New approach to molsidomine active metabolites coming from the results of 2 models of experimental cardiology

2017 ◽  
Vol 95 (2) ◽  
pp. 111-121
Author(s):  
Michał Żorniak ◽  
Katarzyna A. Mitręga ◽  
Maurycy Porc ◽  
Tadeusz F. Krzemiński
Keyword(s):  
Ventricular Arrhythmias ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Antiarrhythmic Action ◽  
Hemodynamic Parameters ◽  
Active Metabolites ◽  
Pressure Derivative ◽  
Hypotensive Action ◽  
Invasive Cardiology

Molsidomine is a well-known vasodilatating, antianginal drug. Despite earlier studies with its metabolites (3-morpholino-syndnonimine (SIN-1) and N-nitroso-N-morpholino-amino-acetonitrile (SIN-1A)), which indicated a potential favorable cardioprotective activity, a lot of controversy remains. The aim of our research was to compare molsidomine, SIN-1, SIN-1A, and lidocaine influence on arrhythmias and hemodynamic parameters in 2 experimental models in rats. In the Langendorff heart study, SIN-1A markedly elevated left ventricular systolic pressure, maximum rise and fall of the first pressure derivative, coronary flow, and myocardial oxygen consumption. In addition, SIN-1A more so than SIN-1 significantly lowered creatine kinase release. The antiarrhythmic action of SIN-1 was observed, while lidocaine significantly diminished ventricular arrhythmias duration in comparison with the control. In the ischemia–reperfusion-induced arrhythmias model, hypotensive action of molsidomine was observed as well as the reduction in pressure rate product. Molsidomine also prolonged ventricular tachycardia duration. On the other hand, no significant effects on hemodynamic parameters as well as on ventricular arrhythmias were found in any of the SIN-1 and SIN-1A groups. In conclusion, our research suggests a possible direct, cardioprotective action of SIN-1A. It seems worthwhile to further investigate molsidomine derivatives, especially SIN-1A, because of its potential use in invasive cardiology procedures such as percutaneous transluminal coronary angioplasty.

Abstract P293: Endogenous Lats2 Plays an Important Role in Mediating Myocardial Injury Caused by Ischemia/Reperfusion Through Inhibition of FoxO3

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Dan Shao ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Oxidative Stress ◽  
Myocardial Injury ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Dominant Negative ◽  
Area At Risk ◽  
Perfused Heart ◽  
Developed Pressure

Lats2 is a tumor suppressor and a serine/threonine kinase, acting downstream of mammalian sterile 20 like kinase1 (Mst1), which stimulates apoptosis and inhibits hypertrophy in cardiomyocytes (CM). We investigated the role of Lats2 in mediating myocardial injury after ischemia/reperfusion (IR). Phosphorylation of YAP, an in vivo substrate of Lats2, was increased after 45 minutes ischemia followed by 24 hours reperfusion in control mouse hearts compared with sham, but not in dominant negative (DN) Lats2 transgenic mouse (Tg) hearts, suggesting that Lats2 is activated by IR. The size of myocardial infarction (MI)/area at risk was significantly smaller in Tg mice than in NTg mice (19% and 49%, p<0.01). And there were fewer TUNEL positive cells in Tg than in NTg mice (0.04% and 0.11%, p<0.05). Following 30 min of global ischemia and 60 min of reperfusion in Langendorff perfused heart preparations, left ventricular (LV) systolic pressure (100 vs 71mmHg, p<0.05) and LV developed pressure (79 vs 47 mmHg, p<0.05) were significantly greater in Tg than in NTg mice, indicating that suppression of Lats2 induces better functional recovery after IR. Oxidative stress, as evaluated by 8-OHdG staining, was attenuated in Tg mice. In cultured CMs, DN-Lats2 significantly decreased H 2 O 2 -induced cell death. Overexpression of Lats2 significantly downregulated (51% and 75%, p<0.05), whereas that of DN-Last2 upregulated (100 and 70%, p<0.05), MnSOD and catalase, suggesting that Lats2 negatively regulates expression of antioxidants. Reporter gene assays showed that overexpression of Lats2 significantly inhibits (−70%), whereas knocking down Lats2 by sh-Lats2 increases (+60%), FoxO3-mediated transcriptional activity. Overexpression of Lats2 in CMs inhibited FoxO3 expression, whereas that of DN-Lats2 significantly inhibited FoxO3 downregulation after IR in vivo, suggesting that Lats2 negatively regulates FoxO3 protein expression, which may lead to the downregulation of MnSOD and catalase. Taken together, these results suggest that endogenous Lats2 plays an important role in mediating myocardial injury in response to IR, In part through downregulation of FoxO3 and consequent downregulation of antioxidants and increased oxidative stress in the heart.

