Differing cardioprotective efficacy of the Na+/Ca2+ exchanger inhibitors SEA0400 and KB-R7943

2003 ◽  
Vol 284 (3) ◽  
pp. H903-H910 ◽  
Author(s):  
William P. Magee ◽  
Gayatri Deshmukh ◽  
Michael P. Deninno ◽  
Jill C. Sutt ◽  
Justin G. Chapman ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Recovery Of Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Negative Effects ◽  
Artery Ligation ◽  
Regional Ischemia ◽  
Developed Pressure ◽  
Postischemic Recovery

KB-R7943 and SEA0400 are Na+/Ca2+ exchanger (NCX) inhibitors with differing potency and selectivity. The cardioprotective efficacy of these NCX inhibitors was examined in isolated rabbit hearts (Langendorff perfused) subjected to regional ischemia (coronary artery ligation) and reperfusion. KB-R7943 and SEA0400 elicited concentration-dependent reductions in infarct size (SEA0400 EC50: 5.7 nM). SEA0400 was more efficacious than KB-R7943 (reduction in infarct size at 1 μM: SEA0400, 75%; KB-R7943, 40%). Treatment with either inhibitor yielded similar reductions in infarct size whether administered before or after regional ischemia. SEA0400 (1 μM) improved postischemic recovery of function (±dP/d t), whereas KB-R7943 impaired cardiac function at ≥1 μM. At 5–20 μM, KBR-7943 elicited rapid and profound depressions of heart rate, left ventricular developed pressure, and ±dP/d t. Thus the ability of KB-R7943 to provide cardioprotection is modest and limited by negative effects on cardiac function, whereas the more selective NCX inhibitor SEA0400 elicits marked reductions in myocardial ischemic injury and improved ±dP/d t. NCX inhibition represents an attractive approach for achieving clinical cardioprotection.

Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart

2013 ◽  
Vol 305 (4) ◽  
pp. H542-H550 ◽  
Author(s):  
Toshihiro Shinbo ◽  
Kenichi Kokubo ◽  
Yuri Sato ◽  
Shintaro Hagiri ◽  
Ryuji Hataishi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Left Ventricular ◽  
Hydrogen Gas ◽  
Coronary Artery Ligation

Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H2 is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H2 (2%), or NO + H2, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H2 alone. NO inhalation plus H2 reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H2 with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H2. In conclusion, breathing NO + H2 during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H2 gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.

Abstract 402: Vitamin C Deficiency Impairs Cardiac Function and Post-infarction Survival in the Mouse

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Adolfo G Mauro ◽  
Donatas Kraskauskas ◽  
Bassem M Mohammed ◽  
Bernard J Fisher ◽  
Eleonora Mezzaroma ◽  
...  
Keyword(s):  
Vitamin C ◽  
Cardiac Function ◽  
Diastolic Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Additional Group ◽  
Gulonolactone Oxidase ◽  
Low Levels ◽  
Systolic And Diastolic Function

Introduction: L-gulonolactone oxidase (Gulo) is the rate limiting enzyme for Vitamin C (VitC) biosynthesis. Humans rely on dietary VitC for collagen synthesis, extracellular matrix formation, and tissue regeneration. VitC deficiency is an unrecognized condition and its role in cardiac homeostasis and post-acute myocardial infarction (AMI) remodeling is unknown. Hypothesis: Low levels of VitC impair cardiac function and tissue repair following AMI. Methods: Adult male Gulo -/- knockout mice (C57BL6 background, N=8) and control C57BL (N=8), which are able to synthesize VitC were used. VitC deficiency was maintained supplying low levels of VitC (30mg/l) to Gulo -/- mice in drinking water. Mice underwent M-mode and Doppler echocardiography to measure left ventricular (LV) diameters and wall thicknesses, fractional shortening (FS), E and A waves, E/A ratio, isovolumetric relaxation time (IRT) and myocardial performance index (MPI). Experimental AMI was induced by coronary artery ligation for 7 days. An additional group of Gulo -/- were mice supplemented with physiological levels of VitC (330 mg/l) and underwent AMI. Results: VitC deficient Gulo -/- mice exhibited significantly reduced LV wall thicknesses, reduced FS, and impaired diastolic function, measured as significantly reduced E/A ratio and longer IRT (Panel A, B & C). Following AMI, 100% (8/8) of deficient Gulo -/- mice died within 5 days. Supplementation with physiological levels of VitC significantly improved survival after AMI (Panel D). Conclusion: VitC deficiency impairs systolic and diastolic function. Moreover, VitC is critical for the post-AMI survival.

