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To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending (LAD) coronary artery, we first randomly divided 16 male Bama pigs into a sham group and a model group. After anesthesia, we separated the arteries and veins. Subsequently, we rapidly located the LAD coronary artery at the beginning of its first diagonal branch through a mid-chest incision. Then, we loosened and released the ligation line after five minutes of pre-occlusion. Finally, we ligated the LAD coronary artery in situ two minutes later and loosened the ligature 60 min after ischemia. Compared with the sham group, electrocardiogram showed multiple continuous lead ST-segment elevations, and ultrasound cardiogram showed significantly lower ejection fraction and left ventricular fractional shortening at one hour and seven days postoperation in the model group. Twenty-four hours after the operation, cardiac troponin T and creatine kinase-MB isoenzyme levels significantly increased in the model group, compared with the sham group. Hematoxylin and eosin staining showed the presence of many inflammatory cells infiltrating the interstitium of the myocardium in the model group but not in the sham group. Masson staining revealed a significant increase in infarct size in the ischemia/reperfusion group. All eight pigs in the model group recovered with normal sinus heart rates, and the survival rate was 100%. In conclusion, the method can provide an accurate and stable large animal model for preclinical research on ischemia/reperfusion with a high success rate and homogeneity of the myocardial infarction area. [ABSTRACT FROM AUTHOR]

Background: Ayurdvedic derived medicines are most promising and effective in the treatment of several cardiovascular diseases. Cocculus hirsutus (CH) has been reported for broad spectrum of activities like anticancer, antidiabetic, antioxidant, cardiotonic and hypotensive etc. Objectives: The present study aimed to find the cardio-protective effect of CH in experimental hypertension in rats. Materials and methods: For acute renal hypertension, CH animals were pre-treated with CH-1 (250 mg/kg) and CH-2 (500 mg/kg) p. o. for 14 days. On the 15th day, hypertension was induced by renal occlusion and the mean arterial blood pressure (MABP) was recorded. For CAL pretreatment of CH-1 and CH-2 was given for 7 days on the 8th day animals were operated on for ligation. The MABP and the time of onset of ventricular tachycardia (VT), premature ventricular systole (PVS) were recorded. For induction of hypercholesterolemia, animals were fed with a high cholesterol diet (CD) with CH-1 and CH-2 for 21 days. The antioxidant potential of CH was done using the assay of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx). Results: CH treatment significantly decreases the MABP, the onset of VT and PVS. The histology show intact cardiac muscle with minimum necrosis and inflammation. CH treatment shows significant decrease in cholesterol, triglycerides, and glucose while HDL levels are significantly increased. The aortic section of CH-treated animals shows the intact layers of the artery, normal thickness and restoration of antioxidant enzymatic activity. Conclusion: The study shows significant cardio protective effect of CH in experimental animals.

Approximately 7 million people are affected by acute myocardial infarction (MI) each year, and despite significant therapeutic and diagnostic advancements, MI remains a leading cause of mortality worldwide. Preclinical animal models have significantly advanced our understanding of MI and have enabled the development of therapeutic strategies to combat this debilitating disease. Notably, some drugs currently used to treat MI and heart failure (HF) in patients had initially been studied in preclinical animal models. Despite this, preclinical models are limited in their ability to fully reproduce the complexity of MI in humans. The preclinical model must be carefully selected to maximise the translational potential of experimental findings. This review describes current experimental models of MI and considers how they have been used to understand drug mechanisms of action and support translational medicine development. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc [ABSTRACT FROM AUTHOR]

Background: Cardiovascular research heavily relies on mouse (Mus musculus) models to study disease mechanisms and to test novel biomarkers and medications. Yet, applying these results to patients remains a major challenge and often results in noneffective drugs. Therefore, it is an open challenge of translational science to develop models with high similarities and predictive value. This requires a comparison of disease models in mice with diseased tissue derived from humans., Results: To compare the transcriptional signatures at single-cell resolution, we implemented an integration pipeline called OrthoIntegrate, which uniquely assigns orthologs and therewith merges single-cell RNA sequencing (scRNA-seq) RNA of different species. The pipeline has been designed to be as easy to use and is fully integrable in the standard Seurat workflow.We applied OrthoIntegrate on scRNA-seq from cardiac tissue of heart failure patients with reduced ejection fraction (HFrEF) and scRNA-seq from the mice after chronic infarction, which is a commonly used mouse model to mimic HFrEF. We discovered shared and distinct regulatory pathways between human HFrEF patients and the corresponding mouse model. Overall, 54% of genes were commonly regulated, including major changes in cardiomyocyte energy metabolism. However, several regulatory pathways (e.g., angiogenesis) were specifically regulated in humans., Conclusions: The demonstration of unique pathways occurring in humans indicates limitations on the comparability between mice models and human HFrEF and shows that results from the mice model should be validated carefully. OrthoIntegrate is publicly accessible (https://github.com/MarianoRuzJurado/OrthoIntegrate) and can be used to integrate other large datasets to provide a general comparison of models with patient data., (© The Author(s) 2024. Published by Oxford University Press GigaScience.)

