Untreated Myocardial Infarction Rats Research Articles

Rats with Postinfarction Heart Failure: Effects of Propranolol Therapy on Intracellular Calcium Regulation and Left Ventricular Function

Patients with heart failure may live longer if they receive chronic treatment with beta-adrenergic blocking medications. Unresolved are the mechanisms underlying the beneficial effects and if they may be applied to ischemic heart failure. Rats (n = 28) underwent echocardiographic-Doppler exams one and six weeks following a simulated operation or myocardial infarction (MI). After the first echocardiography, rats were randomized to either no therapy or 500 mg/l of propranolol in their drinking water. The noninfected left ventricular (LV) papillary muscles were used to record isometric contractions and intracellular Ca transients simultaneously. Untreated MI rats had a restrictive LV diastolic filling pattern, decreased systolic function (13% ± 2%), and significant LV dilatation (10.6 ± 0.4 mm vs. 8.9 ± 0.3 mm, MI vs. control). The LV chamber diameters of the propranolol-treated MI rats were 10.6 ± 0.5 mm, and systolic performance (13% ± 2%). Higher LV end-diastolic pressures (27 ± 2 mmHg vs. 20 ± 3 mmHg) and a more constrained LV diastolic filling pattern (increased ratio of early to late filling velocities and faster E wave deceleration rate) were seen in the propranolol-treated animals. Papillary muscle contractility in untreated MI rats was lower (1.6 ± 0.3 g mm²). Furthermore, the inotropic response to isoproterenol was attenuated, and Ca transients were extended. During isoproterenol stimulation, beta-adrenergic blocking administration had no effect on force development (1.6 ± 0.3 g mm²) or the length of Ca transients. Rats with postinfarction heart failure receiving chronic propranolol treatment did not have improvements in systolic function or LV remodeling. Propranolol exacerbated LV diastolic pressures and filling patterns. Additionally, there was no discernible improvement in intracellular contractility following treatment, Calcium control, or beta-adrenergic sensitivity in the myocardium that is not infarcted).

Attenuation of lipid metabolic abnormalities, proinflammatory cytokines, and matrix metalloproteinase expression by biochanin-A in isoproterenol-induced myocardial infarction in rats

In the present study, we assessed the therapeutic potential of Biochanin-A (BCA) (10 mg/kg BW/day) pretreatment for 30 days on lipid metabolic abnormalities, proinflammatory cytokines and matrix metalloproteinase expression in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. We measured the potential role of BCA on tissue and circulatory lipid profiles as well as on lipid metabolic enzymes: serum inflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-6 and MCP1) and serum Matrix Metalloproteinases (particularly, MMP-2 and MMP-9) together with mRNA expressions of TNF-α, IL-6, MMP-2 and MMP-9 by RT-PCR analysis. Administration of ISO to rats significantly distorted their lipid metabolism and augmented inflammatory process, MMP expression and proteolytic activity. In addition, pretreatment with BCA of ISO-induced MI rats significantly reestablished the altered lipid metabolism and concealed the inflammation of cytokines. BCA suppressed the expressions of proinflammatory cytokines and MMPs in ISO-induced MI in rats when compared to normal untreated MI rats. Hence, these results established that BCA could improve the pathological processes of myocardial remodeling which was confirmed by histopathology of heart in MI rats and might be an effective beneficial ingredient for the management of heart failure disorders.

S-allylcysteine therapy reduces adverse cardiac remodelling after myocardial infarction in a rat model

• S-allylcysteine therapy post MI attenuates cardiac hypertrophy in rats. • S-allylcysteine therapy post MI limits cardiac fibrosis in rats. • S-allylcysteine therapy post MI blunted oxidative stress in rats. • S-allylcysteine therapy post MI regulates ACE-AT1 axis in rats. Adverse cardiac remodelling such as hypertrophy and fibrosis are strong determinants of heart failure and sudden death after myocardial infarction (MI). This study investigated the impact of S-allylcysteine therapy on adverse cardiac remodelling after MI in a preclinical rat model. Wistar rats (n = 6–8/group) were subjected to MI via isoprenaline overdose and were then administered with S-allylcysteine (50 or 100 mg/kg) orally for 7 days. Compared to the sham controls, untreated MI rats showed enhanced cardiac hypertrophy and fibrosis 7 days after MI, accompanied by a significant reduction in left ventricle glutathione and glutathione reductase activities with concomitant increase in protein oxidation. S-allylcysteine therapy however, significantly attenuated cardiac hypertrophy, fibrosis and oxidative stress after MI. S-allylcysteine therapy also prevented upregulation of angiotensin converting enzyme and angiotensin II type I receptor in these rat hearts. These findings altogether suggested that S-allylcysteine therapy reduced adverse cardiac remodelling after MI in rats.

