ABSTRACT
PURPOSE: Esaxerenone, a mineralocorticoid receptor blocker, attenuates global ischemia-induced myocardial damage and coronary endothelial dysfunction. This study aimed to determine whether esaxerenone exerted cardioprotective effects against cardioplegic arrest in Wistar rat hearts. METHODS: Isolated male Wistar rat hearts aerobically perfused via the Langendorff method for 20 min were randomly allocated to the Control (n = 6; perfused for an additional 10 min and subjected to no treatment) or Esax (n = 6; perfused with 0.1 µmol/L esaxerenone in perfusate for 10 min before ischemia) groups. Hearts in both groups were perfused with St. Thomas' Hospital No. 2 solution (STH2) for 2 min and subjected to 28 min of global ischemia. The recovery of left ventricular developed pressure (LVDP) and total troponin T leakage were measured after reperfusion. RESULTS: The final recovery of LVDP (expressed as a percentage of pre-ischemic value) in the Control and Esax groups was 50.8 ± 3.5% and 62.1 ± 5.6%, respectively (p <0.05, Esax vs. Control). The total troponin T leakage in the Control and Esax groups was 138.8 ± 18.5 ng/g heart wt and 74.3 ± 18.6 ng/g heart wt, respectively (p <0.05, Esax vs. Control). CONCLUSION: The administration of esaxerenone before cardioplegic arrest enhanced the cardioprotective effect exerted by STH2.
Subject(s)
Disease Models, Animal , Heart Arrest, Induced , Isolated Heart Preparation , Mineralocorticoid Receptor Antagonists , Myocardial Reperfusion Injury , Rats, Wistar , Sulfones , Troponin T , Ventricular Function, Left , Ventricular Pressure , Animals , Male , Ventricular Function, Left/drug effects , Mineralocorticoid Receptor Antagonists/pharmacology , Myocardial Reperfusion Injury/prevention & control , Myocardial Reperfusion Injury/physiopathology , Troponin T/blood , Time Factors , Sulfones/pharmacology , Ventricular Pressure/drug effects , Recovery of Function , Myocardium/metabolism , Myocardium/pathology , Cardioplegic Solutions/pharmacology , PyrrolesABSTRACT
Despite important advancements in the diagnosis and treatment of cardiovascular diseases (CVDs), the field is in urgent need of increased research and scientific advancement. As a result, innovation, improvement and/or repurposing of the available research toolset can provide improved testbeds for research advancement. Langendorff perfusion is an extremely valuable research technique for the field of CVD research that can be modified to accommodate a wide array of experimental needs. This tailoring can be achieved by personalizing a large number of perfusion parameters, including perfusion pressure, flow, perfusate, temperature, etc. This protocol demonstrates the versatility of Langendorff perfusion and the feasibility of achieving longer perfusion times (4 h) without graft function loss by utilizing lower perfusion pressures (30-35 mmHg). Achieving extended perfusion times without graft damage and/or function loss caused by the technique itself has the potential to eliminate confounding elements from experimental results. In effect, in scientific circumstances where longer perfusion times are relevant to the experimental needs (i.e., drug treatments, immunological response analysis, gene editing, graft preservation, etc.), lower perfusion pressures can be key for scientific success.
Subject(s)
Perfusion , Animals , Perfusion/methods , Rats , Heart Transplantation/methods , Isolated Heart Preparation/methodsABSTRACT
Antiviral therapies for treatment of COVID-19 may be associated with significant proarrhythmic potential. In the present study, the potential cardiotoxic side effects of these therapies were evaluated using a Langendorff model of the isolated rabbit heart. 51 hearts of female rabbits were retrogradely perfused, employing a Langendorff-setup. Eight catheters were placed endo- and epicardially to perform an electrophysiology study, thus obtaining cycle length-dependent action potential duration at 90% of repolarization (APD90), QT intervals and dispersion of repolarization. After generating baseline data, the hearts were assigned to four groups: In group 1 (HXC), hearts were treated with 1 µM hydroxychloroquine. Thereafter, 3 µM hydroxychloroquine were infused additionally. Group 2 (HXC + AZI) was perfused with 3 µM hydroxychloroquine followed by 150 µM azithromycin. In group 3 (LOP) the hearts were perfused with 3 µM lopinavir followed by 5 µM and 10 µM lopinavir. Group 4 (REM) was perfused with 1 µM remdesivir followed by 5 µM and 10 µM remdesivir. Hydroxychloroquine- and azithromycin-based therapies have a significant proarrhythmic potential mediated by action potential prolongation and an increase in dispersion. Lopinavir and remdesivir showed overall significantly less pronounced changes in electrophysiology. In accordance with the reported bradycardic events under remdesivir, it significantly reduced the rate of the ventricular escape rhythm.
