scholarly journals 2297 The direct effect of trimethylamine N-oxide (TMAO) on cardiac muscle contractile mechanics

2018 ◽  
Vol 2 (S1) ◽  
pp. 30-30
Author(s):  
Carlee I. Oakley ◽  
David Sanborn ◽  
Nikita Rafie ◽  
Matt Hendrix ◽  
Michael Grillo ◽  
...  
Keyword(s):  
Contractile Function ◽  
Ex Vivo ◽  
Isometric Force ◽  
Isometric Tension ◽  
Right Atrial ◽  
Organ Bath ◽  
Cardiac Contractile Function ◽  
Rat Cardiomyocytes ◽  
Vehicle Treatment ◽  
Beating Frequency

OBJECTIVES/SPECIFIC AIMS: The objective of this study was to determine if trimethylamine N-oxide (TMAO) alone could acutely alter cardiac contractile function on a beat-to-beat basis. METHODS/STUDY POPULATION: CD1 adult mouse hearts were extracted, attached to a force transducer, oxygenated, and paced within an organ bath. Changes in contractility were measured after pipetting or reverse perfusing TMAO through the aorta via a modified Langendorff apparatus to facilitate TMAO delivery into the myocardium. To determine if our findings translated to the human heart, we performed contractility experiments using human right atrial appendage biopsy tissue retrieved during cardiopulmonary bypass procedures. To investigate whether TMAO alters contractile rate, in a separate series of experiments, the atria and sinoatrial node of isolated hearts were kept intact to allow for spontaneous beating without artificial pacing and were treated with TMAO or vehicle. In addition, intracellular calcium measurements were performed on spontaneously beating embryonic rat cardiomyocytes after TMAO or vehicle treatment. RESULTS/ANTICIPATED RESULTS: We found acute exposure to TMAO, diluted into the organ bath, increased average contraction amplitude 20% and 41% at 300 µM and 3000 µM, respectively (p<0.05, n=6). Langendorff reverse perfusion of mouse hearts ex vivo with 300 µM TMAO generated an even greater response than nonperfusion peripheral exposure and increased isometric force 32% (p<0.05, n=3). Consistent with what we observed in mouse hearts, incubation of human atrial muscle tissue with TMAO at 3000 µM increased isometric tension 31% compared with vehicle (p<0.05, n=4). TMAO treatment (3000 µM) also increased average beating frequency of ex vivo mouse hearts by 27% compared with vehicle (p<0.05, n=3) and increased the spontaneous beating frequency of primary rat cardiomyocytes by 13% compared with vehicle treatment (p<0.05, n=4). DISCUSSION/SIGNIFICANCE OF IMPACT: TMAO, at pathological concentrations, directly increases the force and rate of cardiac contractility. Initially, these inotropic and chronotropic effects may be adaptive during CKD; however, chronic increases in isometric tension and beating frequency can promote cardiac remodeling and heart failure. Further translational studies are needed to understand the intricate relationship between the microbiome, kidneys, and heart and to examine if TMAO represents a therapeutic target for reducing cardiovascular mortality in CKD patients.

scholarly journals Proinflammatory Cytokines Are Soluble Mediators Linked with Ventricular Arrhythmias and Contractile Dysfunction in a Rat Model of Metabolic Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Evaristo Fernández-Sada ◽  
Alejandro Torres-Quintanilla ◽  
Christian Silva-Platas ◽  
Noemí García ◽  
B. Cicero Willis ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Ventricular Arrhythmias ◽  
Mechanical Performance ◽  
Contractile Function ◽  
Ex Vivo ◽  
Heart Function ◽  
Control Group ◽  
Serum Triglycerides ◽  
Rat Cardiomyocytes ◽  
Proinflammatory Mediators