Roselle attenuates cardiac hypertrophy after myocardial infarction in vivo and in vitro.

Roselle (Hibiscus sabdariffa Linn) has been traditionally used as folk medicine for hypertension and maintaining cardiovascular health, with therapeutic potential in protecting against numerous cardiovascular diseases. However, it remains unclear whether roselle can be used for management of cardiac hypertrophy seen after myocardial infarction (MI). This study therefore investigated the effects of aqueous roselle extract on cardiac hypertrophy arising from myocardial infarction both in vivo and in vitro. For in vivo study, male Sprague-Dawley rats were divided into control or MI groups (receiving 85 mg/kg isoproterenol s.c. for 2 days) and were given roselle extract (100 mg/kg, p.o daily) for 28 days. Cardiac structure and functional changes were evaluated at study end-point using histology, Langendorff analysis and gene expression analysis. In vitro effects of roselle were also assessed on ANG II-induced cardiomyocytes hypertrophy using H9c2 cells, simulating cardiac hypertrophy evident after MI. Roselle significantly ameliorated MI-induced cardiac systolic and diastolic dysfunction, as seen across improvement in left ventricular developed pressure (LVDP) and its derivative (LVdP/dtmax) and isovolumic relaxation (Tau). Oxidative stress evident across elevated pro-oxidant markers (NOX2 subunit of NADPH oxidase and 8-isoprostane) as well as reduced antioxidant markers (superoxide dismutase and glutathione) were also significantly attenuated by roselle. Furthermore, roselle treatment markedly reduced markers of cardiac remodeling (cardiac hypertrophy and fibrosis) compared to the untreated MI rats. On in vitro analysis, roselle significantly attenuated ANG II-induced cardiomyoycte hypertrophy in dose-dependent manner. This study demonstrated that roselle attenuates cardiac hypertrophy and dysfunction seen after MI both in vivo and in vitro, and these effects are likely mediated by phenolic compounds found in roselle extract.

Cognitive Deficits Following a Post-Myocardial Infarct in the Rat Are Blocked by the Serotonin-Norepinephrine Reuptake Inhibitor Desvenlafaxine.

Myocardial infarction (MI) in animal models induces cognitive deficits as well as the activation of caspase in the limbic system; both can be blocked by 2 weeks of treatment following MI using tricyclic antidepressants or selective serotonin uptake blockers. Here we used three different treatment schedules to test the short- and long-term effects of the combined serotonin-norepinephrine reuptake inhibitor desvenlafaxine on post-MI-associated cognitive deficits and caspase activation. MI was induced in 39 young adult rats, and 39 rats served as sham-operated controls. Desvenlafaxine (3 mg/kg/day, i.p.) or saline was administered according to one of three schedules: (1) for 2 weeks, starting right after surgery; (2) for 16 weeks, starting 2 weeks after surgery; (3) for 16 weeks, starting right after surgery. Behavior was tested 2 weeks (social interaction, passive avoidance) and 16 weeks (forced swimming, Morris water maze) after surgery. Caspase-3 and caspase-6 activities were measured 16 weeks after surgery. At 2 and 16 weeks post-surgery, saline-treated MI rats displayed performance deficits compared to desvenlafaxine-treated rats, regardless of the treatment schedule. Caspase-3 activity was higher in the amygdala (medial and lateral) and hippocampal CA3 region in untreated MI rats, whereas caspase-6 activity was higher in the CA1 region. Caspase-6 activity correlated positively with deficits in the Morris water maze. These results indicate that, independently of treatment schedules, various treatment schedules with desvenlafaxine can prevent MI-associated cognitive deficits and decrease caspase activities in the limbic system.