Subject(s)
Action Potentials , Antiviral Agents , Isolated Heart Preparation , Animals , Rabbits , Female , Antiviral Agents/pharmacology , Antiviral Agents/toxicity , Action Potentials/drug effects , COVID-19 Drug Treatment , Hydroxychloroquine/toxicity , Hydroxychloroquine/pharmacology , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/physiopathology , Cardiotoxicity , Alanine/analogs & derivatives , Alanine/pharmacology , Heart Rate/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/toxicity , Adenosine Monophosphate/pharmacology , Heart/drug effectsABSTRACT
BACKGROUND: We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear. METHODS AND RESULTS: The effects of ibrutinib on cardiac electrical activity and Ca2+ dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca2+-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P<0.002) and shorter action potential durations during pacing at various frequencies (P<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (P<0.05). Significant changes in myocardial Ca2+ transients included lower amplitude alternans ratios (P<0.05), longer times-to-peak (P<0.05), and greater spontaneous intracellular Ca2+ elevations (P<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside ameliorated abnormalities in action potential and Ca2+ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside, P<0.05) in hearts from ibrutinib-treated rats. CONCLUSIONS: VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.
Subject(s)
AMP-Activated Protein Kinases , Action Potentials , Adenine , Arrhythmias, Cardiac , Piperidines , Pyrazoles , Pyrimidines , Animals , Adenine/analogs & derivatives , Adenine/pharmacology , Piperidines/pharmacology , Action Potentials/drug effects , Pyrimidines/pharmacology , AMP-Activated Protein Kinases/metabolism , Pyrazoles/pharmacology , Male , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/metabolism , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/prevention & control , Protein Kinase Inhibitors/pharmacology , Heart Rate/drug effects , Isolated Heart Preparation , Calcium/metabolism , Rats , Disease Models, Animal , Rats, Sprague-Dawley , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Calcium Signaling/drug effects , Time FactorsABSTRACT
AIMS: Electroanatomical adaptations during the neonatal to adult phase have not been comprehensively studied in preclinical animal models. To explore the impact of age as a biological variable on cardiac electrophysiology, we employed neonatal and adult guinea pigs, which are a recognized animal model for developmental research. METHODS AND RESULTS: Electrocardiogram recordings were collected in vivo from anaesthetized animals. A Langendorff-perfusion system was employed for the optical assessment of action potentials and calcium transients. Optical data sets were analysed using Kairosight 3.0 software. The allometric relationship between heart weight and body weight diminishes with age, it is strongest at the neonatal stage (R2 = 0.84) and abolished in older adults (R2 = 1E-06). Neonatal hearts exhibit circular activation, while adults show prototypical elliptical shapes. Neonatal conduction velocity (40.6 ± 4.0 cm/s) is slower than adults (younger: 61.6 ± 9.3 cm/s; older: 53.6 ± 9.2 cm/s). Neonatal hearts have a longer action potential duration (APD) and exhibit regional heterogeneity (left apex; APD30: 68.6 ± 5.6 ms, left basal; APD30: 62.8 ± 3.6), which was absent in adults. With dynamic pacing, neonatal hearts exhibit a flatter APD restitution slope (APD70: 0.29 ± 0.04) compared with older adults (0.49 ± 0.04). Similar restitution characteristics are observed with extrasystolic pacing, with a flatter slope in neonates (APD70: 0.54 ± 0.1) compared with adults (younger: 0.85 ± 0.4; older: 0.95 ± 0.7). Neonatal hearts display unidirectional excitation-contraction coupling, while adults exhibit bidirectionality. CONCLUSION: Postnatal development is characterized by transient changes in electroanatomical properties. Age-specific patterns can influence cardiac physiology, pathology, and therapies for cardiovascular diseases. Understanding heart development is crucial to evaluating therapeutic eligibility, safety, and efficacy.