Cardiorenal syndrome (CRS) is a clinical disorder involving combined heart and kidney dysfunction, which leads to poor clinical outcomes. To understand the complex pathophysiology and mechanisms that lie behind this disease setting, and design/evaluate appropriate treatment strategies, suitable animal models are required. Described here are the protocols for establishing surgically induced animal models of CRS including important methods to determine clinically relevant measures of cardiac and renal function, commonly used to assess the degree of organ dysfunction in the model and treatment efficacy when evaluating novel therapeutic strategies., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Diagnosing early myocardial ischemia (the initial 4 to 6 h after interruption of blood flow to part of the myocardium) remains a challenge for clinical and forensic pathologists. Several immunohistochemical markers have been proposed for improving postmortem detection of early myocardial ischemia; however, no single marker appears to be both sufficiently specific as well as sensitive. This review summarizes the diverse categories of molecular tissue markers that have been investigated in human autopsy samples with acute myocardial infarction as well as in the well-established and widely used in vivo animal model of early myocardial ischemia (permanent ligation of the coronary artery). Recently identified markers appearing during the initial 2 h of myocardial ischemia are highlighted. Among them, only six were tested for specificity (C5b-9, hypoxia-inducible factor 1-alpha, vascular endothelial growth factor, heart fatty acid binding protein, connexin 43, and JunB). Despite the discovery of several potentially promising markers (in terms of early expression and specificity), many of them remain to be tested and validated for application in routine diagnostics in clinical and forensic pathology. In particular, research investigating the postmortem stability of these markers is required before any might be implemented into routine diagnostics. Establishing a standardized panel of immunohistochemical markers may be more useful for improving sensitivity and specificity than searching for a single marker. [ABSTRACT FROM AUTHOR]

Constitutive regulation by PKA has recently been shown to contribute to L-type Ca2+ current (ICaL) at the ventricular t-tubule in heart failure. Conversely, reduction in constitutive regulation by PKA has been proposed to underlie the downregulation of atrial ICaL in heart failure. The hypothesis that downregulation of atrial ICaL in heart failure involves reduced channel phosphorylation was examined. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, N=10) or equivalent sham-operation (Sham, N=12). Left atrial myocytes were isolated ~18 wk postsurgery and whole cell currents recorded (holding potential=-80 mV). ICaL activated by depolarizing pulses to voltages from -40 to +50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cell capacitances were ~1.67- fold greater than Sham (P ≤ 0.0001). Maximal ICaL conductance (Gmax) was downregulated more than 2-fold in CAL vs. Sham myocytes (P < 0.0001). Norepinephrine (1 μmol/l) increased Gmax >50% more effectively in CAL than in Sham so that differences in ICaL density were abolished. Differences between CAL and Sham Gmax were not abolished by calyculin A (100 nmol/l), suggesting that increased protein dephosphorylation did not account for ICaL downregulation. Treatment with either H-89 (10 μmol/l) or AIP (5 μmol/l) had no effect on basal currents in Sham or CAL myocytes, indicating that, in contrast to ventricular myocytes, neither PKA nor CaMKII regulated basal ICaL. Expression of the L-type α1C-subunit, protein phosphatases 1 and 2A, and inhibitor-1 proteins was unchanged. In conclusion, reduction in PKA-dependent regulation did not contribute to downregulation of atrial ICaL in heart failure. [ABSTRACT FROM AUTHOR]

To investigate the feasibility and effectiveness of establishing porcine ischemia-reperfusion models by ligating the left anterior descending (LAD) coronary artery, we first randomly divided 16 male Bama pigs into a sham group and a model group. After anesthesia, we separated the arteries and veins. Subsequently, we rapidly located the LAD coronary artery at the beginning of its first diagonal branch through a mid-chest incision. Then, we loosened and released the ligation line after five minutes of pre-occlusion. Finally, we ligated the LAD coronary artery in situ two minutes later and loosened the ligature 60 min after ischemia. Compared with the sham group, electrocardiogram showed multiple continuous lead ST-segment elevations, and ultrasound cardiogram showed significantly lower ejection fraction and left ventricular fractional shortening at one hour and seven days post-operation in the model group. Twenty-four hours after the operation, cardiac troponin T and creatine kinase-MB isoenzyme levels significantly increased in the model group, compared with the sham group. Hematoxylin and eosin staining showed the presence of many inflammatory cells infiltrating the interstitium of the myocardium in the model group but not in the sham group. Masson staining revealed a significant increase in infarct size in the ischemia/reperfusion group. All eight pigs in the model group recovered with normal sinus heart rates, and the survival rate was 100%. In conclusion, the method can provide an accurate and stable large animal model for preclinical research on ischemia/reperfusion with a high success rate and homogeneity of the myocardial infarction area.

