title: Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes.
abstract: OBJECTIVE
  The acute administration of growth hormone (GH) or insulin-like growth factor-1 (IGF-1) improves cardiac performance, possibly contributing to the beneficial effects of GH therapy on heart failure (HF). GH can induce the production of IGF-1 and thus the actions of GH may be mediated through its IGF-1 induction. However, these effects have not yet been demonstrated in failing hearts and the cellular basis of GH or IGF-1-induced inotropic effects remains unknown. We examined the direct effects of GH and IGF-1 on the contractile function and intracellular calcium ([Ca2+]i) homeostasis in normal and failing myocytes.
  
  
  METHODS
  To determine whether GH and IGF-1 have a direct effect on myocardial contractility and whether the GH/IGF-1-induced effect was the results of changes in Ca2+ activation, cell shortening and [Ca2+]i transient were simultaneously measured in the left ventricular myocyte preparations, isolated from normal and rapid pacing-induced HF dogs.
  
  
  RESULTS
  Basal shortening of HF myocytes was reduced by 64% (p < 0.01). In normal and HF myocytes, GH (0.4-40 x 10(-3) IU/ml) had no effect on either cell shortening or [Ca2+]i transients. In normal myocytes, IGF-1 exerted a positive inotropic effect in a time- and dose-dependent manner (25-500 ng/ml), associated with a parallel increase of [Ca2+]i transient amplitude. IGF-1 increased the shortening magnitude in normal (121 +/- 5% increase from baseline, p < 0.05) and HF (118 +/- 4% increase from baseline, p < 0.05) myocytes. It also increased [Ca2+]i transient amplitude in normal and HF cells by 124 +/- 4 and 125 +/- 7%, respectively. The percent increase of cell shortening and [Ca2+]i transient amplitude was comparable between normal and HF myocytes. Furthermore, IGF-1 did not shift the trajectory of the relaxation phase in the phase-plane plots of cell length vs. [Ca2+]i, indicating that it did not change myofilament Ca2+ sensitivity.
  
  
  CONCLUSIONS
  In both normal and HF conditions, IGF-1 exerted an acute direct positive inotropic effect in adult cardiac myocytes by increasing the availability of [Ca2+]i to the myofilaments, possibly explaining the beneficial effect of GH on HF.
authors.affiliation: Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kinugawa
authors.forename: H
authors.initials: H
authors.lastname: Tsutsui
authors.forename: T
authors.initials: T
authors.lastname: Ide
authors.forename: R
authors.initials: R
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Arimura
authors.forename: K
authors.initials: K
authors.lastname: Egashira
authors.forename: A
authors.initials: A
authors.lastname: Takeshita
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D048429:Cell Size / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D013006:Growth Hormone / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006706:Homeostasis; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011804:Quinolines / Q000494:pharmacology; D013268:Stimulation, Chemical; D013829:Thiadiazines / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; C004717:diacetylmonoxime; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D003931:Diacetyl; D002118:Calcium