Subject(s)
Action Potentials , Adaptation, Physiological , Animals, Newborn , Animals , Guinea Pigs , Age Factors , Heart Rate/physiology , Electrocardiography , Aging/physiology , Isolated Heart Preparation , Calcium Signaling , Male , Heart/physiology , Voltage-Sensitive Dye Imaging , Time Factors , Body Weight , Heart Conduction System/physiology , FemaleABSTRACT
ABSTRACT: Exercise preconditioning has been shown to protect against doxorubicin (DOX)-induced cardiac dysfunction when hearts are maintained under resting conditions. However, it is unclear whether this exercise-induced protective effect is maintained when the heart is challenged with the ß 1 -adrenergic receptor agonist dobutamine (DOB), which mimics acute exercise stress. Fischer 344 rats were randomly assigned to sedentary (SED) or voluntary wheel running (WR) groups for 10 weeks. At week 11, rats were treated with either 15 mg/kg DOX or saline. Five days later, ex vivo cardiac function was assessed using an isolated working heart model at baseline, during the infusion of 7.5 µg·kg -1 ·min -1 DOB, and during recovery. DOB infusion significantly increased left ventricular developed pressure (LVDP), maximal (dP/dt max ) and minimal (dP/dt min ) rate of left ventricular pressure development, and heart rate in all groups ( P < 0.05). SED + DOX also showed a lower baseline and recovery LVDP than WR + DOX (83 ± 12 vs. 109 ± 6 mm Hg baseline, 76 ± 11 vs. 100 ± 10 mm Hg recovery, P < 0.05). WR + DOX showed higher dP/dt max and lower dP/dt min when compared with SED + DOX during DOB infusion (7311 ± 1481 vs. 5167 ± 1436 mm Hg/s and -4059 ± 1114 vs.-3158 ± 1176 mm Hg/s, respectively). SED + DOX dP/dt max was significantly lower during baseline and during recovery when compared with all other groups ( P < 0.05). These data suggest that exercise preconditioning preserved cardiac function after DOX exposure even when the heart is challenged with DOB, and it appeared to preserve the heart's ability to recover from this functional challenge.
Subject(s)
Adrenergic beta-1 Receptor Agonists , Dobutamine , Doxorubicin , Rats, Inbred F344 , Recovery of Function , Ventricular Function, Left , Animals , Dobutamine/pharmacology , Male , Ventricular Function, Left/drug effects , Adrenergic beta-1 Receptor Agonists/pharmacology , Physical Conditioning, Animal , Heart Rate/drug effects , Rats , Isolated Heart Preparation , Disease Models, Animal , Ventricular Pressure/drug effects , Antibiotics, Antineoplastic/toxicity , CardiotoxicityABSTRACT
BACKGROUND: The heart can metabolize the microbiota-derived short-chain fatty acid butyrate. Butyrate may have beneficial effects in heart failure, but the underlying mechanisms are unknown. We tested the hypothesis that butyrate elevates cardiac output by mechanisms involving direct stimulation of cardiac contractility and vasorelaxation in rats. METHODS AND RESULTS: We examined the effects of butyrate on (1) in vivo hemodynamics using parallel echocardiographic and invasive blood pressure measurements, (2) isolated perfused hearts in Langendorff systems under physiological conditions and after ischemia and reperfusion, and (3) isolated coronary arteries mounted in isometric wire myographs. We tested Na-butyrate added to injection solutions or physiological buffers and compared its effects with equimolar doses of NaCl. Butyrate at plasma concentrations of 0.56 mM increased cardiac output by 48.8±14.9%, stroke volume by 38.5±12.1%, and left ventricular ejection fraction by 39.6±6.2%, and lowered systemic vascular resistance by 33.5±6.4% without affecting blood pressure or heart rate in vivo. In the range between 0.1 and 5 mM, butyrate increased left ventricular systolic pressure by up to 23.7±3.4% in isolated perfused hearts and by 9.4±2.9% following ischemia and reperfusion, while reducing myocardial infarct size by 81.7±16.9%. Butyrate relaxed isolated coronary septal arteries concentration dependently with an EC50=0.57 mM (95% CI, 0.23-1.44). CONCLUSIONS: We conclude that butyrate elevates cardiac output through mechanisms involving increased cardiac contractility and vasorelaxation. This effect of butyrate was not associated with adverse myocardial injury in damaged hearts exposed to ischemia and reperfusion.