scholarly journals Baicalin Prevents Myocardial Ischemia/Reperfusion Injury Through Inhibiting ACSL4 Mediated Ferroptosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhenyu Fan ◽  
Liangliang Cai ◽  
Shengnan Wang ◽  
Jing Wang ◽  
Bohua Chen
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Receptor Protein ◽  
H9c2 Cells ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Baicalin is a natural flavonoid glycoside that confers protection against myocardial ischemia/reperfusion (I/R) injury. However, its mechanism has not been fully understood. This study focused on elucidating the role of ferroptosis in baicalin-generated protective effects on myocardial ischemia/reperfusion (I/R) injury by using the myocardial I/R rat model and oxygen–glucose deprivation/reoxygenation (OGD/R) H9c2 cells. Our results show that baicalin improved myocardial I/R challenge–induced ST segment elevation, coronary flow (CF), left ventricular systolic pressure , infarct area, and pathological changes and prevented OGD/R-triggered cell viability loss. In addition, enhanced lipid peroxidation and significant iron accumulation along with activated transferrin receptor protein 1 (TfR1) signal and nuclear receptor coactivator 4 (NCOA4)-medicated ferritinophagy were observed in in vivo and in vitro models, which were reversed by baicalin treatment. Furthermore, acyl-CoA synthetase long-chain family member 4 (ACSL4) overexpression compromised baicalin-generated protective effect in H9c2 cells. Taken together, our findings suggest that baicalin prevents against myocardial ischemia/reperfusion injury via suppressing ACSL4-controlled ferroptosis. This study provides a novel target for the prevention of myocardial ischemia/reperfusion injury.

Abstract P144: Effects of Alamandine in Post-ischemic Function

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Jonathas F Almeida ◽  
Robson A Santos
Keyword(s):  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Baseline Period ◽  
Left Ventricular ◽  
Biologically Active ◽  
Ventricular Systolic Pressure ◽  
Infarcted Area ◽  
Rat Hearts ◽  
Ischemic Period ◽  
Isolated Rat

Alamandine, a biologically active peptide of the renin-angiotensin system (RAS), was recently described and characterized. Further it has been shown to present effects similar to those elicited by Ang-(1-7). It has been described that Ang-(1-7) decreases the incidence and duration of ischemia-reperfusion arrhythmias and improved the post-ischemic function in isolated perfused rat hearts. In this study we aimed to evaluate the effects of Alamandine in isolated rat hearts subjected to myocardial infarction (MI). Wistar rats weighing between 250-300g were euthanized and their hearts were placed on Langendorff apparatus to evaluate the cardiac parameters. Hearts were submitted to 30min of stabilization, 30min of partial ischemia by occlusion of the left descending coronary artery and 30min of reperfusion. Drugs (alamandine 22pM, d-pro7-ang-(1-7) 220pM) were added to the perfusion setting from the beginning of the experiment until the end. 2,3,5-trypheniltetrazolium chloride were used to evaluate the extension of infarcted area. In control hearts (CON), there was a decrease on the left ventricular systolic pressure (LVSP) on ischemic period (54,6 ± 6,9mmHg) compared to the baseline period (84,6 ± 11,6mmHg). Alamandine (ALA) attenuated that decrease in the ischemic period (66,9 ± 7,9mmHg) vs (82,3 ± 8,9mmHg). Further, ischemia led to a decrease in the left ventricular developed pressure (dLVP), dP/dt maximum and minimum when compared to baseline values. ALA, once more, kept the ischemic parameters of dLVP and dP/dt max and min (58,9 ± 8mmHg; 1629 ± 202,2mmHg/s; 1101 ± 130mmHg/s, respectively) similar to those of baseline period (68,9 ± 8,92; 1682 ± 248,8; 1179 ± 118,6 mmHg, respectively). Ischemia/reperfusion induced an arrhythmia severity index (ASI) in control hearts (4,9 ± 1,26) higher than in hearts treated with ALA (1,10 ± 0,58). ALA also reduced infarcted area (19,64 ± 2,61%) compared with CON (33,85 ± 4,55%). All those effects were blocked by D-PRO7-Ang-(1-7). In conclusion, our data shown that Alamandine exert cardioprotective effects in post-ischemic function in isolated rat hearts by preventing LVSP, dLVP , dP/dt max and min decrease. Furthermore it reduced the infarcted area and I/R arrhythmias, apparently involving MrgD receptor participation.

