Bu çalışma, Deutsche Forschungsgemeinschaft (KFO 196 &quot;Signaltransduktion bei adaptativen und maladaptiven kardialen Remodeling-Prozessen&quot;, 1638 / 1-2 FR) tarafından Kalp ve Damar Araştırma, Sağlık Araştırma Merkezleri Alman bir kısmı için DZHK (Almanca Merkezi tarafından desteklenen Bir BMBF (Eğitim ve Araştırma Alman Bakanlığı) girişimi) olan.

Not: izolasyon prosedürü temel adımları Şekil 1 &#39;de belirtilen etaplar aşağıdaki protokolde ayrıntılı olarak tarif edilmiştir.. Papiller kas izolasyonu, organ banyosu odasında montaj, toplama ve analiz ardışık ve zorunlu zaman ölçeğini yapılır. Tüm hayvan deneyleri hayvanların korunması Alman mevzuatına göre yapılmış ve Heidelberg Üniversitesi Etik Değerlendirme Kurulu tarafından onaylanmıştır. Enstrümantasyon hazırlanması 1. <ol><li> Kontraktilite için ölçümler multichambered organ banyosu kurulumu kullanın. Bir ex vivo kontraktilite organ banyosu kurulum bileşenleri, Şekil 2 de gösterilmiştir. NOT: papiller kas hazırlanması ve deney protokolünde başlangıcı arasındaki süreyi kurmak ekipman en aza indirmek ve deneysel tissue.This toplama provid için tamponlar önce hazırlamak içinDoku deneyler için canlı kalır zaman büyük miktarda es. </li><li> Bilgisayar ve veri toplama ekipmanı başlatın. Organ banyosu ısı (önceden ayarlanmış 32 ° C) açın ve önceden sıcaklığa birimleri izin verir. </li><li> Edinim ekipmanı hazırlayın. Yazılım kılavuzunda belirtildiği gibi verileri kaydetmeye başlayın. </li><li> Giriş ve her kanalda (gerekirse) kalibrasyonu yapmak ve sertifikalı ağırlıkça verilen bir 2-g kuvvetine (yani, kanal ile ilişkili) karşılıklı kuvvet dönüştürücü temin elektrik sinyali standardize etmek için tüm kanallar sıfır. </li><li> Organ banyosu odalarına gaz temini (% 95 O 2 /% 5 CO 2) açın. Sürekli tüm protokol ölçümleri sırasında tüm odaları gaz. </li></ol> Tamponlar ve Fizyolojik Çözümler 2. Hazırlık <ol><li> 119 mM NaCI nihai konsantrasyonlar elde etmek için Krebs-Henseleit tampon çözeltisi hazırlayın; 25 mM NaHCO 3; 4,6 mM KCI; 11mm glukoz; 1 mM Na-pyruvate; 1,5 mM CaCl2; 1.64 mM 4 MgSO; 1.18 mM KH 2 PO 4 ve (Tablo 1 Fizyolojik çözüm bakınız) 7.4 pH ayarlamak. </li><li> Ek 30 mM 2,3-Butandion monoxime (BDM) ve 50 IE Heparin / ml ile adım 2.1 &#39;de açıklandığı gibi izolasyonu sırasında kullanmak üzere ayrı Krebs-Henseleit tampon çözeltisi hazırlayın. 4 ° C (Tablo 1 Hazırlama çözeltisi bakınız) soğutun çözeltisi. Tablo 1 de tarif edildiği gibi işemi simülasyonu için, iskemi-solüsyon hazırlanır. </li><li> Ca 2 + protokolü için - bağımlı kontraktilite, istenen nihai konsantrasyona Krebs-Henseleit tampon çözeltisine Ca 2+ ekleyin. NOT: doğrudan kullanmadan önce bu çözümleri hazırlamak ve Calciumcarbonate çökmesini önlemek için karbojen ile Gass. Kullanmadan önce 32 ° C&#39;ye kadar ön ısıtılması çözeltisi. </li></ol> Papiller Eksizyon Prosedür sırasında kullanılan Gazlı Tüp ve Diseksiyon Dish 3. Hazırlık <ol><li> Yumuşak bir gaz bağlayınuzman çalışma ile gaz bağlantısı (% 100 oksijen, alternatif karbojen) tüp (dış çapı 2-4 mm) şarkı. </li><li> Diseksiyon çanak içine uydurma gazlama tüpün kapalı halka oluşturun. Gazlama tüpü sürekli köpürme güvence birkaç kez delinme. Bu gazlaştırma içi tüpü birkaç kez kullanılabilir. </li><li> Pimleri içine sıkışmış, böylece altta (0.5 cm kalınlığında) bir silikon elastomer diseksiyon çanak hazırlayın. Bu yemek birkaç kez kullanılabilir. </li></ol> Fareler ile Sol Ön Papiller kas 4. İzolasyonu NOT: papiller kas izolasyonu başlamadan önce, gaz hatları tıkanmalar açık olup olmadığını kontrol edin. <ol><li> Papiller kas hazırlık başlamadan önce protokol bölümünde 1-3 bahsedildiği gibi organ banyosu kurulumu hazırlayın. Deney günü tüm çözümleri hazırlayın. </li><li> Servikal dislokasyon accordi tarafından (yaklaşık 8-12 haftalık) fare Kurbanuzman çalışma ve kurumsal kurallarına ng. </li><li> Forepaws sabitleyerek dorsal pozisyonda hayvan düzeltmek ve bir diseksiyon gemide arka pençeleri, keskin kemik makasla kaburga ile keserek her iki tarafta toraks yanal açın, daha sonra bir çapraz kesim ile diyafram kesti. Perikard çıkarın. Şimdi kalp ve aort erişilebilir. </li><li> Kalbine yakın damar trunkustan üzerinde künt forseps ile kalbi düzeltmek ve akciğerlerden makas ve çevresindeki doku ile hızlı bir şekilde kalbi ayırın. </li><li> Oksijen (adım 2.2) ile gaz verilerek soğutulmuş hazırlık solüsyonu ile dolu bir Petri kabı kalpte aktarın. Kalp yendi ve forseps ile kardiyak apeks dokunmadan yoluyla usulca kalp kasılmalarını uyarmak için izin verin. </li><li> En kısa sürede kalbi tamamen kansızdırlar olduğunu O 2 ile soğutulan hazırlık solüsyonu (adım 2.2) ile doldurulur ve gazlı diseksiyon çanak aktarın. Kullanımı konusunda bu aşamada bir stereomikroskopta itibaren. </li><li> Hea FixKalp (sağ ventrikül operatörün görünümü sağ tarafta yer alan) dorsal görüldüğü şekilde sağ ventrikül ile küçük bir iğne ile rt. </li><li> Kullanımı mikrocerrahi makas ventriküllerin doku bağlayan atriyoventriküler düzeyde hem atriyumları kesmek ayırmak ve atın. Herhangi bir mekanik basınç kaçınarak kalbin apeks AV-valf-seviyesinden ventrikül duvarından bir kesim yapın. </li><li> Ventrikül açın ve dolayısıyla sol ventrikül papiller kas hem bakmak zorunda, forseps ile sol taraflı serbest duvarı sabitleyin. </li><li> Biraz papiller kas hazırlama kapak yelken bir kısmını koruyarak sol ön papiller kas her iki tarafında ventrikül doku yanal kesip ve dokunaklı önlemek veya mümkün olduğunca papiller kas germe. Papiller kas kalan ventrikül duvar dokusu teşrih. </li><li> Papiller kas hazırlık her iki tarafında takın ipek ipler (7/0, metrik 0.5)preparasyonu, kapak yelken biri ve kas parçası üzerinde tek. Sıcaklık 32 ° C olduğu ileri sürülmektedir, organ banyosu çözeltisi ile doldurulur ve karbojen gazı verilmiş organ banyosu odası içinde hazırlanmasını sabitleyin. </li></ol> Papiller kas 5. Dengeleme ve Uyarım <ol><li> Hemen organ banyosunda fiksasyon sonra 1 Hz stimülasyon frekansında dikdörtgen darbeler (2 ms süresi ve 100 mA akım) ile papiller kas hazırlık Canlandıracak. </li><li> Sürekli değişim ya da kullanılan organ banyosu Çeşidi kurulum göre sık manuel değişim (her 5 dk) yoluyla, organ banyosu çözeltisi sık değişiklik sağlayın. </li><li> Ulaştı giderek maksimal seğirme kuvveti kadar gösteriş artırın. Gösteriş artış seğirme yürürlükte bir başka güçlendirme tarafından takip değilken maksimal seğirme gücü ulaşılır. </li><li> Dengeleme 45-60 dakika sonra, deneysel protokol başlatın. </li></ol> NOT: Aşağıda belirtilen deneysel protokol fizyolojik ve patofizyolojik koşullarda kalp kasılmasını karakterize standart manevraları içermektedir. Temsili bölümde de temsili sonuçları gösteren ayrıntılı olarak bu protokolleri tanımlar (ayrıca bkz Tablo 2). <ol><li> Kayıt ve deneysel protokollerinin analizi <ol><li> Kayıt için yeterli temporal çözünürlük (satın alma oranı ≥ 1kHz) uygun bir yazılımı kullanın. </li><li> Seğirme kuvvet genliği (yükseklik), gerginlik (TTP) ve (örnek olarak bakınız Şekil 4, ADInstruments ve 5.5 Grafik) yazılım programında belirtildiği gibi yarım maksimal gevşeme zamanı (R 50 sırasıyla / TFall) zirve zaman gibi parametreleri analiz edin. </li></ol></li></ol>

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Yazarlar hiçbir rakip mali çıkarlarını var olduğunu beyan ederiz.

