Wortmannin-Sensitive Pathway : Studies in Rat and Ferret Isolated Muscles Through a 2 + Myocardial Contractility by Sensitizing the Myofilament to Ca Insulin-like Growth Factor-1 but Not Growth Hormone Augments Mammalian

A growing body of evidence has been accumulated recently suggesting that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) affect cardiac function, but their mechanism(s) of action is unclear. In the present study, GH and IGF-1 were administered to isolated isovolumic aequorin-loaded rat whole hearts and ferret papillary muscles. Although GH had no effect on the indices of cardiac function, IGF-1 increased isovolumic developed pressure by 24% above baseline. The aequorin transients were abbreviated and demonstrated decreased amplitude. The positive inotropic effects of IGF-1 were not associated with increased intracellular Ca 21 av ilability to the contractile machinery but to a significant increase of myofilament Ca 21 sensitivity. Accordingly, the Ca -force relationship obtained under steady-state conditions in tetanized muscle was shifted significantly to the left (EC 50, 0.4460.02 versus 0.5260.03mmol/L with and without IGF-1 in the perfusate, respectively; P,0.05); maximal Ca -activated tetanic pressure was increased significantly by 12% (211 63 versus 235 62 mm Hg in controls and IGF-1–treated hearts, respectively;P,0.01). The positive inotropic actions of IGF-1 were not associated with changes in either pH i o high-energy phosphate content, as assessed by P nuclear magnetic resonance spectroscopy, and were blocked by the phosphatidylinositol 3-kinase inhibitor wortmannin. Concomitant administration of IGF binding protein-3 blocked IGF-1–positive inotropic action in ferret papillary muscles. In conclusion, IGF-1 is an endogenous peptide that through a wortmannin-sensitive pathway displays distinct positive inotropic properties by sensitizing the myofilaments to Ca 21 without increasing myocyte [Ca ]i. (Circ Res. 1998;83:50-59.)