Subject(s)
Butyrates , Cardiotonic Agents , Myocardial Contraction , Vasodilation , Vasodilator Agents , Ventricular Function, Left , Animals , Male , Myocardial Contraction/drug effects , Ventricular Function, Left/drug effects , Vasodilation/drug effects , Cardiotonic Agents/pharmacology , Butyrates/pharmacology , Vasodilator Agents/pharmacology , Isolated Heart Preparation , Rats , Myocardial Reperfusion Injury/physiopathology , Myocardial Reperfusion Injury/prevention & control , Myocardial Reperfusion Injury/metabolism , Cardiac Output/drug effects , Stroke Volume/drug effects , Rats, Wistar , Coronary Vessels/drug effects , Coronary Vessels/physiopathology , Dose-Response Relationship, Drug , Disease Models, Animal , Rats, Sprague-DawleyABSTRACT
BACKGROUND: Although moderate endurance exercise has been reported to improve cardiovascular health, its effects on cardiac structure and function are not fully characterized, especially with respect to sexual dimorphism. We aimed to assess the effects of moderate endurance exercise on cardiac physiology in male versus female mice. METHODS AND RESULTS: C57BL/6J mice of both sexes were run on a treadmill for 6 weeks. ECG and echocardiography were performed every 2 weeks. After 6 weeks of exercise, mice were euthanized, and triple parametric optical mapping was performed on Langendorff perfused hearts to assess cardiac electrophysiology. Arrhythmia inducibility was tested by programmed electrical stimulation. Left ventricular tissue was fixed, and RNA sequencing was performed to determine exercise-induced transcriptional changes. Exercise-induced left ventricular dilatation was observed in female mice alone, as evidenced by increased left ventricular diameter and reduced left ventricular wall thickness. Increased cardiac output was also observed in female exercised mice but not males. Optical mapping revealed further sexual dimorphism in exercise-induced modulation of cardiac electrophysiology. In female mice, exercise prolonged action potential duration and reduced voltage-calcium influx delay. In male mice, exercise reduced the calcium decay constant, suggesting faster calcium reuptake. Exercise increased arrhythmia inducibility in both male and female mice; however, arrhythmia duration was increased only in females. Lastly, exercise-induced transcriptional changes were sex dependent: females and males exhibited the most significant changes in contractile versus metabolism-related genes, respectively. CONCLUSIONS: Our data suggest that moderate endurance exercise can significantly alter multiple aspects of cardiac physiology in a sex-dependent manner. Although some of these effects are beneficial, like improved cardiac mechanical function, others are potentially proarrhythmic.
Subject(s)
Arrhythmias, Cardiac , Mice, Inbred C57BL , Physical Conditioning, Animal , Animals , Female , Male , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/etiology , Physical Conditioning, Animal/physiology , Mice , Sex Factors , Ventricular Function, Left/physiology , Action Potentials , Physical Endurance/physiology , Ventricular Remodeling/physiology , Heart Rate/physiology , Isolated Heart Preparation , Sex CharacteristicsABSTRACT
Decreased nicotinamide adenine dinucleotide (NAD+) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD+ precursor due to efficient NAD+ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and 13C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) ("mild glycolysis group"), (b) lactate + pyruvate + FA ("no glycolysis group"), or (c) glucose + FA + insulin ("high glycolysis group"). NR increased cardiac NAD+ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the "no glycolysis" hearts, NR protection was lost, whereas NR still increased S7P. In the insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high 13C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining "no glycolysis" hearts or "high glycolysis" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of insulin because of already elevated glycolysis.
Subject(s)
Glycolysis , Insulin , Mice, Inbred C57BL , Myocardial Reperfusion Injury , Niacinamide , Pyridinium Compounds , Animals , Pyridinium Compounds/pharmacology , Glycolysis/drug effects , Insulin/metabolism , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/prevention & control , Niacinamide/pharmacology , Niacinamide/analogs & derivatives , Male , Myocardium/metabolism , Mice , Isolated Heart Preparation , Metabolomics , NAD/metabolism , Disease Models, Animal , Citric Acid Cycle/drug effectsABSTRACT
Nicotine is the primary addictive component of tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. To assess the underlying mechanisms, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days before performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the first to third thoracic vertebrae, and ß-adrenergic responsiveness was additionally evaluated following norepinephrine (NE) perfusion. Baseline ex vivo heart rate (HR) and SNS stimulation threshold were higher in NIC versus CT (P = 0.004 and P = 0.003, respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC versus CT at baseline (P = 0.002) and during SNS (P = 0.0003), with similar results obtained for Ca2+ transient alternans. SNS shortened the PCL at which alternans emerged in CT but not in NIC hearts. NIC-exposed hearts tended to have slower and reduced HR responses to NE perfusion, but ventricular responses to NE were comparable between groups. Although fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P = 0.03) but no difference in NE content versus CT. These results suggest both sympathetic hypoinnervation of the myocardium and regional differences in ß-adrenergic responsiveness with NIC. This autonomic remodeling may contribute to the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with long-term use.NEW & NOTEWORTHY Here, we show that chronic nicotine exposure was associated with increased heart rate, increased susceptibility to alternans, and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to sympathetic hypoinnervation of the myocardium and diminished ß-adrenergic responsiveness of the sinoatrial node following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this proarrhythmic remodeling.
Subject(s)
Action Potentials , Heart Rate , Heart , Nicotine , Sympathetic Nervous System , Animals , Nicotine/toxicity , Nicotine/adverse effects , Rabbits , Heart Rate/drug effects , Action Potentials/drug effects , Heart/innervation , Heart/drug effects , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/physiopathology , Male , Nicotinic Agonists/toxicity , Nicotinic Agonists/administration & dosage , Calcium Signaling/drug effects , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/metabolism , Transdermal Patch , Isolated Heart Preparation , Administration, Cutaneous , Norepinephrine/metabolismABSTRACT
BACKGROUND: Cold static storage and normothermic ex vivo heart perfusion are routinely limited to 6 h. This report describes intermittent left atrial (LA) perfusion that allows cardiac functional assessment in a working heart mode. METHODS: Using our adult porcine model, general anesthesia was induced and a complete cardiectomy was performed following cardioplegic arrest. Back-table instrumentation was completed and normothermic ex vivo heart perfusion (NEHP) was initiated in a nonworking heart mode (Langendorff). After 1 h of resuscitation and recovery, LA perfusion was initiated and the heart was transitioned to a coronary flow-only working heart mode for 30 min. Baseline working heart parameters were documented and the heart was returned to nonworking mode. Working heart assessments were performed for 30 min every 6 h for 24 h. RESULTS: Twenty-four-hour NEHP on 9 consecutive hearts (280â ±â 42.1 g) was successful and no significant differences were found between working heart parameters at baseline and after 24 h of perfusion. There was no difference between initial and final measurements of LA mean pressures (5.0â ±â 3.1 versus 9.0â ±â 6.5 mm Hg, P â =â 0.22), left ventricular systolic pressures (44.3â ±â 7.2 versus 39.1â ±â 9.0 mm Hg, P â =â 0.13), mean aortic pressures (30.9â ±â 5.8 versus 28.1â ±â 8.1 mm Hg, P â =â 0.37), and coronary resistance (0.174â ±â 0.046 versus 0.173â ±â 0.066 mL/min/g, P â =â 0.90). There were also no significant differences between lactate (2.4â ±â 0.5 versus 2.6â ±â 0.4 mmol/L, P â =â 0.17) and glucose (173â ±â 75 versus 156â ±â 70 mg/dL, P â =â 0.37). CONCLUSIONS: A novel model using intermittent LA perfusion to create a coronary flow-only working heart mode for assessment of ex vivo cardiac function has been successfully developed.
