abolished by PD98059 (22.5±2.3%). Western Blots revealed that SIL significantly increased phosphorylation of ERK1/2 which was blocked by PKG inhibitor, KT5823 in the heart and adult myocytes. Selective knockdown of PKG in cardiomyocytes with short hairpin RNA of PKG also blocked the phosphorylation of ERK1/2. Conclusion: SIL-induced cardioprotection involves the activation and phosphorylation of ERK which appear to be intimately linked with a PKG-dependent survival pathway. This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).

Abstract 1568: Loss of Ischemic Postconditioning in the Mouse Hearts Lacking Adenosine A 1 or Bradykinin B 2 Receptors

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Lei Xi ◽  
Anindita Das ◽  
Zhi-Qing Zhao ◽  
Vanessa F Merino ◽  
Michael Bader ◽  
...  
Keyword(s):  
Infarct Size ◽  
G Protein ◽  
Contractile Function ◽  
Gene Knockout ◽  
Myocardial Infarct ◽  
Membrane Receptors ◽  
Ischemic Postconditioning ◽  
Myocardial Infarct Size ◽  
G Protein Coupled

Background: Ischemic postconditioning (PostC) is a recently described cardioprotective modality against reperfusion injury, through a series of brief episodes of reperfusion/ischemia at the very onset of reperfusion. It has been well recognized that PostC can activate cellular signaling cascade, in which the role of G protein-coupled membrane receptors serving as upstream triggers of PostC remains to be established. Hence the goal of this study was to determine a definitive role of adenosine A 1 receptors (A1) and bradykinin B 1 or B 2 receptors (B1 or B2) in PostC, using gene knockout (KO) mice. Methods & Results: The hearts isolated from adult male C57BL/6J wild-type mice (C57-WT) or A1, B1, or B2 KO mice (n=7–9 per group) were subjected to 20 min of zero-flow global ischemia and 30 min of reperfusion with or without PostC in a Langendorff isolated, buffer-perfused heart model. PostC, consisted of 6 cycles of 10 sec of reperfusion and 10 sec of ischemia, significantly reduced myocardial infarct size (22.8±3.1%, Mean±SEM) as compared with C57-WT controls (35.1±2.8%, P<0.05). As shown in Figure below, the infarct-limiting protection of PostC was absent in A1-KO (34.9±2.7%) or B2-KO (33.3±1.7%) and was partially attenuated in B1-KO (25.6±2.9%) mice, as compared with the corresponding non-PostC controls under same genetic background (P>0.05). However, cardiac contractile function and coronary flow at the end of reperfusion were not significantly altered by PostC. Conclusion: PostC-induced infarct size reduction in globally ischemic mouse hearts is triggered by activation of multiple G protein-coupled membrane receptors, which include A1, B2, and, to a lesser extent, B1 receptors.

Myocardial temperature in acute myocardial infarction: protection with mild regional hypothermia

1997 ◽  
Vol 273 (1) ◽  
pp. H220-H227 ◽  
Author(s):  
S. L. Hale ◽  
R. A. Kloner
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Control Group ◽  
Myocardial Infarct Size ◽  
Local Cooling ◽  
Risk Zone ◽  
Myocardial Temperature

This study tests the hypothesis that a 2-4 degrees C reduction in myocardial temperature, obtained by using topical regional hypothermia (TRH), reduces infarct size. Anesthetized rabbits received coronary artery occlusion and reperfusion. We cooled hearts in the TRH group by applying an ice bag directly over the risk zone; the control group received no intervention. Risk zone myocardial temperature (MT) in the TRH group was reduced at occlusion by 2 degrees C from baseline and after 5 min of occlusion by 3.6 degrees C. In the control group, MT in the risk region remained within 0.3 degree C of baseline. The ischemic area was similar in both groups, yet infarct size in the TRH group was reduced by an average of 65% compared with the control group. Infarct size closely correlated with MT in the risk region at the time of occlusion. In a second protocol in which all hearts were paced, infarct size was 21% of the risk region in TRH hearts compared with 44% in controls. These results strongly support the important role of MT in the progression of necrosis and demonstrate that the application of local cooling to the risk region profoundly reduces myocardial infarct size.

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