Published online before print December 12, 2002, doi: 10.1161/01.RES.0000051885.70159.12
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Submitted on August 29, 2001
Revised on November 11, 2002
Accepted on December 3, 2002
Insulin-Like Growth Factor-1 Exerts Ca2+-Dependent Positive Inotropic Effects in Failing Human Myocardium
Dirk von Lewinski ;
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.
* To whom correspondence should be addressed. 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 (PI-3-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 PI-3-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 PI-3-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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