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Cardiovascular Research 2000 46(1):162-171; doi:10.1016/S0008-6363(00)00011-0
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Attenuated cardiac contractile responsiveness to insulin-like growth factor I in ventricular myocytes from biobreeding spontaneous diabetic rats

Jun Ren*

Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, 501 N. Columbia Road, Grand Forks, ND 58203, USA

* Tel.: +1-701-777-3916; fax: +1-701-777-4490 jren{at}medicine.nodak.edu

Objective: Insulin-like growth factor I (IGF-1) stimulates cardiac growth and contraction, but resistance to its action has been reported in diabetes. This study was to determine if IGF-1-induced cardiac contractile action is altered in rats genetically predisposed to diabetes. Method: Ventricular myocytes were isolated from spontaneously biobreeding diabetes-prone (BB/DP) rats and their diabetes-resistant littermates (BB/DR). Mechanical properties were evaluated in cardiomyocytes using a video-based edge-detection system. Myocytes were electrically stimulated at 0.5 Hz. Contractile properties analyzed included peak shortening (PS), time-to-PS (TPS) and time-to-90% relengthening (TR90). Intracellular Ca2+ transients were measured as changes in fura-2 fluorescence intensity ({Delta}FFI). Results: Myocytes from BB/DP rats displayed increased PS, prolonged TPS and TR90, as well as reduced resting FFI compared to the BB/DR group. IGF-1 (10–10–10–6 M) caused a dose-dependent increase in PS in myocytes from BB/DR but not BB/DP rats. The increase of PS was blunted by IGF-1 antagonist H-1356, phosphatidylinositol-3 (PI-3) kinase inhibitor wortmannin, but not tyrosine kinase inhibitor genistein. None of these agents affected responses to IGF-1 in BB/DP myocytes. Interestingly, IGF-1 elicited a comparable dose-dependent increase in Ca2+ transients in myocytes from both BB/DR and BB/DP rats. Conclusion: These results suggest that the attenuation of IGF-1-induced cardiac contractile response in chemically-induced diabetes also exists in diabetes of genetic origin, possibly due to mechanisms involving PI-3 kinase and intracellular Ca2+ sensitivity.

KEYWORDS Calcium (cellular); Contractile function; Diabetes; Excitation–contraction (E–C) coupling; Growth factors; Myocytes


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