Effects of sodium–glucose cotransporter-2 inhibitors on cardiac structural and electrical remodeling: from myocardial cytology to cardiodiabetology

2021 ◽  
Vol 20 ◽  
Author(s):  
Maria Marketou ◽  
Joanna Kontaraki ◽  
Spyros Maragkoudakis ◽  
Christos Danelatos ◽  
Sofia Papadaki ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Ventricular Hypertrophy ◽  
Myocardial Cell ◽  
Left Ventricular ◽  
Antiarrhythmic Action ◽  
Matrix Remodeling ◽  
Beneficial Effects ◽  
Concentric Hypertrophy ◽  
Sodium Glucose Cotransporter ◽  
Pleiotropic Actions

Abstract: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have changed the clinical landscape of diabetes mellitus (DM) therapy through their favourable effects on cardiovascular outcomes. Notably, the use of SGLT2i has been linked to cardiovascular benefits regardless of DM status, while their pleiotropic actions remain to be fully elucidated. What we do know is that SGLT2i exert beneficial effects even at the level of the myocardial cell, and that these are linked to an improvement in the energy substrate, resulting in less inflammation and fibrosis. SGLT2i ameliorate myocardial extracellular matrix remodeling, cardiomyocyte stiffness and concentric hypertrophy, achieving beneficial remodeling of the left ventricle with significant implications for the pathogenesis and outcome of heart failure. Most studies show a significant improvement in markers of diastolic dysfunction along with a reduction in left ventricular hypertrophy. In addition to these effects there is electrophysiological remodeling, which explains initial data suggesting that SGLT2i have an antiarrhythmic action against both atrial and ventricular arrhythmias. However, future studies need to clarify not only the exact mechanisms of this beneficial functional, structural, and electrophysiological cardiac remodeling, but also its magnitude, and to determine whether this is a class or a drug effect.

Hyperbaric Oxygen Preconditioning Alleviates Myocardial Ischemic Injury in Rats

2008 ◽  
Vol 233 (11) ◽  
pp. 1448-1453 ◽  
Author(s):  
Cuihong Han ◽  
Li Lin ◽  
Weidong Zhang ◽  
Li Zhang ◽  
Shijun Lv ◽  
...  
Keyword(s):  
Infarct Size ◽  
Hyperbaric Oxygen ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Capillary Density ◽  
Left Ventricular ◽  
Ischemic Myocardium ◽  
Sham Surgery ◽  
Vegf Protein