Alda‑1, an aldehyde dehydrogenase‑2 agonist, improves long‑term survival in rats with chronic heart failure following myocardial infarction.

Alda-1, an aldehyde dehydrogenase 2 (ALDH2) agonist, has been demonstrated to reduce injury caused by acute myocardial infarction (MI) and ischemia/reperfusion. The present study aimed to investigate whether oral administration of Alda-1 improved long-term survival of rats with chronic heart failure (CHF) post-MI. MI model rats treated daily with Alda-1 exhibited an increase in 20-week survival rate compared with untreated MI rats. Alda-1 treatment decreased the heart weight/body weight ratio, collagen volume, left ventricular (LV) internal diameter at the end of diastole and LV internal diameter at the end of systole, while increasing LV ejection fraction with evident LV fractional shortening. Myocardial cell apoptosis index, the activity of caspase-3 and the expression of cleaved-caspase-3 were also reduced by Alda-1 treatment. The protective effects of Alda-1 were associated with reduced 4-hydroxynonenal accumulation. The results of the present study revealed that the long-term treatment with Alda-1 prevented the progression of ventricular remodeling and improved the long-term survival of rats with CHF post-MI.

Pyridoxamine improves survival and limits cardiac dysfunction after MI

Advanced glycation end products (AGEs) play a key role in the progression of heart failure. Whether treatments limiting AGEs formation would prevent adverse left ventricular remodeling after myocardial infarction (MI) remain unknown. We investigated whether pyridoxamine (PM) could limit adverse cardiac outcome in MI. Rats were divided into MI, MI + PM and Sham. Echocardiography and hemodynamic parameters were used to assess cardiac function 8 weeks post-surgery. Total interstitial collagen, collagen I and collagen III were quantified using Sirius Red and polarized light microscopy. PM improved survival following LAD occlusion. Pre-treatment with PM significantly decreased the plasma AGEs levels. MI rats treated with PM displayed reduced left ventricular end-diastolic pressure and tau compared to untreated MI rats. Deformation parameters were also improved with PM. The preserved diastolic function was related to the reduced collagen content, in particular in the highly cross-linked collagen type I, mainly in the peri-infarct region, although not via TGF-β1 pathway. Our data indicate that PM treatment prevents the increase in AGEs levels and reduces collagen levels in a rat model of MI, resulting in an improved cardiac phenotype. As such, therapies targeting formation of AGEs might be beneficial in the prevention and/or treatment of maladaptive remodeling following MI.

Astragaloside attenuates myocardial injury in a rat model of acute myocardial infarction by upregulating hypoxia inducible factor-1α and Notch1/Jagged1 signaling

The present study aimed to investigate the mechanisms underlying the cardioprotective effect of Astragaloside against myocardial injury following myocardial infarction (MI) in a rat model. Male Wistar rats were subjected to left anterior descending branch ligation. The rats that survived 24 h (n=18) were randomly and equally assigned to three groups: MI model group, and 2.5 and 10 mg/kg/day Astragaloside group. A further six rats underwent identical surgical procedures without artery ligation, serving as sham controls. Following 28 days of treatment, the left ventricle was harvested for morphological analysis, and mRNA and protein expression levels of hypoxia inducible factor-1α (HIF-1α), Notch1 and Jagged1 were measured. Treatment with Astragaloside attenuated pathological changes in the myocardium. Compared with untreated MI rats, rats treated with Astragaloside exhibited significantly increased mRNA expression levels of HIF-1α, Notch1 and Jagged1 (all P<0.01). HIF-1α demonstrated a dose-dependent effect (P<0.05). Astragaloside (10 mg/kg/day) significantly increased HIF-1α (P<0.05), Notch1 (P<0.01) and Jagged1 (P<0.01) protein expression levels. Additionally, 2.5 mg/kg Astragaloside significantly increased Jagged1 protein expression levels compared with untreated MI rats. Furthermore, there was a dose-dependent effect of Astragaloside treatment (P<0.01). These findings suggested that the cardioprotective effects of Astragaloside against myocardial injury following MI may involve upregulation of HIF-α, Notch1 and Jagged1 signaling, implicating these molecules as therapeutic targets for the treatment of MI.