To examine the effects of houttuynin on ventricular remodeling induced by coronary artery ligation in rats and the underlying mechanisms. A rat model of ventricular remodeling was established by left coronary artery ligation (CAL). Rats were randomly divided into four groups: CAL control, CAL plus 40 mg/kg captopril, CAL plus 100 mg/kg houttuynin and sham-operated control. The rats were administered intragastrically with the corresponding drugs or distilled water for 7 weeks. At the end of the experiment, the left ventricular weight index (LVWI) and heart weight index (HWI) were determined. Myocardium tissue was stained with hematoxylin and eosin or picric acid/Sirius red for cardiomyocyte cross-section area or collagen content measurements respectively. The concentrations of angiotensin I (Ang I), angiotensin II (Ang II), aldosterone (ALD) and endothelin-1 (ET-1) in myocardium or serum were detected by radioimmunoassay. The hydroxyproline (Hyp) concentration was measured by alkali hydrolysis. Ultraviolet spectrophotometry was used to determine glutathione peroxidase (GSH-Px) and catalase (CAT) activities in serum. Houttuynin significantly diminished LVWI and HWI, decreased Ang I, Ang II, ALD, ET-1 and Hyp concentrations in myocardium or serum, increased NO concentration and GSH-Px, CAT activities after 7 weeks of treatment. Houttuynin could also reduce cardiomyocyte cross-section area and collagen deposition. Houttuynin attenuates ventricular remodeling in coronary artery ligation rats by restricting the excessive activation of rennin-angiotensin-aldosterone system (RAAS) and the peroxidation. [ABSTRACT FROM AUTHOR]

Introduction. Ischemic heart disease is a major public health problem in western countries. Appropriate animal experimental models of chronic myocardial infarction is an essential first step in order to investigate and develop new therapeutic interventions. Aim. The aim of this study was to find an optimal place for a coronary artery ligation to induce an optimal chronic myocardial infarction and also a new heart approach that will not require oro-tracheal intubation. Material and methods. To achieve these goals we used a group of rabbits and after induction of anesthesia and cardiac exposure by rib osteotomy (rib III, IV and V) at the costo-sternal junction level on the right side we performed three different left anterior descending artery (LAD) ligation at different distances (5, 10 and 15 mm) in relation to the apex. Thirty days after the acute myocardial infarction, we correlated laboratory investigations (serology, ECG, cardiac ultrasound) with histopathological findings. Results. Heart approach achieved by rib osteotomy (rib III, IV and V) at the costo-sternal junction level on the right side, maintains the integrity of the ribcage, allowing it to take part in respiratory movements and the animal model does not need oro-tracheal intubation. Ligation of LAD at 15 mm from the apex was incompatible with life; ligation of LAD at 5 mm from the apex does not achieved transmural myocardial infarction and ligation of LAD at 10 mm from the apex achieved a transmural myocardial infarction of the left ventricle which also involved the distal part of the interventricular septum. Conclusion. Ligation of LAD at 10 mm from the apex achieved a transmural myocardial infarction of the left ventricle,is in an easily accessible area from technical point of view, it is sufficiently expanded to induce hemodynamic effects that can be quantified with paraclinical examination and also it is compatible with the experimental animal life. If the heart is approached by rib III, IV and V osteotomy at the costo-sternal junction level on the right side combined with neuroleptic anaesthesia, the animal does not need assisted ventilation [ABSTRACT FROM AUTHOR]

[Objective] To discuss the protection effects of rutaecarpine (Kul) on the acute myocardial ischemia injury of tested animal. [Methods] Acute myocardial ischemia model of mice induced by pituitrin and isoproterenol was established. The activities of lactate dehydrogenase (LDH) and creatine kinase (CK) in serum were detected. The rat model of coronary artery ligation was adopted. The hemodynamic parameters were detected, as well as the serum LDH, CK, superoxide dismutase (SOD) and malondialdehyde (MDA). [Results] Compared with model group, Kut group could reduce the increase of serum LDH and CK in mice induced by pituitrin and isoproterenol (P <0.05). In the rat model of coronary artery ligation. Rut group could improve the changes of hemodynamic parameters in rats; the LDH and CK activities and MDA content in serum reduced, while SOD activity enhanced (p<0.05), compared with model group. [Conclusions] Rut had certain protection effects on the acute myocardial ischemia injury of tested animal. [ABSTRACT FROM AUTHOR]