Subject(s)
Models, Animal , Perfusion , Animals , Perfusion/methods , Time Factors , Isolated Heart Preparation , Swine , Coronary Circulation , Organ Preservation/methods , Ventricular Function, Left , Heart Transplantation , Sus scrofaABSTRACT
Abstract Background: D-limonene (DL) is a monoterpene and is the major component in the essential oil of citrus fruit. It presents antihyperglycemic and vasodilatation activities. Objectives: This study evaluated the cardiovascular effects and potential antiarrhythmic of DL in rats. Methods: Hemodynamic and electrocardiographic (ECG) parameters were measured in male Wistar rats, which under anesthesia had been cannulated in the abdominal aorta and lower vena cava and had electrodes subcutaneously implanted. In the in vitro approach, the heart was removed and perfused using the Langendorff technique. The significance level adopted was 5% (p < 0.05). Results: DL, in doses of 10, 20, and 40 mg/kg (i.v), produced intense and persistent bradycardia associated with hypotension. Bradycardia with prolonged QTc was observed in the ECG in vivo recording. In the in vivo model of arrhythmia induced by Bay K8644, DL (10 mg/kg) decreased the arrhythmia score from 15.33 ± 3.52 to 4.0 ± 2.64 u.a (p < 0.05, n = 4). In isolated perfused hearts, DL (10-3 M) promoted significant reductions in heart rate (from 228.6 ± 8.5 ms to 196.0 ± 9.3 bpm; p < 0.05) and left ventricular development pressure (from 25.2 ± 3.4 to 5.9 ± 1.8 mmHg; n = 5, p < 0.05). Conclusions: DL produces bradycardia and antiarrhythmic activity in rat heart.
Resumo Fundamento: O D-limoneno (DL) é um monoterpeno e o principal componente do óleo essencial de frutas cítricas. Ele apresenta atividades anti-hiperglicêmicas e vasodilatadoras. Objetivos: Este estudo avaliou os efeitos cardiovasculares e antiarrítmicos potenciais do DL em ratos. Métodos: Os parâmetros hemodinâmicos e eletrocardiográficos (ECG) foram mensurados em ratos Wistar machos que, sob anestesia, tiveram a aorta abdominal e a veia cava inferior canuladas e receberam eletrodos implantados subcutaneamente. Na abordagem in vitro, o coração foi removido e perfundido utilizando a técnica de Langendorff. O nível de significância adotado foi de 5% (p < 0,05). Resultados: DL, nas doses de 10, 20 e 40 mg/kg (i.v), produziu bradicardia intensa e persistente associada à hipotensão. A bradicardia com QTc prolongado foi observada no registro in vivo do ECG. No modelo in vivo de arritmia induzida por Bay K8644, DL (10 mg / kg) houve diminuição do escore da arritmia de 15,33 ± 3,52 para 4,0 ± 2,64 u.a (p < 0,05, n = 4). Em corações perfundidos isolados, o DL (10-3 M) promoveu reduções significativas na frequência cardíaca (de 228,6 ± 8,5 ms para 196,0 ± 9,3 bpm; p < 0,05) e na pressão desenvolvida do ventrículo esquerdo (de 25,2 ± 3,4 para 5,9 ± 1,8 mmHg; n = 5, p < 0,05). Conclusões: O DL produz bradicardia e atividade antiarrítmica no coração de ratos.