Metabolic syndrome (MS) increases cardiovascular risk and is associated with cardiac dysfunction and arrhythmias, although the precise mechanisms are still under study. Chronic inflammation in MS has emerged as a possible cause of adverse cardiac events. Male Wistar rats fed with 30% sucrose in drinking water and standard chow for 25–27 weeks were compared to a control group. The MS group showed increased weight, visceral fat, blood pressure, and serum triglycerides. The most important increases in serum cytokines included IL-1β(7-fold), TNF-α(84%), IL-6 (41%), and leptin (2-fold), the latter also showing increased gene expression in heart tissue (35-fold). Heart function ex vivo in MS group showed a decreased mechanical performance response to isoproterenol challenge (ISO). Importantly, MS hearts under ISO showed nearly twofold the incidence of ventricular fibrillation. Healthy rat cardiomyocytes exposed to MS group serum displayed impaired contractile function and Ca2+handling during ISO treatment, showing slightly decreased cell shortening and Ca2+transient amplitude (23%), slower cytosolic calcium removal (17%), and more frequent spontaneous Ca2+release events (7.5-fold). As spontaneous Ca2+releases provide a substrate for ventricular arrhythmias, our study highlights the possible role of serum proinflammatory mediators in the development of arrhythmic events during MS.

scholarly journals Redox-Active Drug, MnTE-2-PyP5+, Prevents and Treats Cardiac Arrhythmias Preserving Heart Contractile Function

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Andrezza M. Barbosa ◽  
José F. Sarmento-Neto ◽  
José E. R. Menezes Filho ◽  
Itamar C. G. Jesus ◽  
Diego S. Souza ◽  
...  
Keyword(s):  
Cardiac Arrhythmias ◽  
Contractile Function ◽  
Antiarrhythmic Effect ◽  
Cardiac Contractile Function ◽  
Rat Cardiomyocytes ◽  
Cell Contractility ◽  
Redox Active ◽  
Intracellular Ca

Background. Cardiomyopathies remain among the leading causes of death worldwide, despite all efforts and important advances in the development of cardiovascular therapeutics, demonstrating the need for new solutions. Herein, we describe the effects of the redox-active therapeutic Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, AEOL10113, BMX-010 (MnTE-2-PyP5+), on rat heart as an entry to new strategies to circumvent cardiomyopathies. Methods. Wistar rats weighing 250-300 g were used in both in vitro and in vivo experiments, to analyze intracellular Ca2+ dynamics, L-type Ca2+ currents, Ca2+ spark frequency, intracellular reactive oxygen species (ROS) levels, and cardiomyocyte and cardiac contractility, in control and MnTE-2-PyP5+-treated cells, hearts, or animals. Cells and hearts were treated with 20 μM MnTE-2-PyP5+ and animals with 1 mg/kg, i.p. daily. Additionally, we performed electrocardiographic and echocardiographic analysis. Results. Using isolated rat cardiomyocytes, we observed that MnTE-2-PyP5+ reduced intracellular Ca2+ transient amplitude, without altering cell contractility. Whereas MnTE-2-PyP5+ did not alter basal ROS levels, it was efficient in modulating cardiomyocyte redox state under stress conditions; MnTE-2-PyP5+ reduced Ca2+ spark frequency and increased sarcoplasmic reticulum (SR) Ca2+ load. Accordingly, analysis of isolated perfused rat hearts showed that MnTE-2-PyP5+ preserves cardiac function, increases SR Ca2+ load, and reduces arrhythmia index, indicating an antiarrhythmic effect. In vivo experiments showed that MnTE-2-PyP5+ treatment increased Ca2+ transient, preserved cardiac ejection fraction, and reduced arrhythmia index and duration. MnTE-2-PyP5+ was effective both to prevent and to treat cardiac arrhythmias. Conclusion. MnTE-2-PyP5+ prevents and treats cardiac arrhythmias in rats. In contrast to most antiarrhythmic drugs, MnTE-2-PyP5+ preserves cardiac contractile function, arising, thus, as a prospective therapeutic for improvement of cardiac arrhythmia treatment.

scholarly journals Cardioprotective Natural Compound Pinocembrin Attenuates Acute Ischemic Myocardial Injury via Enhancing Glycolysis