Sustained preconditioning induced by cardiac transgenesis with the tetracycline transactivator

2006 ◽  
Vol 290 (3) ◽  
pp. H1103-H1109 ◽  
Author(s):  
Lynne Turnbull ◽  
Hui-Zhong Zhou ◽  
Philip M. Swigart ◽  
Sally Turcato ◽  
Joel S. Karliner ◽  
...  
Keyword(s):  
Recovery Of Function ◽  
Ischemic Injury ◽  
Left Ventricular ◽  
Temporal Window ◽  
New Therapies ◽  
Tetracycline Transactivator ◽  
Tet System ◽  
Developed Pressure ◽  
Regulated Gene Expression ◽  
Postischemic Recovery

Preconditioning protocols that protect the heart from ischemic injury may aid in the development of new therapies. However, the temporal window of cardioprotection is limited to a few days after the preconditioning stimulus. Here we report a sustained cardioprotected phenotype in mice expressing a tetracycline transactivator (tTA) transcription factor under the control of the α-myosin heavy chain (αMHC) promoter. αMHC-tTA mice were originally designed for tetracycline-regulated gene expression in the heart (Tet system). However, we found that after 45 min of global ischemia at 37°C, left ventricular developed pressure (LVDP) of Langendorff-perfused αMHC-tTA mouse hearts rapidly recovered in 5 min to 60% of initial levels, whereas LVDP of wild-type (WT) littermates recovered to only 10% of the initial level. Improved postischemic recovery of function for αMHC-tTA hearts was associated with a 50% decrease of infarct size and a significantly smaller release of lactate dehydrogenase to the coronary effluent. Improved postischemic recovery was not attributable to differences in coronary flow that was similar for WT- and αMHC-tTA hearts during recovery. Moreover, improved postischemic recovery of αMHC-tTA hearts was not abolished by inhibitors of classical cardioprotective effectors (mitochondrial ATP-sensitive K+ channels, PKC, or adenosine receptors), suggesting a novel mechanism. Finally, the tetracycline analog doxycycline, which inhibits binding of tTA to DNA, did not abolish improved recovery for αMHC-tTA hearts. The sustained cardioprotected phenotype of αMHC-tTA hearts may have implications for developing new therapies to minimize cardiac ischemic injury. Furthermore, investigations of cardioprotection using the Tet system may be aberrantly influenced by sustained preconditioning induced by cardiac transgenesis with tTA.

scholarly journals Cardiac surgery in acute myocardial infarction: crystalloid versus blood cardioplegia – an experimental study

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Andreas Boening ◽  
Maximilian Hinke ◽  
Martina Heep ◽  
Kerstin Boengler ◽  
Bernd Niemann ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Cardiac Surgery ◽  
Cardiac Function ◽  
Infarct Size ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Cardioplegic Arrest ◽  
Blood Cardioplegia ◽  
Cardioplegia Solution