It has been shown that after ischemia-reperfusion, application of hyperbaric oxygen (HBO) reduces cardiac injury. In this study we tested the hypothesis that HBO preconditioning reduces injury to the ischemic myocardium. One hundred and eight adult male Sprague-Dawley rats (250–280 g) were randomly divided into four groups: normoxia + sham surgery (CS), normoxia + permanent occlusion of the left anterior descending (LAD) coronary artery (CMI), HBO preconditioning + sham surgery (HS), and HBO preconditioning + permanent LAD occlusion (HMI). Rats receiving HBO preconditioning were intermittently exposed to 100% O2 at 2.5 atmosphere absolute (ATA) for 60 min, twice daily for 2 days followed by 12 hrs of recovery in room air prior to the myocardial ischemic insult induced by LAD ligation. Rats in the normoxia group were time-matched with the HBO group and maintained under normoxic conditions prior to LAD occlusion. At 3 and 7 days after LAD occlusion, heart function parameters were measured by inserting a catheter into the left ventricle, infarct size was calculated using the method of TTC staining, myocardial capillary density was determined by immunohistochemical staining with a monoclonal anti-CD31/PECAM-1 antibody, and VEGF protein level was determined by Western blot analysis. At 3 days after LAD ligation, the infarct size of the HMI group was significantly smaller than that of the CMI group (26 ± 2.5% vs. 38 ± 3%, P < 0.05). The heart function parameters including left ventricular systolic pressure (LVSP), +dP/dtmax and −dP/dtmax were significantly improved in the HMI group compared to the CMI group at 3 and 7 days after LAD occlusion. Capillary density and VEGF protein levels were significantly increased in the ischemic myocardium pre-exposed to HBO. We conclude that HBO preconditioning alleviates myocardial ischemia in rat model.

Novel soluble epoxide hydrolase inhibitor protects mitochondrial function following stress

2012 ◽  
Vol 90 (6) ◽  
pp. 811-823 ◽  
Author(s):  
Sri N. Batchu ◽  
Stephen B. Lee ◽  
Victor Samokhvalov ◽  
Ketul R. Chaudhary ◽  
Haitham El-Sikhry ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Epoxide Hydrolase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Soluble Epoxide Hydrolase ◽  
Left Ventricular ◽  
Ros Generation ◽  
The Novel ◽  
Active Metabolites ◽  
Developed Pressure

Epoxyeicosatrienoic acids (EETs) are active metabolites of arachidonic acid that are inactivated by soluble epoxide hydrolase enzyme (sEH) to dihydroxyeicosatrienoic acid. EETs are known to render cardioprotection against ischemia reperfusion (IR) injury by maintaining mitochondrial function. We investigated the effect of a novel sEH inhibitor (sEHi) in limiting IR injury. Mouse hearts were perfused in Langendorff mode for 40 min and subjected to 20 min of global no-flow ischemia followed by 40 min of reperfusion. Hearts were perfused with 0.0, 0.1, 1.0 and 10.0 µmol·L–1 of the sEHi N-(2-chloro-4-methanesulfonyl-benzyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinamide (BI00611953). Inhibition of sEH by BI00611953 significantly improved postischemic left-ventricular-developed pressure and reduced infarct size following IR compared with control hearts, and similar to hearts perfused with 11,12-EETs (1 µmol·L–1) and sEH–/– mice. Perfusion with the putative EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, 10 µmol·L–1), or the plasma membrane KATP channels (pmKATP) inhibitor (glibenclamide, 10 µmol·L–1) abolished the improved recovery by BI00611953 (1 µmol·L–1). Mechanistic studies in H9c2 cells demonstrated that BI0611953 decreased ROS generation, caspase-3 activity, proteasome activity, increased HIF-1∝ DNA binding, and delayed the loss of mitochondrial membrane potential (ΔΨm) caused by anoxia–reoxygenation. Together, our data demonstrate that the novel sEHi BI00611953, a nicotinamide-based compound, provides significant cardioprotection against ischemia reperfusion injury.

scholarly journals Impact of Maturation on Myocardial Response to Ischemia and the Effectiveness of Remote Preconditioning in Male Rats

2021 ◽  
Vol 22 (20) ◽  
pp. 11009
Author(s):  
Lucia Kindernay ◽  
Veronika Farkasova ◽  
Jan Neckar ◽  
Jaroslav Hrdlicka ◽  
Kirsti Ytrehus ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Ventricular Arrhythmias ◽  
Glycogen Synthase ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Age Groups ◽  
Left Ventricular ◽  
Male Rats ◽  
Mature Adult ◽  
Survival Proteins