Tetramethylpyrazine and Astragaloside IV Synergistically Ameliorate Left Ventricular Remodeling and Preserve Cardiac Function in a Rat Myocardial Infarction Model.

Tetramethylpyrazine (TMP) and astragaloside IV (AGS-IV) are herbal ingredients that have been demonstrated in animal models to limit infarct size and protect cardiomyocytes in the acute phase of myocardial infarction (MI), yet their long-term cardioprotective effects have not been evaluated. In this study, TMP and/or AGS-IV were administrated to rats for 14 days after MI. Echocardiography revealed that the left ventricular (LV) dimensions and cardiac function were preserved in the MI rats with TMP and AGS-IV treatment, compared with untreated MI rats. Moreover, the LV dimensions and cardiac function in the MI rats with TMP and AGS-IV cotreatment were comparable with the sham-operated rats. In addition, TMP and AGS-IV synergistically inhibited LV fibrosis by attenuating MI-induced collagen deposition and elevation of transforming growth factor β1. TMP and AGS-IV, alone or in synergy, enhanced angiogenesis in the infarcted myocardium and reduced cardiac hypertrophy of the remote myocardium after MI. Furthermore, TMP and AGS-IV mutually upregulated the expression of Sonic hedgehog (Shh), Smoothened, and Glioblastoma-2, the receptor and signal transducer of Shh signaling pathway, in the infarcted myocardium. In summary, in the circumstance of the irreversible ischemic injury, the antifibrotic, and pro-angiogenic properties of TMP and AGS-IV on the nonaffected tissues contribute to the cardioprotection in the healing phase post MI, and the cardioprotective effects are likely to be mediated through the Shh pathway.

Angiotensin‐(1‐7) improves engraftment and reparative potential of cardiac progenitor cells in a rat model of myocardial infarction (1180.17)

Angiotensin‐(1‐7) [Ang‐(1‐7)] has been shown to produce a multitude of effects on endothelial progenitor cells, implicating a role for this peptide in vascular repair. Our studies have shown that Ang‐(1‐7) enhanced proliferative and tube‐forming abilities of cardiac progenitor cells (CPCs), prevented hypoxia‐induced inhibition of migration and protected them against H2O2‐induced cell death. These observations have led us to hypothesize that Ang‐(1‐7) would enhance CPCs reparative capacity and improve cardiac function in a rat model of myocardial infarction (MI). CPCs alone or CPCs overexpressing Ang‐(1‐7) (4 × 106) were intravenously injected into MI rats and cardiac functions were examined to test this hypothesis. Rats with MI exhibited reduced ejection fraction (EF, 33.0% ± 1.5 vs 77.0% ± 3.9 for control), increased left ventricular hypertrophy [VH, 3.6 ± 0.1 vs 2.7 ± 0.1 for control, (g/kg)], and decreased contractility (dP/dtmax, 7235 ± 271.9 vs 10394 ± 326.3 for control, mmHg/sec). Compared with untreated MI rats, administration of CPCs alone restored EF by 42%, decreased VH by 11%, and improved dP/dtmax by 23%; remarkably, treatment with CPCs overexpressing Ang‐(1‐7) improved EF by 79%, decreased VH by 17%, and attenuated the reduction in dP/dtmax by 42%. Furthermore, Ang‐(1‐7) enhanced the engraftment of CPCs by two‐fold in the peri‐infarct myocardium. These observations demonstrate that Ang‐(1‐7) potentiates functionality and improves engraftment of transplanted CPCs to protect against MI. Thus, genetic modification of CPCs with Ang‐(1‐7) could be a valuable therapeutic strategy for ischemic heart diseases.