Background: Ayurdvedic derived medicines are most promising and effective in the treatment of several cardiovascular diseases. Cocculus hirsutus (CH) has been reported for broad spectrum of activities like anticancer, antidiabetic, antioxidant, cardiotonic and hypotensive etc. OBJECTIVES: The present study aimed to find the cardio-protective effect of CH in experimental hypertension in rats., Materials and Methods: For acute renal hypertension, CH animals were pre-treated with CH-1 (250 mg/kg) and CH-2 (500 mg/kg) p. o. for 14 days. On the 15th day, hypertension was induced by renal occlusion and the mean arterial blood pressure (MABP) was recorded. For CAL pretreatment of CH-1 and CH-2 was given for 7 days on the 8th day animals were operated on for ligation. The MABP and the time of onset of ventricular tachycardia (VT), premature ventricular systole (PVS) were recorded. For induction of hypercholesterolemia, animals were fed with a high cholesterol diet (CD) with CH-1 and CH-2 for 21 days. The antioxidant potential of CH was done using the assay of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx)., Results: CH treatment significantly decreases the MABP, the onset of VT and PVS. The histology show intact cardiac muscle with minimum necrosis and inflammation. CH treatment shows significant decrease in cholesterol, triglycerides, and glucose while HDL levels are significantly increased. The aortic section of CH-treated animals shows the intact layers of the artery, normal thickness and restoration of antioxidant enzymatic activity., Conclusion: The study shows significant cardio protective effect of CH in experimental animals., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Purpose: To explore the effects of ethanolic extract of Radix Scrophulariae (EERS) on ventricular remodeling in rats. Methods: Rats with coronary artery ligation (CAL) were randomly assigned to 5 groups: CAL model; CAL plus 40mg/kg captopril; CAL plus 60mg/kg, 120mg/kg, 240mg/kg EERS. Sham operation rats were randomly assigned to 2 groups, sham-operated control and sham-operated plus 120mg/kg EERS. The rats were orally administered with the corresponding drugs or drinking water for 14weeks. The left ventricular weight index (LVWI) and heart weight index (HWI) were determined. Myocardium tissue was stained with hematoxylin and eosin or picric acid/Sirius red for cardiomyocyte cross-section area or collagen content measurements respectively. The concentrations of hydroxyproline (Hyp), matrix metalloproteinase 2 (MMP-2), angiotensin II (Ang II), aldosterone (ALD), endothelin 1 (ET-1), atrial natriuretic peptide (ANP), tumor necrosis factor α (TNF-α) and renin activity (RA) in myocardium or serum were determined. Real-time RT-PCR was used to detect the mRNA expressions of angiotensin converting enzyme (ACE), ET-1 and ANP. Results: EERS could significantly reduce the LVWI and HWI, decrease heart tissue concentrations of Hyp and collagen deposition, diminish cardiomyocyte cross-section area, reduce the tissue level of Ang II, ET-1, ANP and TNF-α. EERS could also down regulate the mRNA expression of ACE, ET-1 and ANP in myocardium. Conclusion: EERS attenuates ventricular remodeling. The mechanisms may be related to restraining the excessive activation of RAAS, TNF-α and modulating some gene expressions associated with cardiac hypertrophy. [Copyright &y& Elsevier]

Abstract: Remodeling of the cardiac extracellular matrix (ECM) is an integral part of wound healing and ventricular adaptation after myocardial infarction (MI), but the underlying mechanisms remain incompletely understood. Fibulin-2 is an ECM protein upregulated during cardiac development and skin wound healing, yet mice lacking fibulin-2 do not display any identifiable phenotypic abnormalities. To investigate the effects of fibulin-2 deficiency on ECM remodeling after MI, we induced experimental MI by permanent coronary artery ligation in both fibulin-2 null and wild-type mice. Fibulin-2 expression was up-regulated at the infarct border zone of the wild-type mice. Acute myocardial tissue responses after MI, including inflammatory cell infiltration and ECM protein synthesis and deposition in the infarct border zone, were markedly attenuated in the fibulin-2 null mice. However, the fibulin-2 null mice had significantly better survival rate after MI compared to the wild-type mice as a result of less frequent cardiac rupture and preserved left ventricular function. Up-regulation of TGF-β signaling and ECM remodeling after MI were attenuated in both ischemic and non-ischemic myocardium of the fibulin-2 null mice compared to the wild type counterparts. Increase in TGF-β signaling in response to angiotensin II was also lessened in cardiac fibroblasts isolated from the fibulin-2 null mice. The studies provide the first evidence that absence of fibulin-2 results in decreased up-regulation of TGF-β signaling after MI and protects against ventricular dysfunction, suggesting that fibulin-2 may be a potential therapeutic target for attenuating the progression of ventricular remodeling. [Copyright &y& Elsevier]

Platelet-derived endothelial cell growth factor (PDECGF) is a potent angiogenic peptide with anti-apoptotic activity expressed widely in tumours. However, its expression in myocardial infarction (MI) is not yet established. This study aimed to assess the myocardial expression of PDECGF in rats after MI. Extracellular matrix (ECM) remodeling plays an important role in angiogenesis; hence, changes in the ECM components were investigated in the myocardium after MI, which was induced in rats by coronary artery ligation (CAL) and verified using biochemical markers and histopathology. Immunohistochemistry, RT-PCR, and activity assays identified the expression pattern of PDECGF on days 1, 2, 4, 8, 16, and 32 after CAL. The levels of TNF-α, MMP-2, collagen, and glycosaminoglycans in the ECM were assessed. Studies on immunohistochemistry, RT-PCR, and PDECGF activity demonstrated elevated levels of PDECGF expression from day 2 after CAL. Macrophages, endothelial cells, fibroblasts, and cardiomyocytes, especially at the border region of the lesion, showed an enhanced expression for PDECGF. Remodeling of the ECM was depicted by changes in the levels of TNF-α, MMP-2, collagen, and GAG. Hence, this study clearly indicated PDECGF as an important angiogenic molecule expressed during MI and the alterations in ECM components facilitated the process of angiogenesis. Le PDECGF (« platelet-derived endothelial cell growth factor ») est un puissant peptide angiogène possédant une activité anti-apoptotique, exprimé largement dans les tumeurs. Son expression lors de l’infarctus du myocarde (IM) reste encore à démontrer. Cette étude avait pour but d’évaluer l’expression du PDECGF dans le myocarde de rat après un IM. Le remodelage de la matrice extra-cellulaire (MEC) joue un rôle important dans l’angiogenèse et ce faisant, des changements dans la composition de la MEC ont été étudiés dans le myocarde après un IM. L’IM a été induit chez le rat par une ligature de l’artère coronaire (LAC) et confirmé à l’aide de marqueurs biochimiques et par histopathologie. L’immunohistochimie, la RT-PCR et des essais d’activité ont été réalisés pour identifier le patron d’expression du PDECFG aux jours 1, 2, 4, 8, 16 et 32 après la LAC. Les niveaux de TNF-α, de MMP-2, de collagène et de glycosaminoglycanes de la MEC ont été évalués. Les études en immunohistochimie, par RT-PCR et par mesure de l’activité du PDECGF ont mis en évidence des niveaux élevés d’expression de PDECGF à partir du jour 2 après la LAC. Les macrophages, les cellules endothéliales, les fibroblastes et les cardiomyocytes retrouvés spécialement à la bordure de la région lésée, exprimaient davantage de PDECGF. Le remodelage de la MEC était caractérisé par des changements dans les niveaux de TNF-α, de MMP-2, de collagène et de GAG. Ainsi, cette étude a clairement démontré que le PDECGF est une importante molécule angiogène exprimée lors de l’IM et que les modifications de la composition de la MEC ont facilité le processus d’angiogenèse. [ABSTRACT FROM AUTHOR]