Abstract Background Because hearts in acute myocardial infarction are often prone to ischemia-reperfusion damage during cardiac surgery, we investigated the influence of intracellular crystalloid cardioplegia solution (CCP) and extracellular blood cardioplegia solution (BCP) on cardiac function, metabolism, and infarct size in a rat heart model of myocardial infarction. Methods Following euthanasia, the hearts of 50 rats were quickly excised, cannulated, and inserted into a blood-perfused isolated heart apparatus. A regional myocardial infarction was created in the infarction group (18 hearts) for 120 min; the control group (32 hearts) was not subjected to infarction. In each group, either Buckberg BCP or Bretschneider CCP was administered for an aortic clamping time of 90 min. Functional parameters were recorded during reperfusion: coronary blood flow, left ventricular developed pressure (LVDP) and contractility (dp/dt max). Infarct size was determined by planimetry. The results were compared between the groups using analysis of variance or parametric tests, as appropriate. Results Cardiac function after acute myocardial infarction, 90 min of cardioplegic arrest, and 90 min of reperfusion was better preserved with Buckberg BCP than with Bretschneider CCP relative to baseline (BL) values (LVDP 54 ± 11% vs. 9 ± 2.9% [p = 0.0062]; dp/dt max. 73 ± 11% vs. 23 ± 2.7% [p = 0.0001]), whereas coronary flow was similarly impaired (BCP 55 ± 15%, CCP 63 ± 17% [p = 0.99]). The infarct in BCP-treated hearts was smaller (25% of myocardium) and limited to the area of coronary artery ligation, whereas in CCP hearts the infarct was larger (48% of myocardium; p = 0.029) and myocardial necrosis was distributed unevenly to the left ventricular wall. Conclusions In a rat model of acute myocardial infarction followed by cardioplegic arrest, application of BCP leads to better myocardial recovery than CCP.

Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

2005 ◽  
Vol 288 (5) ◽  
pp. H2491-H2497 ◽  
Author(s):  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Cardiac Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mineralocorticoid Receptors ◽  
Artery Ligation ◽  
Sympathetic Hyperactivity ◽  
Air Jet ◽  
Baroreflex Function ◽  
Adrenoceptor Agonist ◽  
The Brain

In rats post-myocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors (MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via Na+ channels, presumably epithelial Na+ channels (ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post-MI, we examined effects of blockade of MR and Na+ channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 ng·kg−1·h−1) or its vehicle, or with benzamil (4 μg·kg−1·h−1) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air-jet stress, intracerebroventricular injection of the α2-adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats (∼31%). In rats treated post-MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain Na+ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction.

Abstract 162: c-fos Protects the Myocardium from Ischemic Injury and Improves Cardiac Function

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Xiangru Lu ◽  
Ming Lei ◽  
Fuli Xiang ◽  
Qingping Feng
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemic Injury ◽  
Coronary Artery Ligation ◽  
Area At Risk ◽  
Artery Ligation ◽  
Protein Ratio ◽  
Myocardial Apoptosis ◽  
Bax Protein

Background: c-fos is an immediate early response gene. c-Fos proteins form heterodimers with Jun family proteins, and the resulting AP-1 complexes regulate transcription by binding to the AP-1 sequence found in many cellular genes. c-fos is activated in cardiomyocytes following myocardial infarction. However, the role of c-fos in regulating cardiomyocyte survival and cardiac function post myocardial infarction (MI) is not known. In the present study, we hypothesized that c-fos protects the myocardium from ischemic injury and improves cardiac function. Methods and Results: The generation of mice with cardiomyocyte specific c-fos −/ − was achieved by crossing the floxed c-fos mice with mice over-expressing Cre recombinase under the control of α-myosin heavy chain. Wild-type (WT) littermates were used as controls. MI was induced by coronary artery ligation. Infarct size, myocardial apoptosis and cardiac function were determined at 2 days post-MI. While area at risk was similar between the 2 groups, infarct size was significantly increased in c-fos −/ − compared to WT mice (58 ± 4% vs. 44 ± 3%, P< 0.05). Myocardial caspase-3 activity and cytosolic DNA fragments in the peri-infarct region were significantly increased while Bcl-2/Bax protein ratio was significantly decreased in c-fos −/− mice ( P< 0.05). LV pressure volume relationship was assessed in vivo using a Millar pressure conductance catheter. LV end-systolic elastance ( E es ) and +d P /dt max were significantly decreased in c-fos −/− compared to WT mice (1.7 ± 0.4 vs. 5.1 ± 1.0 mmHg/μL; 4776 ± 567 vs. 7006 ± 319 mmHg/s, P< 0.01). Conclusions: Deficiency in c-fos increases infarct size and myocardial apoptosis leading to impaired cardiac function post-MI. Our results suggest that c-fos protects the myocardium from ischemic injury and improves cardiac function.

