© 1996 American Heart Association, Inc.
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Exogenously Administered Growth Hormone and Insulin-like Growth Factor-I Alter Intracellular Ca2+ Handling and Enhance Cardiac Performance
In Vitro Evaluation in the Isolated Isovolumic Buffer-Perfused Rat Heart
the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory, Cardiovascular Division, Department of Medicine, Beth Israel Hospital and Harvard Medical School, Boston, Mass.
Correspondence to James P. Morgan, MD, PhD, Cardiovascular Division, Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215. E-mail jmorgan@bih.harvard.edu.
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 
s) were assessed by increasing Ca2+ in the perfusate in a stepwise fashion and plotting systolic wall stress (s) 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. s 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 s.
Key Words: somatotropin • insulin-like growth factor-I • myocardial contractility • isolated heart • Ca2+
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