Abstract: Aim: To compare the effects of crocetin and crocin on myocardial injury in rats. Methods: In vitro, the myocardial cells injured by low glucose and hypoxia were treated with serum from rats given crocetin (50 mg·kg−1) or crocin (150 mg·kg−1). The levels of LDH, CK, MDA and SOD in culture medium were measured and the cell activity was detected by MTT. In vivo, a rat myocardial ischemia model was set up using the coronary ligation technique. J point shift and T wave change in the electrocardiograph (ECG) in 6 hours after the treatment and area of myocardial infarction were assessed. The histopathological change of myocardium was observed by HE staining. The serum samples were collected to measure the levels of LDH and CK. Results: In vitro, serum containing crocetin decreased the levels of LDH, CK and MDA, increased the level of SOD and the activity of cardiac myocytes. However, serum containing crocin showed no significant protective effect. Compared to the model group, crocetin downshifted the J point and T wave in the ECG evaluation, decreased the levels of serum LDH and CK and the area of the myocardial infarction. Crocetin reduced the histopathological changes caused by myocardial injury. Conclusions: ig crocetin can significantly protect the injured myocardial cell both in vivo and in vitro while ig crocin can not. It suggests that crocetin by oral administration is suitable to cure myocardial ischemia in clinical practice, while crocin by oral administration is not. [Copyright &y& Elsevier]

Abstract: It has been recently suggested that bradykinin (BK) may act as a cardioprotectve agent. In the present investigation, we evaluated the effects of captopril, an angiotensin-converting enzyme inhibitor (ACEI), and kinin B2 receptor antagonist, d-Arg-[Hyp3-d-Phe7]-BK, on the duration of survival after acute coronary artery ligation for 15min in spontaneously hypertensive rats (SHR). The captopril treatment (16 and 32ug/kg, i.v.) resulted in a significant (p &#60;0.05) increase in survival time of SHR as compared with saline-treated control SHR. Kinin B2 receptors antagonist (4ug/kg, i.v.) pretreatment abolished (p >0.05) the beneficial effect of captopril on survival time as compared to saline-treated control SHR. Both the ligation of coronary artery and captopril treatment resulted in a significant (p &#60;0.001) fall in systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) of SHR as compared to the saline-treated control SHR. In addition, captopril administration caused a significant (p &#60;0.05) fall in the SBP, DBP and HR of SHR before ligation of the coronary artery (preligation). However, there was no significance (p >0.05) in SBP, DBP and HR between saline- and kinin B2 receptor antagonist plus captopril-treated SHR during preligation. These finding might indicate that captopril possesses a cardioprotective property as demonstrated by increased in survival time of SHR. This beneficial effect of captopril is mediated via the kinin B2 receptor pathway because kinin B2 receptor antagonist pretreatment blocked the captopril-induced increase in survival time of SHR. [Copyright &y& Elsevier]

Abstract: The mechanism by which Na+–H+ exchange (NHE) inhibition results in attenuation and reversal of postinfarction remodelling and heart failure remains controversial. In this study, we investigated the possible contribution of mitochondrial involvement by determining the effect of the NHE-1-specific inhibitor EMD-87580 (EMD) on mitochondrial permeability transition (MPT) and respiratory function during the postinfarction remodelling process. Male Sprague–Dawley rats were subjected to either 12 or 18 weeks of coronary artery ligation (CAL) or sham procedure. EMD was provided in the diet immediately after ligation. MPT pore opening was determined by perfusing hearts with 2-deoxy-[3H]-glucose ([3H]-DOG) and measurement of mitochondrial [3H]-DOG entrapment. The respiratory function of isolated mitochondria was measured using Clark-type oxygen electrode. Remodelling was associated with significant hypertrophy and there was an increase in MPT pore opening in hearts both 12 and 18 weeks following CAL. Mitochondrial respiratory function, especially state 2 and state 3 rates were significantly decreased in hearts subjected to CAL. EMD suppressed MPT pore opening by 40% (P &#60; 0.01) and 35% (P &#60; 0.01) 12 and 18 weeks after ligation, respectively. Mitochondria isolated from EMD treated hearts exhibited increased respiratory chain activity for oxidation of substrates at complex I and II. These beneficial effects of EMD were associated with decreased mitochondrial vulnerability to exogenous Ca2+. We conclude that NHE-1 inhibition has a protective effect on mitochondrial function, attenuating MPT pore opening and improving the respiratory function, which may contribute to the salutary effect of NHE-1 inhibitors in heart failure. [Copyright &y& Elsevier]