Apolipoprotein A-I Is a Potential Mediator of Remote Ischemic Preconditioning

BackgroundRemote ischemic preconditioning (RIPC) has emerged as an attractive strategy in clinical settings. Despite convincing evidence of the critical role played by circulating humoral mediators, their actual identities remain unknown. In this study, we aimed to identify RIPC-induced humoral mediators using a proteomic approach.Methodsand Results Rats were exposed to 10-min limb ischemia followed by 5- (RIPC 5′) or 10-min (RIPC 10′) reperfusion prior to blood sampling. The control group only underwent blood sampling. Plasma samples were analyzed using surface-enhanced laser desorption and ionization - time of flight - mass spectrometry (SELDI-TOF-MS). Three protein peaks were selected for their significant increase in RIPC 10′. They were identified and confirmed as apolipoprotein A-I (ApoA-I). Additional rats were exposed to myocardial ischemia-reperfusion (I/R) and assigned to one of the following groups RIPC+myocardial infarction (MI) (10-min limb ischemia followed by 10-min reperfusion initiated 20 minutes prior to myocardial I/R), ApoA-I+MI (10 mg/kg ApoA-I injection 10 minutes before myocardial I/R), and MI (no further intervention). In comparison with untreated MI rats, RIPC reduced infarct size (52.2±3.7% in RIPC+MI vs. 64.9±2.6% in MI; p<0.05). Similarly, ApoA-I injection decreased infarct size (50.9±3.8%; p<0.05 vs. MI).ConclusionsRIPC was associated with a plasmatic increase in ApoA-I. Furthermore, ApoA-I injection before myocardial I/R recapitulated the cardioprotection offered by RIPC in rats. This data suggests that ApoA-I may be a protective blood-borne factor involved in the RIPC mechanism.

Modification of oxidative stress on gene expression profiling in the rat infarcted heart

Cardiac oxidative stress is developed following myocardial infarction (MI) particularly in the first week of MI. The influence of reactive oxygen species (ROS) on gene expression profiling and molecular pathways in the infarcted myocardium remains uncertain and is explored in the present study. Rats with MI were treated with or without antioxidants for 1 week. Normal rats served as controls. Cardiac oxidative stress and gene profiling were investigated. Compared to normal hearts, malondialdehyde, a marker of oxidative stress, was significantly increased in the infarcted myocardium, which was significantly suppressed by antioxidants. Microarray assay showed that over a thousand genes were differentially expressed in the infarcted myocardium. Antioxidants significantly altered the expression of 159 genes compared to untreated MI rats. Ingenuity pathway analysis indicated that multiple pathway networks were affected by antioxidants, including those related to cell movement, growth/development, death, and inflammatory/fibrotic responses. IPA further identified that these changes were primarily related to NFκB, p38 MAPK, and ERκ1/2 pathways. Hub genes were identified in the associated gene networks. This study reveals the gene networks associated with cardiac oxidative stress postMI. These observations indicate that ROS regulate various molecular and cellular actions related to cardiac repair/remodeling through multiple gene networks.

Continuous reduction of heart rate by ivabradine cannot prevent deterioration of cardiac function in middle‐aged rats with a large myocardial infarction

A large myocardial infarction (MI) initiates progressive structural remodeling that leads to a decline in left ventricular (LV) performance. Four weeks of heart rate reduction (HRR) in post‐MI rats by ivabradine (IVA), a selective inhibitor of the pacemaker If current, attenuated LV systolic dysfunction without modifying cardiac remodeling. However, continuation of this beneficial effect after an extended period of IVA treatment remains to be confirmed. Accordingly, we designed our study to determine whether prolonged HRR by IVA alters post‐MI LV remodeling and functional performance. A large MI (&gt;; 50% of the LV free wall) was induced in 12‐month‐old male Sprague‐Dawley rats by ligation of the left coronary artery and the rats were then assigned in two experimental groups. In the first group, rats were treated with IVA i.p. via osmotic pumps in a dose of 10.5 mg/kg/d for 3 months (MI+IVA), while in the second group, rats received placebo (MI). Three months after MI, the infarct size and its composition, LV chamber dimensions and a degree of myocardial hypertrophy were comparable between MI and MI+IVA rats. At the same time, IVA‐treated rats showed a similar reduction in LV ejection fraction compared to untreated MI rats (0.32±0.02 vs. 0.30±0.02, respectively). Our data demonstrate that a prolonged period of HRR by ivabradine cannot prevent deterioration of LV systolic performance in middle‐aged rats after a large MI.Grant Funding Source: Internal Award from the NYCOM Office of Research (E.I. Dedkov) and Research Grant from the IRI Servier (R.J. Tomanek)