Aging attenuates cardiac tolerance to ischemia/reperfusion (I/R) associated with defects in protective cell signaling, however, the onset of this phenotype has not been completely investigated. This study aimed to compare changes in response to I/R and the effects of remote ischemic preconditioning (RIPC) in the hearts of younger adult (3 months) and mature adult (6 months) male Wistar rats, with changes in selected proteins of protective signaling. Langendorff-perfused hearts were exposed to 30 min I/120 min R without or with prior three cycles of RIPC (pressure cuff inflation/deflation on the hind limb). Infarct size (IS), incidence of ventricular arrhythmias and recovery of contractile function (LVDP) served as the end points. In both age groups, left ventricular tissue samples were collected prior to ischemia (baseline) and after I/R, in non-RIPC controls and in RIPC groups to detect selected pro-survival proteins (Western blot). Maturation did not affect post-ischemic recovery of heart function (Left Ventricular Developed Pressure, LVDP), however, it increased IS and arrhythmogenesis accompanied by decreased levels and activity of several pro-survival proteins and by higher levels of pro-apoptotic proteins in the hearts of elder animals. RIPC reduced the occurrence of reperfusion-induced ventricular arrhythmias, IS and contractile dysfunction in younger animals, and this was preserved in the mature adults. RIPC did not increase phosphorylated protein kinase B (p-Akt)/total Akt ratio, endothelial nitric oxide synthase (eNOS) and protein kinase Cε (PKCε) prior to ischemia but only after I/R, while phosphorylated glycogen synthase kinase-3β (GSK3β) was increased (inactivated) before and after ischemia in both age groups coupled with decreased levels of pro-apoptotic markers. We assume that resistance of rat heart to I/R injury starts to already decline during maturation, and that RIPC may represent a clinically relevant cardioprotective intervention in the elder population.

Simulated microgravity increases myocardial susceptibility to ischemia–reperfusion injury via a deficiency of AMP-activated protein kinase

2017 ◽  
Vol 95 (1) ◽  
pp. 59-71 ◽  
Author(s):  
Yuan-Ming Lu ◽  
Bo Jiao ◽  
Jun Lee ◽  
Lin Zhang ◽  
Zhi-Bin Yu
Keyword(s):  
Protein Kinase ◽  
Infarct Size ◽  
Simulated Microgravity ◽  
Ischemia Reperfusion Injury ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Ampk Phosphorylation ◽  
Amp Activated Protein Kinase

Gravitation is an important factor in maintaining cardiac contractility. Our study investigated whether simulated microgravity increases myocardial susceptibility to ischemia–reperfusion (IR) injury. Using the Langendorff-perfused heart model with 300 beats/min pacing, 4-week tail suspension (SUS) and control (CON) male Sprague-Dawley rats (n = 10 rats/group) were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 120 min of reperfusion. Left ventricular end-systolic pressure (LVESP), left ventricular end-diastolic pressure (LVEDP), creatine kinase (CK) and lactate dehydrogenase (LDH) activity, and infarct size were assessed. Data demonstrated that there were significantly increased LVEDP, CK, LDH, and infarct size in SUS compared with CON (P < 0.05), accompanied by decreased LVESP (P < 0.05). Furthermore, TUNEL-positive cardiomyocytes were higher in SUS than that in CON (P < 0.01), and AMP-activated protein kinase (AMPK) phosphorylation and Bcl-2/Bax in SUS were less compared with CON (P < 0.05). Similarly, isolated hearts pre-treated with A-769662 exhibited better recovery of cardiac function, increased AMPK phosphorylation, and reduced necrosis and apoptosis. Furthermore, AMPKα protein showed a significant suppression in 4-week hindlimb unweighting rats. These results suggest that AMPK deficiency increases myocardial susceptibility to IR injury in rats subjected to simulated microgravity.

Na+/Ca2+ exchange inhibition protects the rat heart from ischemia-reperfusion injury by blocking energy-wasting processes

2005 ◽  
Vol 288 (4) ◽  
pp. H1699-H1707 ◽  
Author(s):  
Hiroji Hagihara ◽  
Yoshiro Yoshikawa ◽  
Yoshimi Ohga ◽  
Chikako Takenaka ◽  
Ken-ya Murata ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Mechanical Energy ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Reverse Mode ◽  
Rat Hearts ◽  
Total Mechanical Energy ◽  
Contractile Failure