Several anesthetics are known to cause respiratory and cardiovascular depression in humans and animals; but, these diverse effects have not been extensively investigated in laboratory rodents. The objective of this study is to choose a suitable anesthetic combination for use in surgical models eg. coronary artery ligation in rats. Male Wistar rats were anesthetized with three different drugs viz. diazepam-ketamine (DK) (2.5 mg/Kg, intraperitoneally (i.p); 50 mg/Kg, i.p), xylazine-ketamine (XK) (5 mg/Kg i.p; 50 mg/Kg i.p) and thiopentone (T) (40 mg/Kg i.p) and the respiratory and cardiovascular functions were assessed after coronary artery ligation. Heart rate (HR), mean arterial pressure (MAP), partial pressure of carbon dioxide (PaCO2), partial pressure of oxygen (PaO2), oxygen saturation percentage (O2 sat (%)), arterial blood pH and rectal body temperature were studied in detail. During the anesthetic regime, HR was lower till 60 min in XK and T ligated group (333 ± 6; 304 ± 8 beats/min) and it was near normalcy in the case of DK ligated group (394 ± 6 beats/min). Significant respiratory depression was particularly reflected in the T ligated group with an increase in PaCO2 at 30 min (40.32 ± 2.64 mmHg), which decreased to 38.2 ± 2.23 mmHg at 60 min. Throughout the investigation, DK showed the least overall effects compared to XK and T on respiratory functions. Thus, DK could be considered to be a suitable anesthetic for use in a surgical model such as coronary artery ligation in albino rats. [Copyright &y& Elsevier]

There is evidence that the kallikrein-kinin system (KKS) is an important mediator in the regulation of blood pressure, and cardiac and renal hemodynamics. The present study was designed to examine the effect of tissue kallikrein and Trasylol, an inhibitor of tissue kallikrein, on survival time after continuous (prolonged) coronary artery ligation in spontaneously hypertensive rats (SHR). Tissue kallikrein (8 and 16 μg/kg, i.v.) treatment caused significant (p < 0.05) increases in the survival time of SHR as compared with the saline-treated control SHR. Trasylol pretreatment abolished (p < 0.05) the beneficial effect of tissue kallikrein on survival time. The tissue kallikrein treatment resulted in a significant (p < 0.05) reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) of SHR as compared to the saline-treated control SHR. Trasylol (6 μg/kg) treatment antagonized the effects of tissue kallikrein associated with survival time, SBP, DBP and HR. Ligation of the coronary artery caused a significant (p < 0.001) reduction in the SBP, DBP and HR of SHR, when the mean values were compared between before coronary artery ligation and after coronary artery ligation. However, there was no significant difference (p > 0.05) in SBP, DBP and HR between saline and kallikrein-treated SHR after coronary artery ligation. These findings may suggest that tissue kallikrein is able to act as a cardioprotective agent as demonstrated by an increase in survival time of SHR with prolonged coronary artery ligation. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

It is known that the tissue kallikrein–kinin system is located in the cardiac tissue, and the lack of this system in the cardiac tissue might induce cardiac dysfunctions. In this study, we investigated the potential role of tissue kallikrein and Trasylol, an inhibitor of tissue kallikrein, on survival time with acute left coronary artery ligation for 15 min in spontaneously hypertensive rats (SHR). Tissue kallikrein (8 and 16 μg/kg, i.v.) treatment caused significant (P<0.05) increases in the survival time of SHR as compared with the saline-treated control SHR. Trasylol pretreatment abolished (P<0.05) the beneficial effect on tissue kallikrein on survival time. The ligation of coronary artery resulted in significant (P<0.05) reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) of SHR compared with the saline-treated control SHR. The tissue kallikrein treatment caused greater (P<0.001) reduction in the SBP, DBP and HR of SHR, when the mean values were compared between before coronary artery ligation and after coronary artery ligation. Trasylol (6 μg/kg) treatment antagonized the effects of tissue kallikrein associated with survival time, SBP, DBP and HR. These findings may suggest that tissue kallikrein is able to act as a cardioprotective agent as demonstrated by the increase in survival time of SHR with acute coronary artery ligation. The significance of these observations is discussed. [Copyright &y& Elsevier]