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yanjun Zheng ◽  
Guoqing Wan ◽  
Bo Yang ◽  
Xuefeng Gu ◽  
Jingrong Lin
Keyword(s):  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Glycolytic Enzyme ◽  
Isolated Rat Heart ◽  
Cardiac Contractile Function ◽  
Direct Stimulation ◽  
Underlying Mechanisms

Purpose. Emerging evidence has shown that pinocembrin protects the myocardium from ischemic injury in animals. However, it is unknown whether it has cardioprotection when given at the onset of reperfusion. Also, mechanisms mediating the cardioprotective actions of pinocembrin were largely unknown. Thus, this study is aimed at investigating the effects of pinocembrin postconditioning on ischemia-reperfusion (I/R) injury and the underlying mechanisms. Methods. The in vivo mouse model of myocardial I/R injury, ex vivo isolated rat heart with global I/R, and in vitro hypoxia/reoxygenation (H/R) injury model for primary cardiomyocytes were used. Results. We found that pinocembrin postconditioning significantly reduced the infarct size and improved cardiac contractile function after acute myocardial I/R. Mechanically, in primary cardiomyocytes, we found that pinocembrin may confer protection in part via direct stimulation of cardiac glycolysis via promoting the expression of the glycolytic enzyme, PFKFB3. Besides, PFKFB3 inhibition abolished pinocembrin-induced glycolysis and protection in cardiomyocytes. More importantly, PFKFB3 knockdown via cardiotropic adeno-associated virus (AAV) abrogated cardioprotective effects of pinocembrin. Moreover, we demonstrated that HIF1α is a key transcription factor driving pinocembrin-induced PFKFB3 expression in cardiomyocytes. Conclusions. In conclusion, these results established that the acute cardioprotective benefits of pinocembrin are mediated in part via enhancing PFKFB3-mediated glycolysis via HIF1α, which may provide a new therapeutic target to impede the progression of myocardial I/R injury.

Abstract P089: Estradiol Impairs Cardiac Contractile Function in Male Rodents

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Georgios Kararigas ◽  
Virginie Bito ◽  
Hanna Tinel ◽  
Barbara Albrecht ◽  
Karin R Sipido ◽  
...  
Keyword(s):  
Animal Studies ◽  
Contractile Function ◽  
Ex Vivo ◽  
Cardiac Contractility ◽  
Rna Isolation ◽  
High Risk Group ◽  
Cardiac Contractile Function ◽  
Cell Shortening ◽  
Causal Pathways ◽  
Increased Risk

Several clinical and animal studies have challenged the notion that 17beta-estradiol (E2) is cardioprotective. Recently, we identified that in E2-treated male human cardiac tissues there was an increased expression level of the myosin regulatory light chain (Mrlc) interacting protein (Mylip) gene compared to controls. Mylip has been shown to bind and target Mrlc for proteasomal degradation in neuronal cells. Modulation of contraction by Mrlc in the heart has been well documented. Mutant mice for Mrlc phosphorylation show defects in heart contraction. Here, we tested the hypothesis that the induction of Mylip by E2 is associated with reduced Mrlc protein levels and impaired contractile function. Eleven-month old male C57BL/6J mice were injected intraperitonealy with E2 (n = 6) or vehicle (Ctrl; n = 4). Five hours after injection, cardiomyocytes (CMs) were isolated and were either frozen in TRIzol reagent for RNA isolation or used for cell shortening measurements. Quantitative real-time PCR revealed that E2-treated CMs had higher Mylip levels than Ctrl CMs (49% induction, P < 0.05). In addition, there was a decreased abundance of Mrlc protein in E2-treated CMs compared to Ctrl CMs (74% reduction, P < 0.05). Recordings of unloaded cell shortening at 1, 2 and 4 Hz demonstrated that the treatment with E2 impaired CM contractile function compared to Ctrl CMs (1 Hz: 31%, adjusted P < 0.001; 2 Hz: 30%, adjusted P < 0.01; 4 Hz: 25%, adjusted P < 0.01). Similarly, there was a significant decrease in the rate of contraction of E2-treated CMs compared to controls. Next, we assessed the effect of E2 on cardiac contractility ex vivo using Langendorff-perfused rat hearts. Although at baseline there were no significant changes, the response to isoprenaline was blunted in E2-treated hearts. E2 levels in elderly and/or obese men might increase considerably and they have been associated with an increased risk and incidence of cardiovascular disease. However, explanations for causal pathways and putative mechanisms for this association have not been identified. Based on our present findings, we suggest that MYLIP could contribute to this association and we propose that MYLIP could become a pharmacological target in this high-risk group.