Subject(s)
Animals , Male , Arrhythmias, Cardiac/drug therapy , Bradycardia/drug therapy , Limonene/therapeutic use , Anti-Arrhythmia Agents/therapeutic use , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/chemically induced , Blood Pressure/drug effects , Bradycardia/diagnosis , Rats, Wistar , Ventricular Pressure/drug effects , Models, Animal , Electrocardiography , Isolated Heart Preparation , Limonene/pharmacology , Heart Rate/drug effects , Hemodynamics/drug effects , Hypotension , Anti-Arrhythmia Agents/pharmacologyABSTRACT
Estudios clínicos y epidemiológicos sugieren que el danazol ha sido considerado como un factor de riesgo para desarrollar hipertensión. Para proporcionar información adicional acerca de este fenómeno, en este trabajo fue caracterizado el efecto inducido por el danazol y el hemisuccinato de danazol sobre la presión de perfusión y la resistencia vascular en corazón aislado de rata a flujo constante (modelo de Langendorff). Los resultados, mostraron que; 1) el hemisuccinato de danazol [10-9 M] incrementa la presión de perfusión en comparación con el danazol [10-9 M]; 2) los efectos del derivado de danazol [10-9 M - 10-4 M] sobre la presión de perfusión fueron inhibidos por flutamida [10-6 M]; 3) la nifedipina [10-6 M], bloqueó los efectos ejercidos por el hemisuccinato de danazol [10-9 M -10-4 M] sobre la presión de perfusión y 4) el efecto del derivado de danazol [10-9 M - 10-4 M] sobre la presión de perfusión en presencia del montelukast [10-6 M] fue inhibido significativamente (p=0,008). En conclusión, los efectos inducidos por el danazol y hemisuccinato de danazol sobre la presión de perfusión y la resistencia vascular podrían depender de su estructura química. Este fenómeno podría involucrar la interacción del receptor de andrógenos e indirectamente la activación de la síntesis de leucotrienos D4 (LTD4) y consecuentemente inducir variaciones en la presión de perfusión.
Epidemiological and clinical studies suggest that danazol has been considered a risk factor for hypertension development. In order to provide additional information about this phenomenon, the effect induced by both danazol and hemisuccinate of danazol on perfusion pressure and vascular resistance was characterized in isolated rat heart at constant flow (Langendorff model) and it was evaluated in this work.The results showed that; 1) hemisuccinate of danazol [10-9 M] increases perfusion pressure and vascular resistance in comparison with danazol [10-9 M]; 2) the effects of danazol-derivative [10-9 M - 10-4 M] on perfusion pressure were inhibited by flutamide [10-6 M]; 3) nifedipine [10-6 M] blockaded the effects exerted by hemisuccinate of danazol [10-9 M -10-4 M] on perfusion pressure; and 4) the effect of danazol-derivative [10-9 M - 10-4 M] on perfusion pressure in presence of montelukast [10-6 M] was significantly inhibited (p=0.008). In conclusion, the effects induced by both danazol and hemisuccinate of danazol on perfusion pressure and vascular resistance could depend on their chemical structure. This phenomenon could involve the interaction of androgene steroid-receptor and indirect activation of leukotriene D4 (LTD4) synthesis and consequently, induce variations in the perfusion pressure.
Subject(s)
Animals , Rats , Methylprednisolone Hemisuccinate/pharmacology , Danazol/adverse effects , Danazol/pharmacology , Vascular Resistance/drug effects , Coronary Vessels/drug effects , Danazol/analysis , Isolated Heart PreparationABSTRACT
<p><b>OBJECTIVE</b>To observe field potentials (FPs) and activation sequence at Langendorff perfused guinea pigs heart, SD rat cardiac tissue strips perfused by Tyrode's solution and cultured ventricular cardiomyocytes of suckling mice by microeletrode arrays (MEA) technique.</p><p><b>METHOD</b>FPs and activation sequence were recorded from perfused heart, cardiac tissue strips (5 mm x 5 mm) and cultured ventricular cardiomyocytes by MEA.</p><p><b>RESULTS</b>(1) FPs could be recorded in hearts perfused for 30 to 90 min with a heart rate 90 - 120 beats/min. FP durations of both ventricular and atrial tissue were (210 +/- 78) ms and (164 +/- 58) ms, respectively and atrial ventricular conduction time was (320 +/- 150) ms. (2) The excitability of Tyrode's solution perfused tissue strips was visible for more than 2 h, and FP durations of ventricular and atrial tissue strips were (115.80 +/- 11.61) ms and (83.71 +/- 6.48) ms, respectively. (3) Spontaneous beating frequency (150 +/- 100) beats/min and FPs could be readily recorded in cardiomyocytes cultured between 2 to 72 hours.</p><p><b>CONCLUSION</b>MEAs is a sensitive, low noise and stable technique for observing local tissue action potential and activation sequence of whole heart, cardiac tissue strips and cultured cardiomyocytes.</p>