Bu yazıda farelerde kalp fizyolojisi ve patoloji ile ilişkili çok sayıda bilimsel sorulara cevap olarak transgenik hatların analizi ve yeni farmasötik yaklaşımların keşfedilmesi desteklemek için kullanılabilir in vitro fare papiller kas kontraktilitesini araştırmak için bir yöntem açıklanmaktadır Kalp bozuklukları tedavi etmek için. Biz kalp kası kasılma, fizyolojik, patolojik ve farmakolojik özelliklerini değerlendirmek için bu yöntemin kullanımını göstermektedir (Şekil ...

Kalp kasılmasında için rollerini atıfta iyon kanalları gibi proteinlerin incelenmesi, farklı patomekanizmaların keşfetmek ve iskemi ve kalp yetmezliği gibi kalp hastalıkları için yeni tedavi stratejilerinin oluşturulması esastır. Memeli kardiyomiyositlerde Kontraktil fonksiyonu çeşitli iyon kanalları, taşıyıcılar ve diğer proteinler ile modüle edilmesi bilinmektedir. Aksiyon potansiyeli 2+ kanalları dışı alandan Ca 2 + akını yol açar ve daha sonra Ca 2 + hücresel daralma 2. tetikler Ca 2 + salınımını (YÜÇAM) 1, -kaynaklı Ca voltaj bağımlı sarkolemmal L-tipi aktivasyonunu uyarılmış. Fizyolojik veya patolojik stres kalp kontraktilite ve adaptasyon merkezi bir rol oynar -signaling Ca 2 +. Katekolaminler böylece cAMP&#39;yi sentezler adenilil siklaz (AC) uyarıcı, kalp β-adrenerjik reseptörleri aktive. Aktif hale, protein,n Ca 2 + transientler ve kardiyak kontraktilite 1,3,4 modifikasyonu ile sonuçlanan L-tipi Ca 2 + kanalları, fosfolamban&#39;ın ve ryanodin reseptörleri gibi farklı hücre içi ve zar bağlı proteinleri fosforile A (PKA) kinaz. cAMP fosfodiesteraz (PDE) tarafından parçalanır. Β-adrenoseptörleri dışında Gs-bağlanmış reseptörlerin aktivasyonu, aynı zamanda, cAMP birikmesine yol açar. Izole ventriküler kas şeritlerinde kontraktilite ölçümleri tekniği de daha memeli türler 5-8 için kurulmuştur. Genin olasılığı farelerde hedef dayanarak fare kalp fizyolojisi analiz yöntemleri kurmak önemlidir. Ancak, farelerde izole kas hazırlıkları fizyolojik özellikleri hakkında varolan verileri deneysel koşullara 9-12 bağlı olarak değişiklik gösterir. Anlatılan yöntem sol ventrikül papiller kas öncesi kardiyak kontraktilite analiz etmek için kullanılırin vitro parations. Kardiyak kontraktilite incelenmesi kan basıncı, nörohümoral stimülasyonu ve fiziksel veya metabolik stres gibi in vivo olarak kardiyak kontraktiliteyi, modifiye etkilerin yokluğunda gerçekleştirilir. Müteahhitlik kas hazırlık dayak oranı titizlikle tanımlanmış ve keyfi değiştirilebilir. Seğirme kuvvet belirli kalsiyum konsantrasyonu gibi uyaranlara, frekans veya sıcaklık yenerek bağlamında analiz edilebilir. Buna ek olarak, bu yöntem, farklı sinyal geçiş yolu bileşenlerinin veya araştırmak ve yukarıda belirtilen deney koşullarının kontrol edilmesi suretiyle genetik olarak modifiye edilmiş fare modellerinde kalp performansını karşılaştırmak için kullanılabilir.

<table><tbody><tr><td>Sodium chloride</td><td>Sigma-Aldrich</td><td>S7653</td><td></td></tr><tr><td>Sodium bicarbonate</td><td>Sigma-Aldrich</td><td>S5761&amp;nbsp;</td><td></td></tr><tr><td>Potassium chloride</td><td>Sigma-Aldrich</td><td>P9333</td><td></td></tr><tr><td>Glucose</td><td>Sigma-Aldrich</td><td>D9434&amp;nbsp;</td><td></td></tr><tr><td>Sodium pyruvate</td><td>Sigma-Aldrich</td><td>P5280&amp;nbsp;</td><td></td></tr><tr><td>Calcium chloride dihydrate</td><td>Sigma-Aldrich</td><td>223506</td><td></td></tr><tr><td>Magnesium sulfate heptahydrate</td><td>Sigma-Aldrich</td><td>230391</td><td></td></tr><tr><td>Potassium phosphate monobasic</td><td>Sigma-Aldrich</td><td>P 5655</td><td></td></tr><tr><td>2,3-Butanedione monoxime</td><td>Sigma-Aldrich</td><td>B0753</td><td></td></tr><tr><td>3-Isobutyl-1-methylxanthine</td><td>Sigma-Aldrich</td><td>I5879</td><td>Hazard statement H 302, solve in DMSO</td></tr><tr><td>Dimethyl sulfoxide (DMSO)</td><td>Sigma-Aldrich</td><td>D2650</td><td></td></tr><tr><td>Isoprenaline hydrochloride</td><td>Sigma-Aldrich</td><td>I5627</td><td>Hazard statement H 315-H319-H335</td></tr><tr><td>Sodium Heparine 250.000 IE/10 ml</td><td>ratiopharm</td><td>PZN 3874685</td><td></td></tr><tr><td>Histamine dihydrochloride</td><td>Sigma-Aldrich</td><td>H7250</td><td>Hazard statement H 315-H 317-H319- H334-H335</td></tr></tbody></table>

