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

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. EC 50 of the force-Ca 2+ relationship and maximal Ca 2+ -activated systolic wall stress (max σ s ) were assessed by increasing Ca 2+ in the perfusate in a stepwise fashion and plotting systolic wall stress (σ s ) versus intracellular peak systolic Ca 2+ , measured by the aequorin bioluminescence method. We found a marked increase of systolic pressure (P s ), DevP, and (+dP/dt)/DevP in the treated groups compared with the control group. The combination group showed a blunted effect. σ s was increased in all treated groups for a perfusate Ca 2+ concentration of >1.5 mmol/L. The enhanced systolic performance can be explained by an increase of the overall Ca 2+ responsiveness due to an increased maximal response to Ca 2+ even though the EC 50 of the Ca 2+ -dose response was also slightly increased. P s was further enhanced by an increase of the relative wall thickness induced by the treatment. Diastolic pressure, diastolic Ca 2+ , and the amplitude and time course of the Ca 2+ 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 σ s .