scholarly journals Anti-CCL21 Antibody Attenuates Infarct Size and Improves Cardiac Remodeling After Myocardial Infarction

2015 ◽  
Vol 37 (3) ◽  
pp. 979-990 ◽  
Author(s):  
Yi Jiang ◽  
Jianwen Bai ◽  
Lunxian Tang ◽  
Pei Zhang ◽  
Jun Pu
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Cardiac Remodeling ◽  
Immune Cell ◽  
Serum Levels ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cell Recruitment ◽  
Immune Cell Recruitment

Background/Aims: Over-activation of cellular inflammatory effectors adversely affects myocardial function after acute myocardial infarction (AMI). The CC-chemokine CCL21 is, via its receptor CCR7, one of the key regulators of inflammation and immune cell recruitment, participates in various inflammatory disorders, including cardiovascular ones. This study explored the therapeutic effect of an anti-CCL21 antibody in cardiac remodeling after myocardial infarction. Methods and Results: An animal model of AMI generated by left anterior descending coronary artery ligation in C57BL/6 mice resulted in higher levels of circulating CCL21 and cardiac CCR7. Neutralization of CCL21 by intravenous injection of anti-CCL21 monoclonal antibody reduced infarct size after AMI, decreased serum levels of neutrophil and monocyte chemo attractants post AMI, diminished neutrophil and macrophage recruitment in infarcted myocardium, and suppressed MMP-9 and total collagen content in myocardium. Anti-CCL21 treatment also limited cardiac enlargement and improved left ventricular function. Conclusions: Our study indicated that CCL21 was involved in cardiac remodeling post infarction and anti-CCL21 strategies might be useful in the treatment of AMI.

Mesenchymal Stem Cell Injection After Myocardial Infarction Improves Myocardial Compliance

2007 ◽  
Author(s):  
Dennis Discher ◽  
Adam Engler
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cellular Therapy ◽  
Human Mesenchymal Stem Cells ◽  
Left Ventricular ◽  
Left Ventricular Geometry ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Functional Benefit ◽  
Myocardial Elasticity

Cellular therapy for myocardial injury has improved ventricular function in both animal and clinical studies, though the mechanism of benefit is unclear. This study was undertaken to examine the effects of cellular injection after infarction on myocardial elasticity. Coronary artery ligation of Lewis rats was followed by direct injection of human mesenchymal stem cells (MSC) into the acutely ischemic myocardium. Two weeks post-infarct, myocardial elasticity was mapped by atomic force microscopy. MSC-injected hearts near the infarct region were two-fold stiffer than myocardium from non-infarcted animals but softer than myocardium from vehicle-treated infarcted animals. After eight weeks, the following variables were evaluated: MSC engraftment and left ventricular geometry by histologic methods; cardiac function with a pressure-volume conductance catheter; myocardial fibrosis by Masson trichrome staining; vascularity by immunohistochemistry; and apoptosis by TUNEL assay. The human cells engrafted and expressed a cardiomyocyte protein but stopped short of full differentiation and did not stimulate significant angiogenesis. MSC-injected hearts showed significantly less fibrosis than controls, as well as less left ventricular dilation, reduced apoptosis, increased myocardial thickness, and preservation of systolic and diastolic cardiac function. In summary, MSC injection after myocardial infarction did not regenerate contracting cardiomyocytes but reduced the stiffness of the subsequent scar and attenuated post-infarction remodeling, preserving some cardiac function. Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty.

iASPP protects the heart from ischemia injury by inhibiting p53 expression and cardiomyocyte apoptosis