258 Post-ischemic cardiac remodeling is accelerated in diabetic rats: similarities to clinical and tissue hypothyroidism

We investigated whether postischemic cardiac remodeling (REM) is accelerated in diabetic rats with possible involvement of thyroid hormone (TH) signaling in this response. Changes in TH signaling occur during REM after acute myocardial infarction (MI) and contribute to cardiac dysfunction. Diabetes was induced in Wistar rats by streptozotocin injection (35mg/Kg i.p.). After 30 days diabetic rats (DM-AMI, n=9) were subjected to MI, while control rats were either sham-operated (SHAM, n=10) or subjected to MI (AMI(1), n=10). After 2 weeks, TRα1 and TRα1 expression and TH levels were measured. Hypothyroid rats by propyl-thiouracil administration (0.05%) in water for 3 weeks were subjected to MI (HYPO-AMI, n=6) while untreated MI rats served as controls (AMI(2), n=6). LV dimensions (LVEDD and LVEDS) and ejection fraction (EF%) were used to assess contractility and REM 2 weeks after MI using echocardiography. Cardiac function was markedly decreased in DM –AMI. Scar (mm 2 ) LVEDD (mm) LVEDS (mm) EF% SHAM ----- 6.5 (0.1) 3.8 (0.2) 76 (2.6) AMI(1) 79 (4.0) 7.7 (0.2) * 5.7 (0.2) * 52 (1.5) * DM-AMI 83 (4.9) 8.5 (0.2) ** 7.0 (0.3) ** 39 (2.1) ** * p<0.05 vs SHAM, ** p<0.05 vs SHAM and AMI(1) In AMI(1), TRα1 and TRβ1 protein expression were not changed significantly as compared to SHAM while in DM-AMI, both TRα1 and TRβ1 were decreased 1.7 and 1.9 fold respectively as compared to SHAM, p<0.05. T3 and T4 levels were not different between groups. HYPO-AMI hearts, with scar areas comparable to AMI(2) hearts [97(4.7) vs 105 (10.3), p>0.05], showed a similar unfavorable functional response : EF% was found to be markedly reduced [24 (0.9) in HYPO-AMI vs 36.2 (1.0) in AMI(2), p<0.05], while LVEDS was 8.3 (0.2) for HYPO-AMI and 7.5(0.1) for AMI(2), p<0.05. LVEDD equally increased in the 2 groups. Postischemic cardiac remodeling is accelerated both in hypothyroid and diabetic hearts. Tissue hypothyroidism which occurs in DM after myocardial infarction, may at least in part, account for this response.

Interleukin‐10 improves left ventricular function in rats with heart failure subsequent to myocardial infarction

Evidence has shown that pro-inflammatory cytokines, especially TNF-alpha, are involved in the inflammatory response in the remodelling process after myocardial infarction (MI). Although IL-10, an anti-inflammatory cytokine, has been shown to antagonize some of the deleterious effects of TNF-alpha, little is known about its role in post-MI left ventricular (LV) dysfunction. The aim of the present study was to investigate whether a therapy with rhIL-10 could be beneficial in an animal model of post-MI heart failure (HF). Rats with experimental MI were treated with rhIL-10 (75 microg/kg/d sc) starting directly after MI induction, and continuing for 4 weeks. Controls were untreated MI and sham-operated rats. Cardiac function was assessed by echocardiography and cardiac catheterization 4 weeks after MI induction. Membrane-bound and soluble fractions of TNF-alpha, IL-6 and IL-10, the ratio of TNF-alpha to IL-10, serum levels of MCP-1 as well as myocardial macrophage infiltration, were analyzed. Treatment with rhIL-10 significantly improved post-MI LV function (FS +127%;, dP/dt(max) +131%; LVEDP -36%). This effect was associated with a significant decrease in pro-inflammatory cytokine and chemokine levels (TNF-alpha, IL-6, MCP-1) and furthermore resulted in a reduced myocardial infiltration of macrophages.