We have recently reported that exposure of rat hearts to high Ca2+ produces a Ca2+ overload-induced contractile failure in rat hearts, which was associated with proteolysis of α-fodrin. We hypothesized that contractile failure after ischemia-reperfusion (I/R) is similar to that after high Ca2+ infusion. To test this hypothesis, we investigated left ventricular (LV) mechanical work and energetics in the cross-circulated rat hearts, which were subjected to 15 min global ischemia and 60 min reperfusion. Sixty minutes after I/R, mean systolic pressure-volume area (PVA; a total mechanical energy per beat) at midrange LV volume (mLVV) (PVAmLVV) was significantly decreased from 5.89 ± 1.55 to 3.83 ± 1.16 mmHg·ml·beat−1·g−1 ( n = 6). Mean myocardial oxygen consumption per beat (Vo2) intercept of (Vo2-PVA linear relation was significantly decreased from 0.21 ± 0.05 to 0.15 ± 0.03 μl O2·beat−1·g−1 without change in its slope. Initial 30-min reperfusion with a Na+/Ca2+ exchanger (NCX) inhibitor KB-R7943 (KBR; 10 μmol/l) significantly reduced the decrease in mean PVAmLVV and Vo2 intercept ( n = 6). Although Vo2 for the Ca2+ handling was finally decreased, it transiently but significantly increased from the control for 10–15 min after I/R. This increase in Vo2 for the Ca2+ handling was completely blocked by KBR, suggesting an inhibition of reverse-mode NCX by KBR. α-Fodrin proteolysis, which was significantly increased after I/R, was also significantly reduced by KBR. Our study shows that the contractile failure after I/R is similar to that after high Ca2+ infusion, although the contribution of reverse-mode NCX to the contractile failure is different. An inhibition of reverse-mode NCX during initial reperfusion protects the heart against reperfusion injury.

Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling

2005 ◽  
Vol 288 (4) ◽  
pp. H1997-H2005 ◽  
Author(s):  
Ali Pourdjabbar ◽  
Thomas G. Parker ◽  
Quang Trinh Nguyen ◽  
Jean-Francois Desjardins ◽  
Nathalie Lapointe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ventricular Arrhythmias ◽  
Angiotensin Receptor Blockers ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Lv Function ◽  
High Dose ◽  
Postmyocardial Infarction ◽  
Lv Remodeling ◽  
Cardiac Hemodynamics

Angiotensin receptor blockers (ARBs) reduce adverse left ventricular (LV) remodeling and improve LV function and survival when started postmyocardial infarction (MI). ARBs also reduce ventricular arrhythmias during ischemia-reperfusion injury when started pre-MI. No information exists regarding their efficacy and safety when started pre-MI and continued peri- and post-MI. We evaluated whether the ARB losartan improves the outcome when started pre-MI and continued peri- and post-MI. Male Wistar rats ( n = 502) were treated for 7 days pre-MI with losartan at a high dose (30 mg·kg−1·day−1), progressively increasing dose (3 mg·kg−1·day−1 increased to 10 mg·kg−1·day−1 10 days and 30 mg·kg−1·day−1 20 days post-MI), or no treatment. Ambulatory systolic blood pressure and Holter monitoring were performed for 24 h post-MI. Echocardiography was done 30 days post-MI, and LV remodeling, cardiac hemodynamics, and fetal gene expression were assessed 38 days post-MI. High-dose losartan reduced 24-h post-MI survival compared with the progressive dose and control (21.9% vs. 36.6% and 38.1%, P = 0.033 and P = 0.009, respectively). This was associated with greater hypotension in the high dose and no change in ventricular arrhythmias in all groups. In 24-h post-MI survivors, the progressive dose group had reduced mortality from 24 h to 38 days (8.5% vs. 28.6% for control vs. 38.9% for high dose, P = 0.032 and P = 0.01, respectively). Survivors of both losartan groups demonstrated improved LV remodeling, cardiac hemodynamics, preserved GLUT-4, and reduced cardiac fetal gene expression. Pretreatment with ARBs does not reduce 24-h post-MI ventricular arrhythmias or survival, and high doses increase mortality by causing excessive hypotension. In 24-h post-MI survivors, progressively increasing doses of losartan have multiple beneficial effects, including improved survival.

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