TY - JOUR
T1 - Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes
AU - Kinugawa, Shintaro
AU - Tsutsui, Hiroyuki
AU - Ide, Tomomi
AU - Nakamura, Ryo
AU - Arimura, Ken ichi
AU - Egashira, Kensuke
AU - Takeshita, Akira
N1 - Funding Information:
We thank Erina Tajima for her technical assistance and Mr. Brian Quinn for critically reading the manuscript. This study was supported in part by grants (No. 08258221, 09670724) from the Ministry of Education, Science, and Culture.
PY - 1999/7
Y1 - 1999/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033042214&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033042214&partnerID=8YFLogxK
U2 - 10.1016/S0008-6363(99)00058-9
DO - 10.1016/S0008-6363(99)00058-9
M3 - Article
C2 - 10536700
AN - SCOPUS:0033042214
VL - 43
SP - 157
EP - 164
JO - Cardiovascular Research
JF - Cardiovascular Research
SN - 0008-6363
IS - 1
ER -