Early Ghrelin Treatment after Myocardial Infarction Prevents an Increase in Cardiac Sympathetic Tone and Reduces Mortality

Acute myocardial infarction (MI) initiates an increase in cardiac sympathetic nerve activity (CSNA), which ultimately exacerbates chronic cardiac dysfunction. Ghrelin (Ghr), a GH-releasing peptide, is an effective treatment for improving cardiac function in chronic heart failure. Ghr also suppresses renal sympathetic nerve activity (SNA) and, therefore, may have important therapeutic benefits in the early stages of acute MI: by reducing CSNA. In this study we hypothesized that early Ghr administration may prevent an increase in CSNA in the acute phase after MI. CSNA was continuously recorded in urethane-anaesthetized rats before and for 5 h after acute MI (or sham). MI was induced by ligation of the left anterior descending coronary artery. Rats received an injection of either saline or Ghr (150 microg/kg, sc) 1 min, or 2 h, after the infarct. CSNA remained stable during the 5-h recording duration in sham rats. MI induced a maximal 110% increase in SNA, which was prevented in rats that received Ghr 1 min after infarct. When Ghr was injected 2 h after MI (SNA had increased by approximately 85%), SNA decreased to pre-MI activity. Importantly, early Ghr administration significantly reduced the high mortality rate associated with MI (61% mortality in untreated MI rats cf. approximately 23% in Ghr-treated MI rats). These results show that early Ghr treatment prevents the increase in CSNA after MI, which may contribute to the improved chances of survival. Whether these early beneficial effects of Ghr also have long-term benefits for improving cardiac function is an area that requires further investigation.

Eplerenone, a selective aldosterone blocker, improves diastolic function in aged rats with small-to-moderate myocardial infarction

BackgroundThe incidence of cardiovascular diseases increases rapidly with age, and the elderly suffer higher morbidity and mortality. Aldosterone blockers have shown benefits in patients with left ventricular (LV) dysfunction and heart failure after myocardial infarction (MI). However, aldosterone blockade efficacy has not been explored in aged animals with MI. Methods and resultsSmall-to-moderate MI was induced by coronary artery ligation in 16-month old rats, divided into 3 groups: sham-operated (control, n=9), MI (n=9), and MI fed a diet containing eplerenone (120 mg/kg/day, MI+Eplerenone, n=9) given 18 days postsurgery and up to sacrifice 3 months later. At sacrifice, untreated MI rats did not show overt systolic dysfunction but they had (1) echocardiographic evidences of impaired relaxation (increase of E wave deceleration time and of isovolumic relaxation time, decrease of peak E wave velocity), (2) hemodynamically impaired LV relaxation (LV –dP/dt from 7413 ± 720 to 4956 ± 475 mm Hg/s, P < .05), and (3) significant increase of collagen content in LV interstitium (from 4.27 ± 0.23 to 5.34 ± 0.24%, P < .01) and in aorta (from 19 ± 1 to 24 ± 2%, P < .05). Eplerenone normalized echocardiographic and hemodynamic evidences of diastolic dysfunction, as well as myocardial interstitial collagen and aortic fibrosis (all parameters statistically different from untreated MI). ConclusionIn aged rats with small to moderate MI, eplerenone normalized diastolic relaxation, possibly through a reduction of interstitial fibrosis.

Long-term treatment with Low-Dose, but not High-Dose, guanethidine improves ventricular function and survival of rats with heart failure after myocardial infarction

ObjectivesWe sought to evaluate the effects of various doses of guanethidine, a sympathoinhibitory drug, on ventricular function and survival in chronic heart failure (CHF) after myocardial infarction (MI) in rats. BackgroundDirect inhibition of sympathetic outflow by a sympathoinhibitory drug might be an effective approach to therapy of CHF. However, recent clinical trials suggest that excessive suppression of sympathetic activity has an adverse effect on outcome. It remains unclear whether the beneficial effects of the sympathoinhibitory drug would be modified by its dosage. MethodsThree doses of guanethidine (low-dose [LG], 1 mg/kg/day; medium-dose, 3 mg/kg/day; high-dose, 10 mg/kg/day) were administered via an osmotic mini-pump for 4 weeks. Hemodynamics, left ventricular (LV) diameters, plasma and myocardial norepinephrine (NE) levels, and survival were determined for four weeks after MI. ResultsAs compared with MI rats receiving vehicle, LG suppressed LV dilation (9.2 ± 0.9 mm vs. 11.0 ± 0.8 mm, p < 0.05) and improved LV fractional shortening (25.0 ± 4.5% vs. 16.4 ± 4.7%, p < 0.05) in association with a reduction of plasma NE levels (520 ± 250 pg/ml vs. 1,000 ± 570 pg/ml, p < 0.05), but not with a significant reduction of noninfarcted myocardial NE levels (154 ± 71 ng/g vs. 207 ± 71 ng/g). Low-dose guanethidine reduced 24-h (6%) and 28-day mortality (6%), as compared with untreated MI rats (36% and 52%, respectively). High-dose guanethidine also reduced 24-h mortality (12%) but increased 28-day mortality (91%), in association with a depletion of myocardial NE. Medium-dose guanethidine had no beneficial effects on LV hemodynamics or long-term survival. ConclusionsThese results indicate that the dosage of the sympathoinhibitory drug might be quite important for the treatment of CHF.

