Exogenously Administered Growth Hormone and Insulin-like Growth Factor-I Alter Intracellular Ca 2+ Handling and Enhance Cardiac Performance

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Abstract
It has been proposed that chronic treatment with growth hormone (GH) or insulin-like growth factor-I (IGF-I) in the rat may enhance cardiac function in vivo. To confirm these findings and elucidate the mechanisms by which cardiac function is modulated, we studied isolated buffer-perfused rat hearts after 4 weeks of treatment with high doses of GH and IGF-I alone or in combination. Mechanical parameters were measured at 50% of the intracardiac balloon volume at which maximal developed pressure (DevP) occurred. EC50 of the force-Ca2+ relationship and maximal Ca2+-activated systolic wall stress (max σs) were assessed by increasing Ca2+ in the perfusate in a stepwise fashion and plotting systolic wall stress (σs) versus intracellular peak systolic Ca2+, measured by the aequorin bioluminescence method. We found a marked increase of systolic pressure (Ps), DevP, and (+dP/dt)/DevP in the treated groups compared with the control group. The combination group showed a blunted effect. σs was increased in all treated groups for a perfusate Ca2+ concentration of >1.5 mmol/L. The enhanced systolic performance can be explained by an increase of the overall Ca2+ responsiveness due to an increased maximal response to Ca2+ even though the EC50 of the Ca2+-dose response was also slightly increased. Ps was further enhanced by an increase of the relative wall thickness induced by the treatment. Diastolic pressure, diastolic Ca2+, and the amplitude and time course of the Ca2+ transient were not influenced by any treatment protocol. All treatments caused increases of body and heart weight. These data support the hypothesis that both IGF-I and GH directly affect cardiac performance by altering cardiac geometry as well as by enhancing max σs.