contractility measurements on isolated papillary muscles for the investigation of cardiac inotropy in mice

Yetişkin fare kalpleri izole papiller kas farklı fizyolojik / patolojik koşullar kardiyak kontraktiliteyi incelemek için kullanılabilir. Kasılma özellikleri bağımsız gibi damar tonusunu veya nörohumoral durumu gibi dış etkilerden değerlendirilebilir. Bu izole kardiyak miyositler tek hücreli ölçümler arasında ve ekokardiyografi gibi in vivo çalışmalarda bilimsel bir yaklaşım gösteriyor. Mükemmel bir model kalp fizyolojisi / patofizyolojisini ve farmakolojik maddeler ile modülasyon ve transgenik hayvan modelleri keşfi gibi araştırmalar için kullanılabilir Dolayısıyla, papiller kas preparasyonlar vermektedir. Burada, bir organ banyosu kurulumunda kardiyak kontraktilite araştırmak için fare sol ön papiller kas izole bir yöntem açıklanmaktadır. Ventriküler duvara izole edilmiş bir kas şerit hazırlanmasında aksine, papiller kas, kas tissu zarar vermeden toto hazırlanabilirciddi e. Organ banyosu kurulumun birkaç ısı kontrollü, gazlanmış ve elektrot donatılmış organ banyosu daireden oluşur. İzole papiller kas organ banyosu odasında sabit ve elektriksel uyarılır. Uyarılmış seğirme gücü gibi kuvvet genliği seğirme ve kinetik analiz edilir seğirme gibi basınç dönüştürücü ve parametreler kullanılarak kaydedilir. Farklı deney protokolleri, katekolaminlerin ya da diğer ilaç olarak kontraktil ajanlar, kalsiyum ve frekansa bağlı kasılma yanı sıra doz-tepki eğrileri araştırmak için gerçekleştirilebilir. Ayrıca, akut iskemi gibi patolojik durumlar simüle edilebilir.

İzole fare papiller kas hazırlıkları kontraktilite ölçümleri için bu yazının protokol fizyolojik koşullar altında tekrarlanabilir deneysel sonuçlar elde etmek için optimum koşullara ayarlanmıştır. Optimal deneysel koşullar tanımlamak için biz organ banyosu sıcaklığı ve hücre dışı kalsiyum konsantrasyonu (ayrıca 12 bakınız) değişen Pilot deneyleri yaptık. Burada açıklanan protokol 1,5 mM hücre dışı kalsiyum konsantrasyonu ile 32 ° C arasındaki bir sıcaklıkta gerçek...

Watch this Scientific Journal Video about Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice at JoVE.com

Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice

Murin sol ventrikül papiller kas in vitro kardiyak kontraktiliteyi araştırmak için kullanılabilir. Bu makalede ayrıntılı olarak izolasyon ve deneysel protokoller kalp kasılma özelliklerini incelemek için açıklar.

Farelerde Kardiyak inotropiyi Soruşturma İzole papiller Kaslar kontraktilite Ölçümleri

Papillary muscle isolated from adult mouse hearts can be used to study cardiac contractility during different physiological/pathological conditions. The ...

contractility-measurements-on-isolated-papillary-muscles-for

Universidad de Cartagena UDEC

Research

JoVE Journal

Biology

14.9K Görüntüleme.  Universität Heidelberg.  Murin sol ventrikül papiller kas in vitro kardiyak kontraktiliteyi araştırmak için kullanılabilir. Bu makalede ayrıntılı olarak izolasyon ve deneysel protokoller kalp kasılma özelliklerini incelemek için açıklar. 