2020 ◽  
Author(s):  
Timur Yagudin ◽  
Yue Zhao ◽  
Haiyu Gao ◽  
Yang Zhang ◽  
Ying Yang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Cardiomyocyte Apoptosis ◽  
Coronary Artery Ligation ◽  
Novel Therapy ◽  
Artery Ligation ◽  
P53 Expression

Abstract Currently, there remains a great need to elucidate the molecular mechanism of acute myocardial infarction in order to facilitate the development of novel therapy. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is a member of the ASPP family proteins and an evolutionarily preserved inhibitor of p53 that is involved in many cellular processes, including apoptosis of cancer cells. The purpose of this study was to investigate the possible role of iASPP in acute myocardial infarction. The protein level of iASPP was markedly reduced in the ischemic hearts in vivo and hydrogen peroxide-exposed cardiomyocytes in vitro. Overexpression of iASPP reduced the infarct size and cardiomyocyte apoptosis of mice subjected to 24 h of coronary artery ligation. Echocardiography showed that cardiac function was improved as indicated by the increase in ejection fraction and fractional shortening. In contrast, knockdown of iASPP exacerbated cardiac injury as manifested by impaired cardiac function, increased infarct size, and apoptosis rate. Mechanistically, overexpression of iASPP inhibited, while knockdown of iASPP increased the expressions of p53 and Bax, the key regulators of apoptosis. Taken together, our results suggested that iASPP is an important regulator of cardiomyocyte apoptosis, which represents a potential target in the therapy of myocardial infarction.

Abstract 2673: Myoblast Transplantation Improves Cardiac Function Whether the Cells are Implanted Early or Late After Coronary Ligation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Patrick Farahmand ◽  
Richard D Weisel ◽  
Philippe Menasche ◽  
Ren-Ke Li
Keyword(s):  
Cardiac Function ◽  
Left Ventricular ◽  
Border Zone ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Matrix Remodeling ◽  
Stroke Work ◽  
Artery Ligation ◽  
Skeletal Myoblasts ◽  
Myoblast Transplantation

Background: The inability of skeletal myoblasts to transdifferentiate into cardiomyocytes supports the hypothesis that their beneficial effects on cardiac function after a myocardial infarction (MI) are mediated by paracrine effects. In order to explore the role of the timing of cell therapy on the resultant angiogenesis and matrix remodeling, we compared the effects of myoblast transplantation early or late after MI. Methods: MI was generated in Lewis rats by coronary artery ligation. Skeletal myoblasts (5X10 6 ) or control media were injected into the scar and border zone either 5 days (early; n=33) or 30 days (late; n=29) after ligation. Function was assessed by echocardiography before transplantation (Tx), and 14 and 30 days thereafter. Invasive hemodynamics were measured with a Millar catheter at 30 days after Tx, following which explanted hearts were processed to assess LV volumes (computerized planimetry), fibrillar collagen (confocal microscopy), and myoblast engraftment, angiogenesis and extra-cellular matrix characteristics (immunohistochemistry). Results: Load-independent indices of left ventricular (LV) function (Emax, preload recruitable stroke work) were significantly increased in myoblast recipients compared with controls regardless of whether cells were implanted early (p=0.003, p=0.03, respectively) or late (p=0.003, p=0.0007, respectively) after MI. Changes in fractional shortening (by echocardiography) followed a similar pattern. These changes were associated with a significant reduction in LV volume (p=0.04, p=0.01 for early and late Tx groups vs. controls, respectively), and an increase in angiogenesis (p=0.02) whether the myoblasts were injected early or late after MI. The length and width of collagen fibers both in the scar and remote myocardium were also significantly increased (p<0.001) regardless of the timing of myoblast injection. Conclusions: The data suggest that myoblast transplantation improved cardiac function whether cells were injected early or late after MI. In each case, functional recovery was associated with enhanced angiogenesis, favourable effects on extracellular matrix remodeling, and improved LV geometry, supporting the paracrine hypothesis for myoblast transplantation.

Sign in / Sign up

Export Citation Format

Share Document