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.
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 Ca(2+)-activated systolic wall stress (max sigma s) were assessed by increasing Ca2+ in the perfusate in a stepwise fashion and plotting systolic wall stress (sigma 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. sigma 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 Ca(2+)-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 sigma s.
Strömer
H
H
Charles A. Dana Research Institute, Department of Medicine, Beth Israel Hospital, Boston, MA 02215, USA.
Cittadini
A
A
Douglas
P S
PS
Morgan
J P
JP
D000818:Animals; D002021:Buffers; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology*; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects*
D002021:Buffers; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D002118:Calcium