Video: Contractility Measurements on Isolated Papillary Muscles for the Investigation of Cardiac Inotropy in Mice

In vitro Measurements of Tracheal Constriction Using Mice

Transgenic and knockout mice have been powerful tools for the investigation of the physiology and pathophysiology of airways1,2. In vitro tensometry of isolated tracheal preparations has proven to be a useful assay of airway smooth muscle (ASM) contractile response in genetically modified mice. These in vitro tracheal preparations are relatively simple, provide a robust response, and retain both functional cholinergic nerve endings and muscle responses, even after long incubations.
Tracheal tensometry also provides a functional assay to study a variety of second messenger signaling pathways that affect contraction of smooth muscle. Contraction in trachea is primarily mediated by parasympathetic, cholinergic nerves that release acetylcholine onto ASM (Figure 1). The major ASM acetylcholine receptors are muscarinic M2 and M3 which are Gi/o and Gq coupled receptors, respectively3,4,5. M3 receptors evoke contraction by coupling to Gq to activate phospholipase C, increase IP3 production and IP3-mediated calcium release from the sarcoplasmic reticulum3,6,7. M2/Gi/o signaling is believed to enhance contractions by inhibition of adenylate cyclase leading to a decrease in cAMP levels5,8,9,10. These pathways constitute the so called "pharmaco-contraction coupling" of airway smooth muscle11. In addition, cholinergic signaling through M2 receptors (and modulated by M3 signaling) involves pathways that depolarize the ASM which in turn activate L-type, voltage-dependent calcium channels (Figure 1) and calcium influx (so called "excitation-contraction coupling")4,7. More detailed reviews on signaling pathways controlling airway constriction can be found4,12. The above pathways appear to be conserved between mice and other species. However, mouse tracheas differ from other species in some signaling pathways. Most prominent is their lack of contractile response to histamine and adenosine13,14, both well-known ASM modulators in humans and other species5,15.
Here we present protocols for the isolation of murine tracheal rings and the in vitro measurement of their contractile output. Included are descriptions of the equipment configuration, trachea ring isolation and contractile measurements. Examples are given for evoking contractions indirectly using high potassium stimulation of nerves and directly by depolarization of ASM muscle to activate voltage-dependent calcium influx (1. high K+, Figure 1). In addition, methods are presented for stimulations of nerves alone using electric field stimulation (2. EFS, Figure 1), or for direct stimulation of ASM muscle using exogenous neurotransmitter applied to the bath (3. exogenous ACH, Figure 1). This flexibility and ease of preparation renders the isolated trachea ring model a robust and functional assay for a number of signaling cascades involved in airway smooth muscle contraction.

In vitro Measurements of Tracheal Constriction Using Mice

Transgenic mice have been extremely useful in ascribing physiological function to genes. As such, research in general, and functional studies of airway, in particular, have undergone a remarkable shift toward murine models. Here we provide protocols for in vitro trachea constriction studies to evaluate smooth muscle function in murine airway.

Fare kullanarak Trakeal Konstrüksiyon in vitro ölçümleri ise

Transgenic and knockout mice have been powerful tools for the investigation of the physiology and pathophysiology of airways1,2. In vitro tensometry of ...

Tıp

Cardiac Catheterization in Mice to Measure the Pressure Volume Relationship: Investigating the Bowditch Effect

Animal models that mimic human cardiac disorders have been created to test potential therapeutic strategies. A key component to evaluating these strategies is to examine their effects on heart function. There are several techniques to measure in vivo cardiac mechanics (e.g., echocardiography, pressure/volume relations, etc.). Compared to echocardiography, real-time left ventricular (LV) pressure/volume analysis via catheterization is more precise and insightful in assessing LV function. Additionally, LV pressure/volume analysis provides the ability to instantaneously record changes during manipulations of contractility (e.g., &#946;-adrenergic stimulation) and pathological insults (e.g., ischemia/reperfusion injury). In addition to the maximum (+dP/dt) and minimum (-dP/dt) rate of pressure change in the LV, an accurate assessment of LV function via several load-independent indexes (e.g., end systolic pressure volume relationship and preload recruitable stroke work) can be attained. Heart rate has a significant effect on LV contractility such that an increase in the heart rate is the primary mechanism to increase cardiac output (i.e., Bowditch effect). Thus, when comparing hemodynamics between experimental groups, it is necessary to have similar heart rates. Furthermore, a hallmark of many cardiomyopathy models is a decrease in contractile reserve (i.e., decreased Bowditch effect). Consequently, vital information can be obtained by determining the effects of increasing heart rate on contractility. Our and others data has demonstrated that the neuronal nitric oxide synthase (NOS1) knockout mouse has decreased contractility. Here we describe the procedure of measuring LV pressure/volume with increasing heart rates using the NOS1 knockout mouse model.

This article describes the measurement of murine left ventricular function via pressure/volume analysis at different heart rates.

Bowditch Efekt incelenmesi: Basınç Hacim İlişkisi Tedbir Fare Kardiyak Kateterizasyon

Animal models that mimic human cardiac disorders have been created to test potential therapeutic strategies. A key component to evaluating these ...

