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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Rainer, PP; Doleschal, B; Kirk, JA; Sivakumaran, V; Saad, Z; Groschner, K; Maechler, H; Hoefler, G; Bauernhofer, T; Samonigg, H; Hutterer, G; Kass, DA; Pieske, B; von, Lewinski, D; Pichler, M.
Sunitinib causes dose-dependent negative functional effects on myocardium and cardiomyocytes.
BJU Int. 2012; 110(10):1455-62 Doi: 10.1111/j.1464-410X.2012.11134.x [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Pichler Martin
Rainer Peter
Co-Autor*innen der Med Uni Graz
Bauernhofer Thomas
Doleschal Bernhard
Groschner Klaus
Höfler Gerald
Hutterer Georg
Mächler Heinrich
Pieske Burkert Mathias
Samonigg Hellmut
von Lewinski Dirk

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OBJECTIVES: To examine the acute effects of sunitinib on inotropic function, intracellular Ca(2+) transients, myofilament Ca(2+) sensitivity and generation of reactive oxygen species (ROS) in human multicellular myocardium and isolated mouse cardiomyocytes. To search for microRNAs as suitable biomarkers for indicating toxic cardiac effects. PATIENTS AND METHODS: After exposure to sunitinib (0.1-10 µg/mL) developed force, diastolic tension and kinetic variables were assessed in isolated human myocardium. Changes in myocyte sarcomere length, whole-cell calcium transients, myofilament force-Ca(2+) relationship, and ROS generation were examined in isolated ventricular mouse cardiomyocytes. Microarray and realtime-PCR were used to screen for differentially expressed microRNAs in cultured cardiomyocytes that were exposed for 24 h to sunitinib. RESULTS: We found that higher concentrations of sunitinib (1 and 10 µg/mL) decreased developed force at 30 minutes 76.9 + 2.8 and 54.5 + 6.3%, compared to 96.1 + 2.6% in controls (P < 0.01). Sunitinib exposure significantly decreased sarcomere shortening and Ca2+ transients. Myofilament Ca(2+) sensitivity was not altered, while ROS levels were significantly increased after exposure to the drug. MicroRNA expression patterns were not altered by sunitinib. CONCLUSIONS: Sunitinib elicits a dose-dependent negative inotropic effect in myocardium, accompanied by a decline in intracellular Ca(2+) and increased ROS generation. In clinical practice, these cardiotoxic effects should be considered in cases where cardiac concentrations of sunitinib could be increased.
Find related publications in this database (using NLM MeSH Indexing)
Aged - administration & dosage
Animals - administration & dosage
Antineoplastic Agents - adverse effects
Calcium - metabolism
Dose-Response Relationship, Drug - administration & dosage
Electron Spin Resonance Spectroscopy - administration & dosage
Female - administration & dosage
Heart - drug effects
Humans - administration & dosage
In Vitro Techniques - administration & dosage
Indoles - adverse effects
Male - administration & dosage
Mice - administration & dosage
Mice, Inbred C57BL - administration & dosage
Myocardial Contraction - drug effects
Myocytes, Cardiac - drug effects, metabolism
Protein Kinase Inhibitors - adverse effects
Pyrroles - adverse effects
Reactive Oxygen Species - metabolism
Sarcomeres - drug effects
Sunitinib - administration & dosage

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