Background: Production of several heat shock proteins (Hsp) is enhanced after exposure to stress. There is little information concerning changes in myocardial Hsp under pathophysio­logical conditions. The aim of this study was to determine alterations in Hsp content in the viable left ventricular myocardium during the development of heart failure following coronary artery ligation (CAL). Methods: Myocardial infarction was produced by CAL of Wistar rats. One and eight weeks after the operation, haemodynamic parameters of rats with CAL were determined and then expression of Hsp27, Hsp60 and Hsp72 was measured by western blotting. Results: Animals showed a decrease in cardiac output and an increase in left ventricular end-diastolic pressure, symptoms of chronic heart failure (CHF), 8 weeks after CAL. Myocardial Hsp27 and Hsp72 at 1 week after CAL significantly increased, whereas expression of both proteins at 8 weeks was similar to that in rats which underwent a sham operation (without coronary artery ligation). In contrast, Hsp60 at 8 weeks, but not at 1 week, significantly increased in the sham rats. Conclusions: Diverse changes in myocardial Hsp occurred during the development of CHF. (Heart, Lung and Circulation 2003; 12: 60-65). [ABSTRACT FROM AUTHOR]

Objective: To compare the preventive effect of treatment with different methods of traditional Chinese medicine(TCM) for myocardial ischemia caused by coronary artery ligation in diabetic rats. Methods:Animal models established by streptozotocin plus coronary artery ligation were treated by modified Taoren Chengqi Decoction (MTRCQD) and different combinations of its ingredients respectively, and the effects on ischemia area, occurrence of arrhythmia, T-wave in ECG and 2 hrs post-operational survival rate were observed and compared. Results: MTRCQD and different combinations of its ingredients could reduce the area of ischemia and elevate survival rate significantly (P<0.05-0.01), especially in the group treated with MTRCQD plus leech. Improvement of T-wave was shown in the groups treated with MTRCQD or with MTRCQD plus leech. Conclusion: TCM treatment of invigorating Qi, nourishing Yin, purging Heat and activating blood circulation is an effective treatment for diabetic coronary heart disease. [ABSTRACT FROM AUTHOR]

Regional infarction of the left ventricle is followed by hypertrophy of the viable myocardium. This compensatory growth of cardiac myocytes requires induction of gene transcription and synthesis of proteins. In this study, we examined the expression of the immediate-early response gene c-fos following ligation of the left coronary artery in rat hearts. RNase protection assay demonstrated a rapid increase in the c-fos mRNA level in the ventricular myocardium. After two days of infarction, the c-fos expression was attenuated and was comparable to that observed in sham-operated control hearts. In situ tissue distribution of Fos protein-like immunoreactivity revealed the appearance of positively stained cells adjacent to the lateral border of the ischaemic myocardium, in the left ventricular subendocardial areas, in the papillary muscles of the left ventricle, in the proximity of great transmural vessels, and focally in the normo-perfused subepicardial myocardium. Double staining using antibodies recognizing the Fos protein and α-actinin, confirmed that the accumulation of nuclear Fos protein-like immunoreactivity was mainly seen in the cardiac myocytes. However, double staining of the Fos protein and Hoechst DNA labelling showed that detectable immunoreactivity occurred only in a limited proportion of the total nuclei present in these myocardial regions. Moreover, the regions showing c-fos activation correspond to the areas in which the appearance of subsequent growth responses are most pronounced following myocardial infarction. The present results therefore indicate that an early and regional c-fos activation is taking place in viable cardiac myocytes following left coronary artery ligation, and that c-fos is a possible regulating factor of sequential events leading to altered pattern of gene expression and protein synthesis in the hypertrophying heart. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate whether the decreased early survival rate of diabetic rats submitted to acute experimental myocardial infarction can be improved by pretreatment with lidocaine. Male Wistar rats (±210g) were rendered diabetic with i.v. injection of streptozotocin (50 mg/kg), and only those presenting 1 week later a tail-blood glucose value between 250-400 mg/dl were retained in the protocol. Eleven weeks after induction of diabetes, a bolus of lidocaine (2mg/kg) was administered i.v. about 6 min prior to ligation of the left coronary artery under ether anesthesia in control (n=54) and diabetic (n=48) rats; similar studies were conducted in 53 control and 55 diabetic rats without lidocaine pretreatment. Adequate occlusion was confirmed by an elevation of plasma CK-MB levels 4h later or by a toluidine blue injection technique in rats which died earlier. Rats were followed over 48h and comparison in the survival rate in each group established with the Fisher's exact test. Early survival rate (measured after 20 min) was significantly decreased in diabetic rats (27% vs 45%; p=0.04). This was greatly improved by lidocaine pretreatment in diabetic (60% vs 27%; p=0.0013), but not in control animals (50% vs 45%; p=0.384). Furthermore, the beneficial effect of prophylactic lidocaine observed early after coronary ligation in diabetic rats was maintained throughout the period of observation (48h). These data suggest that the prophylactic use of lidocaine is able to reverse the increased incidence of sudden death following experimental myocardial infarction in chronically diabetic rats. [ABSTRACT FROM AUTHOR]