Echocardiographic Approaches and Protocols for Comprehensive Phenotypic Characterization of Valvular Heart Disease in Mice

The aim of this manuscript and accompanying video is to provide an overview of the methods and approaches used for imaging heart valve function in rodents, with detailed descriptions of the appropriate methods for anesthesia, the echocardiographic windows used, the imaging planes and probe orientations for image acquisition, the methods for data analysis, and the limitations of emerging technologies for the evaluation of cardiac and valvular function. Importantly, we also highlight several future areas of research in cardiac and heart valve imaging that may be leveraged to gain insights into the pathogenesis of valve disease in preclinical animal models. We propose that using a systematic approach to evaluating cardiac and heart valve function in mice can result in more robust and reproducible data, as well as facilitate the discovery of previously underappreciated phenotypes in genetically-altered and/or physiologically-stressed mice.

This protocol provides a detailed description of the echocardiographic approach for comprehensive phenotyping of heart and heart valve function in mice.

Farelerde Kalp Kapak Hastalıkları Kapsamlı Fenotipik Karakterizasyonu için ekokardiyografik Yaklaşımlar ve Protokoller

The aim of this manuscript and accompanying video is to provide an overview of the methods and approaches used for imaging heart valve function in ...

Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes

The use of primary cardiomyocytes (CMs) in culture has provided a powerful complement to murine models of heart disease in advancing our understanding of heart disease. In particular, the ability to study ion homeostasis, ion channel function, cellular excitability and excitation-contraction coupling and their alterations in diseased conditions and by disease-causing mutations have led to significant insights into cardiac diseases. Furthermore, the lack of an adequate immortalized cell line to mimic adult CMs, and the limitations of neonatal CMs (which lack many of the structural and functional biomechanics characteristic of adult CMs) in culture have hampered our understanding of the complex interplay between signaling pathways, ion channels and contractile properties in the adult heart strengthening the importance of studying adult isolated cardiomyocytes. Here, we present methods for the isolation, culture, manipulation of gene expression by adenoviral-expressed proteins, and subsequent functional analysis of cardiomyocytes from the adult mouse. The use of these techniques will help to develop mechanistic insight into signaling pathways that regulate cellular excitability, Ca2+ dynamics and contractility and provide a much more physiologically relevant characterization of cardiovascular disease.

Here we describe the isolation of adult mouse cardiomyoctyes using a Langendorff perfusion system. The resulting cells are Ca2+-tolerant, electrically quiescent and can be cultured and transfected with adeno- or lentiviruses to manipulate gene expression. Their functionality can also be analyzed using the MMSYS system and patch clamp techniques.

İzolasyon, Kültür ve Yetişkin Fare Cardiomyoctyes Fonksiyonel Karakterizasyonu

The use of primary cardiomyocytes (CMs) in culture has provided a powerful complement to murine models of heart disease in advancing our understanding of ...

Biyoloji

Isolation and Physiological Analysis of Mouse Cardiomyocytes

Cardiomyocytes, the workhorse cell of the heart, contain exquisitely organized cytoskeletal and contractile elements that generate the contractile force used to pump blood. Individual cardiomyocytes were first isolated over 40 years ago in order to better study the physiology and structure of heart muscle. Techniques have rapidly improved to include enzymatic digestion via coronary perfusion. More recently, analyzing the contractility and calcium flux of isolated myocytes has provided a vital tool in the cellular and sub-cellular analysis of heart failure. Echocardiography and EKGs provide information about the heart at an organ level only. Cardiomyocyte cell culture systems exist, but cells lack physiologically essential structures such as organized sarcomeres and t-tubules required for myocyte function within the heart. In the protocol presented here, cardiomyocytes are isolated via Langendorff perfusion. The heart is removed from the mouse, mounted via the aorta to a cannula, perfused with digestion enzymes, and cells are introduced to increasing calcium concentrations. Edge and sarcomere detection software is used to analyze contractility, and a calcium binding fluorescent dye is used to visualize calcium transients of electrically paced cardiomyocytes; increasing understanding of the role cellular changes play in heart dysfunction. Traditionally used to test drug effects on cardiomyocytes, we employ this system to compare myocytes from WT mice and mice with a mutation that causes dilated cardiomyopathy. This protocol is unique in its comparison of live cells from mice with known heart function and known genetics. Many experimental conditions are reliably compared, including genetic or environmental manipulation, infection, drug treatment, and more. Beyond physiologic data, isolated cardiomyocytes are easily fixed and stained for cytoskeletal elements. Isolating cardiomyocytes via perfusion is an extremely versatile method, useful in studying cellular changes that accompany or lead to heart failure in a variety of experimental conditions.

Individual cardiomyocytes from wild type and mutant mice can be isolated from the heart in order to study their contractility and calcium transients. This allows characterization of the contribution of cellular dysfunction to heart dysfunction from any cause.

Fare kardiyomiyositlerde İzolasyon ve Fizyolojik Analizi

Cardiomyocytes, the workhorse cell of the heart, contain exquisitely organized cytoskeletal and contractile elements that generate the contractile force ...

