Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated muscles.
A growing body of evidence has been accumulated recently suggesting that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) affect cardiac function, but their mechanism(s) of action is unclear. In the present study, GH and IGF-1 were administered to isolated isovolumic aequorin-loaded rat whole hearts and ferret papillary muscles. Although GH had no effect on the indices of cardiac function, IGF-1 increased isovolumic developed pressure by 24% above baseline. The aequorin transients were abbreviated and demonstrated decreased amplitude. The positive inotropic effects of IGF-1 were not associated with increased intracellular Ca2+ availability to the contractile machinery but to a significant increase of myofilament Ca2+ sensitivity. Accordingly, the Ca2+-force relationship obtained under steady-state conditions in tetanized muscle was shifted significantly to the left (EC50, 0.44+/-0.02 versus 0.52+/-0.03 micromol/L with and without IGF-1 in the perfusate, respectively; P<0.05); maximal Ca2+-activated tetanic pressure was increased significantly by 12% (211+/-3 versus 235+/-2 mm Hg in controls and IGF-1-treated hearts, respectively; P<0.01). The positive inotropic actions of IGF-1 were not associated with changes in either pHi or high-energy phosphate content, as assessed by 31P nuclear magnetic resonance spectroscopy, and were blocked by the phosphatidylinositol 3-kinase inhibitor wortmannin. Concomitant administration of IGF binding protein-3 blocked IGF-1-positive inotropic action in ferret papillary muscles. In conclusion, IGF-1 is an endogenous peptide that through a wortmannin-sensitive pathway displays distinct positive inotropic properties by sensitizing the myofilaments to Ca2+ without increasing myocyte [Ca2+]i.
Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Mass, USA. cittadin@unina.it
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A
Cittadini
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Y
Ishiguro
H
H
Strömer
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M
Spindler
A C
AC
Moses
R
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Clark
P S
PS
Douglas
J S
JS
Ingwall
J P
JP
Morgan
D008841:Actin Cytoskeleton / Q000502:physiology*; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005289:Ferrets; D006321:Heart / Q000187:drug effects / Q000502:physiology; D019382:Human Growth Hormone / Q000494:pharmacology*; D066298:In Vitro Techniques; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D018972:Insulin-Like Growth Factor Binding Protein 3; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D002118:Calcium; D000077191:Wortmannin