Published Online
on May 9, 2005

A more recent version of this article appeared on May 24, 2005

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Submitted on August 10, 2004
Revised on December 20, 2004
Accepted on January 20, 2005

Insulin Causes [Ca²⁺]_i-Dependent and [Ca²⁺]_i-Independent Positive Inotropic Effects in Failing Human Myocardium

Dirk von Lewinski MD, Sebastian Bruns , Stefanie Walther , Harald Kögler MD, and Burkert Pieske MD^*

From Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Göttingen, Germany.

^* To whom correspondence should be addressed. E-mail: pieske{at}med.uni-goettingen.de.

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°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.

Key words: insulin • calcium • heart failure • myocardium • contractility

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