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von Lewinski, D; Bruns, S; Walther, S; Kögler, H; Pieske, B.
Insulin causes Ca2+i-dependent and Ca2+i-independent positive inotropic effects in failing human myocardium.
Circulation. 2005; 111(20):2588-2595 Doi: 10.1161/CIRCULATIONAHA.104.497461 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Pieske Burkert Mathias
von Lewinski Dirk

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BACKGROUND: Insulin has been shown to exert positive inotropic effects in several in vitro and in vivo models, but signal transduction and substrate dependency remain unclear. We examined inotropic responses and signal transduction mechanisms of insulin in human myocardium. METHODS AND RESULTS: Experiments were performed in isolated trabeculae from end-stage failing hearts of 58 nondiabetic and 3 diabetic patients undergoing heart transplantation. The effect of insulin (0.3 and 3 IU/L) on isometric twitch force (37 degrees C, 1 Hz) was tested in the presence of glucose or pyruvate as energetic substrate. Furthermore, intracellular Ca2+ transients (aequorin method), sarcoplasmic reticulum (SR) Ca2+ content (rapid cooling contractures), and myofilament Ca2+ sensitivity (semiskinned fibers) were assessed. In addition, potential signaling pathways were tested by blocking glycolysis, PI-3-kinase, protein kinase C, diacylglycerol kinase, insulin-like growth factor-1 receptors, or transsarcolemmal Ca2+ entry via the Na+/Ca2+ exchanger. Insulin exerted concentration-dependent and partially substrate-dependent positive inotropic effects. The phosphatidylinositol-3-kinase inhibitor wortmannin and the Na2+/Ca2+ exchanger reverse-mode inhibitor KB-R7943 completely or partially prevented the functional effects of insulin. In contrast, insulin-like growth factor-1 receptor blockade, protein kinase C inhibition, and diacylglycerol kinase blockade were without effect. The inotropic response was associated with increases in intracellular Ca2+ transients, SR Ca2+ content, and increased myofilament Ca2+ sensitivity. CONCLUSIONS: Insulin exerts Ca2+-dependent and -independent positive inotropic effects through a phosphatidylinositol-3-kinase-dependent pathway in failing human myocardium. The increased [Ca2+]i originates at least in part from enhanced reverse-mode Na+/Ca2+ exchange and consequently increased SR-Ca2+ load. These nongenomic functional effects of insulin may be of clinical relevance, eg, during insulin-glucose-potassium infusions.
Find related publications in this database (using NLM MeSH Indexing)
1-Phosphatidylinositol 3-Kinase - metabolism
Calcium - metabolism
Cardiotonic Agents - pharmacology
Diabetes Mellitus - pharmacology
Female - pharmacology
Heart Failure, Congestive - drug therapy
Humans - drug therapy
Insulin - pharmacology
Male - pharmacology
Microfilaments - physiology
Middle Aged - physiology
Myocardial Contraction - drug effects
Sarcoplasmic Reticulum - metabolism
Signal Transduction - metabolism
Sodium - metabolism

Find related publications in this database (Keywords)
heart failure
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