The effects of i.v. molsidomine and dopamine infusion on mean haemodynamic changes, myocardial oxygen consumption (pressure-rate-product), and ultimate infarct size were studied in pentobarbital-anaesthetized, open-chest dogs and compared to those occurring in dogs receiving saline infusion. Either agent was administered in a separate setting. Haemodynamic variables and oxygen consumption were determined during a 6-h period after ligation of the left anterior descending coronary artery and collected at 1-h intervals. Infarct size was determined by post-mortem nitroblue tetrazolium stain of intracellular lactic dehydrogenase enzymes. Coronary artery ligation during saline infusion ( n=8) resulted in decreased blood pressure and cardiac output, whereas heart rate, systemic peripheral resistance, end-diastolic filling pressure and myocardial oxygen consumption increased. Infarct size amounted to 24.2±3.2% (i. e., 23.8±3.1 g) of left ventricular mass. Infusion of 1.4 μg/kg/min molsidomine ( n=8) produced significant fall of blood pressure, cardiac output, filling pressure and oxygen consumption while heart rate and peripheral resistance were unaffected. The infarct volume was reduced to 49% ( P<0.01) of that observed in saline controls. The administration of 3 μg/kg/min dopamine ( n=8) elevated blood pressure and cardiac output initially with a subsequent reduction of either parameter. Arteriolar vascular resistance and oxygen consumption increased but filling pressure remained unchanged. Infarct size was not different from saline controls. Infusion of 6 μg/kg/min dopamine, however, significantly increased blood pressure, heart rate, and peripheral resistance. Cardiac output and filling pressure fell and myocardial oxygen consumption rose. The histochemically measured final infarct was reduced to 13.5±1.8% of left ventricle (i. e., 16.2±2.2 g, P<0.05 vs saline control), but the hearts were edematous and haemorrhagic. Therapy with molsidomine appears promising in the treatment of clinical myocardial infarction with haemodynamic sequellae. The safe use of therapy with higher dopamine doses in patients with acute myocardial infarction, however, awaits further investigation. [ABSTRACT FROM AUTHOR]

Objective: The aim was to investigate the effects of glibenclamide, a specific blocker of the ATP sensitive potassium channel, on the incidence of ventricular arrhythmias and the functional changes occurring during myocardial ischaemia and reperfusion. Methods: Hearts (n=10 per group) were obtained from male Wistar rats, weight 250-300 g. The study was performed in isolated Langendorff perfused rat hearts subjected to ligation of the left coronary artery and reperfusion. Because of the occurrence of arrhythmias, cardiac function was not evaluated during reperfusion. Glibenclamide (1 or 10 μM) was added to the perfusion solution before the coronary artery occlusion, during ischaemia or after reperfusion. In some experiments the incidence of various durations of ischaemia (5, 10, 15, and 30 min) was evaluated. Results: During the preischaemic period, glibenclamide induced a marked reduction in coronary flow, with a slight decrease in heart rate and left ventricular pressure. The ischaemia induced decrease in left ventricular pressure was markedly attenuated when glibenclamide was given before ischaemia. Thus the isovolumetric left ventricular pressure measured after 15 min ischaemia, which represents 59(SEM 6)% of the preischaemic value in the control group, was increased to 82(9) and 94(8)% in presence of glibenclamide (1 and 10 (μM, p<0.05 respectively). The effect was less pronounced when glibenclamide was added to the perfusion fluid during the ischaemic period. None of the hearts showed ventricular fibrillation during the ischaemic period. Glibenclamide (1 and 10 μM) did not reduce the incidence of reperfusion induced ventricular fibrillation. However, a defibrillatory action was observed since glibenclamide reduced the duration of ventricular fibrillation during reperfusion. Conclusions: Glibenclamide may increase the probability of spontaneous termination of ventricular fibrillation and facilitate the restoration of the myocardial function during regional ischaemia.Cardiovascular Research 1992;26:1069-1076 [ABSTRACT FROM PUBLISHER]

Study objective – The aim was to determine whether surviving myocardium in the infarcted rat heart retains the ability to respond to sustained increases in afterload.Design – Cardiac mass, ventricular function, and actomyosin ATPase activity were compared in animals subjected to coronary artery ligation to produce infarction, superimposed renal artery constriction 4 weeks after infarction, and in sham operated animals.Experimental material – Female Wistar rats obtained at 10 weeks of age (200-225 g) were used for the studies.Measurements and main results – Four weeks after coronary artery ligation, infarcted hearts showed a 22% increase in heart weight and a significant reduction in peak systolic pressure and +/- dP/dt during acute volume infusion and aortic occlusion compared to sham operated hearts. Eight weeks after the initial surgical intervention, the infarct group showed significant impairment in ventricular performance compared to the sham operated group but no further decrement was observed between hearts with infarction and those with infarct and superimposed renal artery constriction for peak systolic pressure and +/- dP/dt during volume infusion and aortic occlusion. Actomyosin ATPase activity, however, was depressed and the shift to V3myosin isoenzyme was greater in infarct and renal artery constriction compared to infarct alone.Conclusions – Left ventricular myocardium following infarction does not retain the ability to increase cardiac mass and shows depressed levels of actomyosin ATPase activity when exposed to a superimposed chronic afterload from renal artery constriction. However, cardiac function in situ is maintained. [ABSTRACT FROM PUBLISHER]