scholarly journals Methanol (80%) leaf extract of Otostegia integrifolia Benth (Lamiaceae) lowers blood pressure in rats through interference with calcium conductance

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Abel Degu ◽  
Abiy Abebe ◽  
Ephrem Engidawork
Keyword(s):  
Blood Pressure ◽  
Leaf Extract ◽  
Ex Vivo ◽  
Isometric Tension ◽  
Antihypertensive Activity ◽  
Phytochemical Analysis ◽  
Organ Bath ◽  
Dependent Manner ◽  
Traditional Use ◽  
Dose Dependent

Abstract Background Otostegia integrifolia Benth. (Lamiaceae) leaves are used to treat hypertension in Ethiopian folk medicine. However, the claim has so far not been investigated scientifically. Thus, the objective of this study was to evaluate the antihypertensive activity of 80% methanol leaf extract of O. integrifolia in animal model of hypertension and possible underlying mechanisms in isolated rat aorta. Methods Antihypertensive effect of various oral doses of the extract (250, 500 and 1000 mg/kg) was determined in fructose-induced hypertensive rats using the non-invasive tail-cuff method. Thoracic aortic strips of rats were isolated and suspended in organ bath, and the vasodepressor effect as well as the possible mechanism (s) of action were studied by means of isometric tension recording experiments ex vivo. Phytochemical analysis was also performed to suggest possible constituents related to the activity. Results Blood pressure was significantly lowered in a dose-dependent manner following extract administration, suggesting that the extract possesses antihypertensive activity. The extract also caused a dose-dependent relaxation of aortic strip precontracted with KCl at a concentration of 6.25–125 μg/L, with a maximum relaxation (100%) achieved at a cumulative concentration of 318.75 μg/ml. The relaxation mechanism was found to be independent of muscarinic receptors, prostanoids, histamine receptors, ATP dependent K+ channels, sarcoplasmic reticulum stored Ca2+ and the endothelium system. The extract shifted the Ca2+ concentration-response curve to the right similar to that caused by nifedipine, suggesting that vasorelaxation could possibly be mediated via calcium channel blockade. The extract was found to contain phenolic compounds (164.3 mg/g, expressed as gallic acid equivalents) and flavonoids (125.7 mg/g, expressed as quercetin equivalents). Conclusion The findings revealed that the plant is endowed with antihypertensive activity, providing evidence for its traditional use. The effect maybe, at least in part, due to dilation of blood vessels through blockade of Ca+ 2 channels mediated by phenolic and flavonoid constituents.

Cytokines and Cardiac Contractile Function

Circulation ◽  
1997 ◽  
Vol 95 (4) ◽  
pp. 778-781 ◽  
Author(s):  
Ralph A. Kelly ◽  
Thomas W. Smith
Keyword(s):  
Contractile Function ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile

scholarly journals Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise

2021 ◽  
Author(s):  
Sophie N Saxton ◽  
Lauren K Toms ◽  
Robert G Aldous ◽  
Sarah B Withers ◽  
Jacqueline Ohanian ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Contractile Function ◽  
Ex Vivo ◽  
Vascular Complications ◽  
Electrical Field Stimulation ◽  
Organic Cation Transporter ◽  
Nervous Stimulation ◽  
Perivascular Adipose Tissue ◽  
Contractile Effect ◽  
Organic Cation Transporter 3

AbstractPurposePerivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and β3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function.MethodsVascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of β3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT.ResultsHigh fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via β3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing β3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored.ConclusionLoss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.

