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(Circulation Research. 2003;92:169.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Insulin-Like Growth Factor-1 Exerts Ca²⁺-Dependent Positive Inotropic Effects in Failing Human Myocardium

Dirk von Lewinski, Kerstin Voß, Swen Hülsmann, Harald Kögler, Burkert Pieske

From the Abteilung Kardiologie und Pneumologie (D.v.L., K.V., H.K., B.P.) and Abteilung Neuro- und Sinnesphysiologie (S.H.), Georg-August-Universität Göttingen, Germany.

Correspondence to Prof Dr Burkert Pieske, Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. E-mail pieske{at}med.uni-goettingen.de

Myocardial generation of insulin-like growth factor-1 (IGF-1) is altered in hypertrophy and heart failure, but there are no reports on acute functional effects of IGF-1 in human cardiac muscle. We examined inotropic responses and signal transduction mechanisms of IGF-1 in human myocardium. Experiments were performed in isolated trabeculae or cardiomyocytes from 46 end-stage failing hearts. The effect of IGF-1 (0.001 to 0.2 µmol/L) on isometric twitch force (37°C, 1 Hz), intracellular Ca²⁺ transients (aequorin method), sarcoplasmic reticulum (SR) Ca²⁺ content (rapid cooling contractures), L-type Ca²⁺ current (whole-cell voltage clamp), and cAMP concentrations was assessed. In addition, the effects of blocking IGF-1 receptors, phosphoinositide 3-kinase (PI3-kinase), protein kinase C (PKC), or transsarcolemmal Ca²⁺ entry were tested. IGF-1 exerted concentration-dependent positive inotropic effects (twitch force increased to maximally 133±4% of baseline values at 0.1 µmol/L; P<0.05). The IGF-1 receptor antibody IR3 or the PI3-kinase inhibitor wortmannin prevented the functional effects. The inotropic response was paralleled by increases in Ca²⁺ transients and SR Ca²⁺ content. IGF-1 (0.1 µmol/L) increased L-type Ca²⁺ current amplitude by 24±7% (P<0.05). Blockade of SR function did not affect the inotropic response to IGF-1. In contrast, L-type Ca²⁺ channel blockade with diltiazem partially prevented (50%) the inotropic response to IGF-1. Inhibition of PKC (GF109203X), Na⁺-H⁺ exchange (HOE642), or reverse-mode Na⁺-Ca²⁺ exchange (KB-R7943) reduced the response to IGF-1 by 60% to 70%. IGF-1 exerts Ca²⁺-dependent positive inotropic effects through activation of IGF-1 receptors and a PI3-kinase-dependent pathway in failing human myocardium. The increased [Ca²⁺]_i with IGF-1 originates from both enhanced L-type Ca²⁺ currents and enhanced Na⁺-H⁺ exchange-dependent reverse-mode Na⁺-Ca²⁺ exchange. These nongenomic functional effects of IGF-1 may be of clinical relevance.

Key Words: insulin-like growth factor-1 • functional effects • Ca²⁺ handling • heart failure • human myocardium

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