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


METHODS
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 (TR(90)). Intracellular Ca(2+) transients were measured as changes in fura-2 fluorescence intensity (DeltaFFI).


RESULTS
Myocytes from BB/DP rats displayed increased PS, prolonged TPS and TR(90,) 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 Ca(2+) transients in myocytes from both BB/DR and BB/DP rats.


CONCLUSIONS
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 Ca(2+) sensitivity.
Ren
J
J
Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, 501 N. Columbia Road, Grand Forks, ND 58203, USA. jren@medicine.nodak.edu
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016257:Fura-2; D019833:Genistein / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008856:Microscopy, Fluorescence; D009200:Myocardial Contraction / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D011913:Rats, Inbred BB; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; C411572:H 1356; D007334:Insulin-Like Growth Factor I; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D002118:Calcium; D016257:Fura-2; D000077191:Wortmannin