scholarly journals Regulation of Cardiac PKA Signaling by cAMP and Oxidants

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 663
Author(s):  
Friederike Cuello ◽  
Friedrich W. Herberg ◽  
Konstantina Stathopoulou ◽  
Philipp Henning ◽  
Simon Diering
Keyword(s):  
Contractile Function ◽  
Cardiac Contractility ◽  
Cellular Protein ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Main Driver ◽  
Dependent Protein ◽  
Relevant Regulation ◽  
Protein Dysfunction ◽  
Substrate Proteins

Pathologies, such as cancer, inflammatory and cardiac diseases are commonly associated with long-term increased production and release of reactive oxygen species referred to as oxidative stress. Thereby, protein oxidation conveys protein dysfunction and contributes to disease progression. Importantly, trials to scavenge oxidants by systemic antioxidant therapy failed. This observation supports the notion that oxidants are indispensable physiological signaling molecules that induce oxidative post-translational modifications in target proteins. In cardiac myocytes, the main driver of cardiac contractility is the activation of the β-adrenoceptor-signaling cascade leading to increased cellular cAMP production and activation of its main effector, the cAMP-dependent protein kinase (PKA). PKA-mediated phosphorylation of substrate proteins that are involved in excitation-contraction coupling are responsible for the observed positive inotropic and lusitropic effects. PKA-actions are counteracted by cellular protein phosphatases (PP) that dephosphorylate substrate proteins and thus allow the termination of PKA-signaling. Both, kinase and phosphatase are redox-sensitive and susceptible to oxidation on critical cysteine residues. Thereby, oxidation of the regulatory PKA and PP subunits is considered to regulate subcellular kinase and phosphatase localization, while intradisulfide formation of the catalytic subunits negatively impacts on catalytic activity with direct consequences on substrate (de)phosphorylation and cardiac contractile function. This review article attempts to incorporate the current perception of the functionally relevant regulation of cardiac contractility by classical cAMP-dependent signaling with the contribution of oxidant modification.

Myometrial Responses to Beta-Adrenoceptor Antagonists in Gynecological Malignancies

2021 ◽  
pp. 1-8
Author(s):  
Beata Modzelewska ◽  
Marcin Jóźwik ◽  
Tomasz Kleszczewski ◽  
Stanisław Sulkowski ◽  
Maciej Jóźwik
Keyword(s):  
Ovarian Cancer ◽  
Cervical Cancer ◽  
Reference Group ◽  
Ex Vivo ◽  
Contractile Activity ◽  
Organ Bath ◽  
Human Uterus ◽  
Uterine Contractility ◽  
Beta Adrenoceptor ◽  
Gynecological Malignancies

Objective: The aim of the study was to determine the influence of beta-adrenoceptor (ADRB) antagonists on contractile activity of the nonpregnant human uterus in patients affected by gynecological malignancies. Design: This was a controlled and prospective ex vivo study. Setting: The work was conducted as a collaboration between 4 academic departments. Materials and Methods: Myometrial specimens were obtained from women undergoing hysterectomy for benign gynecological disorders (reference group; N = 15), and ovarian (N = 15), endometrial (N = 15), synchronous ovarian-endometrial (N = 3), and cervical cancer (N = 10). Contractions of myometrial strips in an organ bath before and after applications of ADRB antagonists (propranolol, bupranolol, SR 59230A, and butoxamine) were studied under isometric conditions. Results: Propranolol and bupranolol attenuated contractions in the endometrial and cervical cancer groups similar to that in the reference group (all p < 0.05), whereas opposite effects were observed in the ovarian and synchronous ovarian-endometrial cancer groups. SR 59230A and butoxamine significantly increased contractions in the ovarian cancer group (both p < 0.001). Limitations: These results require now to be placed into a firm clinical context. Conclusions: Our study indicates that ovarian cancer considerably alters contractile activity of the nonpregnant human uterus in response to ADRB antagonists. This suggests a pathogenetic role of beta-adrenergic pathways in this malignancy. Furthermore, propranolol and bupranolol substantially influence spontaneous uterine contractility.

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