Dynamic Measurement and Imaging of Capillaries, Arterioles, and Pericytes in Mouse Heart

Coronary arterial tone along with the opening or closing of the capillaries largely determine the blood flow to cardiomyocytes at constant perfusion pressure. However, it is difficult to monitor the dynamic changes of the coronary arterioles and the capillaries in the whole heart, primarily due to its motion and non-stop beating. Here we describe a method that enables monitoring of arterial perfusion rate, pressure and the diameter changes of the arterioles and capillaries in mouse right ventricular papillary muscles. The mouse septal artery is cannulated and perfused at a constant flow or pressure with the other dynamically measured. After perfusion with a fluorescently labeled lectin (e.g., Alexa Fluor-488 or -633 labeled Wheat-Germ Agglutinin, WGA), the arterioles and capillaries (and other vessels) in right ventricle papillary muscle and septum could be readily imaged. The vessel-diameter changes could then be measured in the presence or absence of heart contractions. When genetically encoded fluorescent proteins were expressed, specific features could be monitored. For examples, pericytes were visualized in mouse hearts that expressed NG2-DsRed. This method has provided a useful platform to study the physiological functions of capillary pericytes in heart. It is also suitable for studying the effect of reagents on the blood flow in heart by measuring the vascular/capillary diameter and the arterial luminal pressure simultaneously. This preparation, combined with a state-of-the-art optic imaging system, allows one to study the blood flow and its control at cellular and molecular level in the heart under near-physiological conditions.

Presented here is a protocol to study the coronary microcirculation in living murine heart tissue by ex vivo monitoring of the arterial perfusion pressure and flow that maintains the pressure, as well as vascular tree components including the capillary beds and pericytes, as the septal artery is cannulated and pressurized.

Fare Kalbinde Kılcal Damarlar, Arterioles ve Perisitlerin Dinamik Ölçümü ve Görüntülenmesi

Coronary arterial tone along with the opening or closing of the capillaries largely determine the blood flow to cardiomyocytes at constant perfusion ...

Revealing Subtle Changes in Cardiac Function using Transthoracic Dobutamine Stress Echocardiography in Mice

Left ventricular (LV) dysfunction paves the final pathway for a multitude of cardiac disorders. With the non-invasive high-frequency transthoracic dobutamine stress echocardiography in humans, a reductionist investigation approach to unmask subtle changes in cardiac function has become possible. Here, we provide a protocol for using this technique in mice to facilitate expanded analysis of LV architecture and function in physiology and pathology enabling the observation of alterations in models of cardiac disease hidden in unstressed hearts. This investigation can be performed in one and the same animal and allows both, basal and pharmacologically stress-induced measurements. We outline detailed criteria for appropriate anesthesia, imaging-based LV analysis, consideration of intra- and interobserver variability, and obtaining positive inotrope response that can be attained in mice after intraperitoneal injection of dobutamine under near physiological conditions. To recapitulate the characteristics of human physiology and disease in small animal models, we highlight critical pitfalls in evaluation, e.g., a pronounced Bowditch effect in mice. To further meet translational objectives, we compare stress-induced effects in humans and mice. When used in translational studies, attention must be paid to physiological differences between mice and human. Experimental rigor dictates that some parameters assessed in patients can only be used with caution due to restrictions in spatial and temporal resolution in mouse models.

Left ventricular dysfunction constitutes the final common pathway for a host of cardiac disorders. We here provide a detailed protocol of transthoracic dobutamine stress echocardiography approach for comprehensive evaluation of the left ventricular function of mouse models of cardiac disease as well as cardiac phenotyping.

Left ventricular (LV) dysfunction paves the final pathway for a multitude of cardiac disorders. With the non-invasive high-frequency transthoracic ...

Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling

Heart failure and cardiac arrhythmias are the leading causes of mortality and morbidity worldwide. However, the mechanism of pathogenesis and myocardial malfunction in the diseased heart remains to be fully clarified. Recent compelling evidence demonstrates that changes in the myofilament Ca2+ sensitivity affect intracellular Ca2+ homeostasis and ion channel activities in cardiac myocytes, the essential mechanisms responsible for the cardiac action potential and contraction in healthy and diseased hearts. Indeed, activities of ion channels and transporters underlying cardiac action potentials (e.g., Na+, Ca2+ and K+ channels and the Na+-Ca2+ exchanger) and intracellular Ca2+ handling proteins (e.g., ryanodine receptors and Ca2+-ATPase in sarcoplasmic reticulum (SERCA2a) or phospholamban and its phosphorylation) are conventionally measured to evaluate the fundamental mechanisms of cardiac excitation-contraction (E-C) coupling. Both electrical activities in the membrane and intracellular Ca2+ changes are the trigger signals of E-C coupling, whereas myofilament is the functional unit of contraction and relaxation, and myofilament Ca2+ sensitivity is imperative in the implementation of myofibril performance. Nevertheless, few studies incorporate myofilament Ca2+ sensitivity into the functional analysis of the myocardium unless it is the focus of the study. Here, we describe a protocol that measures sarcomere shortening/re-lengthening and the intracellular Ca2+ level using Fura-2 AM (ratiometric detection) and evaluate the changes of myofilament Ca2+ sensitivity in cardiac myocytes from rat hearts. The main aim is to emphasize that myofilament Ca2+ sensitivity should be taken into consideration in E-C coupling for mechanistic analysis. Comprehensive investigation of ion channels, ion transporters, intracellular Ca2+ handling, and myofilament Ca2+ sensitivity that underlie myocyte contractility in healthy and diseased hearts will provide valuable information for designing more effective strategies of translational and therapeutic value.

Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling

This paper describes a protocol that assesses the changes of myofilament Ca2+ sensitivity during contraction in isolated cardiac myocytes from rat heart. Together with cardiac electrophysiology, systolic/diastolic cytosol Ca2+ levels and contraction/relaxation, this measurement is imperative in underpinning the mechanisms mediating cardiac excitation-contraction coupling in healthy and diseased hearts.

Myofilament Ca Değerlendirilmesi<sup&gt; 2+</sup&gt; Duyarlılık temelinde Kardiyak Uyarma-kasılma Kaplin

Heart failure and cardiac arrhythmias are the leading causes of mortality and morbidity worldwide. However, the mechanism of pathogenesis and myocardial ...

Analysis of Cardiac Contractile Dysfunction and Ca2+ Transients in Rodent Myocytes

Contractile dysfunction and Ca2+ transients are often analyzed at the cellular level as part of a comprehensive assessment of cardiac-induced injury and/or remodeling. One approach for assessing these functional alterations utilizes unloaded shortening and Ca2+ transient analyses in primary adult cardiac myocytes. For this approach, adult myocytes are isolated by collagenase digestion, made Ca2+ tolerant, and then adhered to laminin-coated coverslips, followed by electrical pacing in serum-free media. The general protocol utilizes adult rat cardiac myocytes but can be readily adjusted for primary myocytes from other species. Functional alterations in myocytes from injured hearts can be compared to sham myocytes and/or to in vitro therapeutic treatments. The methodology includes the essential elements needed for myocyte pacing, along with the cell chamber and platform components. The detailed protocol for this approach incorporates the steps for measuring unloaded shortening by sarcomere length detection and cellular Ca2+ transients measured with the ratiometric indicator Fura-2 AM, as well as for raw data analysis.

Analysis of Cardiac Contractile Dysfunction and Ca2+ Transients in Rodent Myocytes

A set of protocols are presented that describe the measurement of contractile function via sarcomere length detection along with calcium (Ca2+) transient measurement in isolated rat myocytes. The application of this approach for studies in animal models of heart failure is also included.

Kemirgen Miyositlerde Kardiyak Kasılma Disfonksiyonu ve Ca2+ Geçicilerinin Analizi

Contractile dysfunction and Ca2+ transients are often analyzed at the cellular level as part of a comprehensive assessment of cardiac-induced injury ...

Measurement of Heart Contractility in Isolated Adult Human Primary Cardiomyocytes

The evaluation of changes in heart contractility is essential during preclinical development for new cardiac- and non-cardiac-targeted compounds. This paper describes a protocol for assessing changes in contractility in adult human primary ventricular cardiomyocytes utilizing the MyoBLAZER, a non-invasive optical method that preserves the normal physiology and pharmacology of the cells. This optical recording method continuously measures contractility transients from multiple cells in parallel, providing both medium-throughput and valuable information for each individual cell in the field of view, enabling the real-time tracking of drug effects. The cardiomyocyte contractions are induced by paced electrical field stimulation, and the acquired bright field images are fed to an image-processing software that measures the sarcomere shortening across multiple cardiomyocytes. This method rapidly generates different endpoints related to the kinetics of contraction and relaxation phases, and the resulting data can then be interpreted in relation to different concentrations of a test article. This method is also employed in the late stages of preclinical development to perform follow-up mechanistic studies to support ongoing clinical studies. Thus, the adult human primary cardiomyocyte-based model combined with the optical system for continuous contractility monitoring has the potential to contribute to a new era of in vitro cardiac data translatability in preclinical medical therapy development.

This protocol describes how to measure contractility in adult human primary cardiomyocytes from donor hearts with the MyoBLAZER system, a reliable platform for assessing drug-induced changes in contractility during preclinical development.

İzole Yetişkin İnsan Primer Kardiyomiyositlerinde Kalp Kontraktilitesinin Ölçülmesi

The evaluation of changes in heart contractility is essential during preclinical development for new cardiac- and non-cardiac-targeted compounds. This ...

Farelerde Kardiyak inotropiyi Soruşturma İzole papiller Kaslar kontraktilite Ölçümleri

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