Effects of angiotensin-converting enzyme inhibition on changes in left ventricular myocardial creatine kinase system after myocardial infarction: their relation to ventricular remodeling and function.

We assessed the effects of angiotensin-converting enzyme (ACE) inhibition on changes in the myocardial intracellular creatine kinase (CK) system in relation to left ventricular (LV) remodeling and function in heart failure after myocardial infarction (MI) in rats. We compared the findings at 4 weeks after MI to those at 12 weeks after MI. LV weight and chamber size were significantly increased and percent fractional shortening (%FS) was decreased in untreated MI rats compared with normal control animals both at 4 and 12 weeks after MI. Animals with MI and treated with the ACE inhibitor temocapril showed significantly reduced LV weight and chamber size and increased %FS compared with untreated MI rats at 12 weeks after MI, but not at 4 weeks after MI. At 4 weeks after MI, no significant changes were found in the total creatine and relative distribution of each CK isoenzyme in either the temocapril-treated or untreated animals with MI compared with the normal controls. In contrast, at 12 weeks after MI, untreated MI rats showed significant reductions in the total creatine and mitochondrial and MM-CK fractions and increases in the MB- and BB-CK fractions compared with the controls. The alterations in the mitochondrial and MB-CK fractions were significantly attenuated after 12 weeks of ACE inhibition. Thus, LV myocardial energy metabolism is progressively impaired and its alteration is not related to the magnitude of geometric changes and LV dysfunction after MI. Most of the beneficial effects of ACE inhibition were observed at 12 weeks after MI. Our results may provide an insight into the therapeutic strategy of ACE inhibition in chronic heart failure after MI.

Effects of captopril and omapatrilat on early post-myocardial infarction survival and cardiac hemodynamics in rats: interaction with cardiac cytokine expression.

The purpose of this study was to evaluate and compare the effects of simultaneous angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) inhibition by the vasopeptidase inhibitor omapatrilat (10 and 40 mg x kg(-1) x day(-1)) with those of the selective ACE inhibitor captopril (160 mg x kg(-1) x day(-1)) on survival, cardiac hemodynamics, and cytokine mRNA expression in left ventricular (LV) tissues 4 days after myocardial infarction (MI) in rats. The effects of the co-administration of both B1 and B2 kinin receptor antagonists (2.5 mg x kg(-1) x day(-1) each) with and without omapatrilat were also evaluated to assess the role of bradykinin (BK) during this post-MI period. Both omapatrilat and captopril treatments improve early (4 days) post-MI survival when started 4 h post-MI. The use of kinin receptor antagonists had no significant effect on survival in untreated MI rats and omapatrilat-treated MI rats. This improvement in survival with omapatrilat and captopril is accompanied by a reduced LV end-diastolic pressure (LVEDP) and pulmonary congestion. The use of kinin receptor antagonists had little effect on cardiac hemodynamics or morphologic measurements. Acute MI significantly increased the expression of cardiac cytokines (TNF-alpha, TGF-beta1, and IL-10). Captopril significantly attenuated this activation, while omapatrilat had variable effects: sometimes increasing but generally not changing activation depending on the cytokine measured and the dose of omapatrilat used. The co-administration of both kinin receptor antagonists attenuates the increase in expression of cardiac TNF-alpha and TGF-beta1 after omapatrilat treatment. Taken together, these results would suggest that despite very marked differences in the way these drugs modified the expression of cardiac cytokines, both omapatrilat and captopril improved early (4 days) post-MI survival and cardiac function to a similar extent.