Effects of wortmannin on insulin- and ischemia-induced stimulation of GLUT4 translocation and FDG uptake in perfused rat hearts

• Published in: Cardiovascular research 1997-08, Vol.35 (2), p.283-293
• Main Authors: EGERT, S, NGUYEN, N, BROSIUS, F. C, SCHWAIGER, M
• Format: Article
• Language: English
• Subjects: Androstadienes - pharmacology; Animals; Biological and medical sciences; Biological Transport - drug effects; Cardiovascular system; Cell Membrane - metabolism; Fluorine Radioisotopes; Fluorodeoxyglucose F18 - pharmacokinetics; Glucose Transporter Type 4; Immunoblotting; Insulin Antagonists - pharmacology; Intracellular Membranes - metabolism; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Monosaccharide Transport Proteins - metabolism; Muscle Proteins; Myocardial Ischemia - metabolism; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Perfusion; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Wortmannin
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/S0008-6363(97)00133-8

Myocardial glucose transport is enhanced by hormonal and other stimuli such as ischemia and hypoxia which induce glucose transporter 4 (GLUT4) translocation. Whether insulin and ischemia share a common signaling mechanism is not yet known. This study investigated whether phosphatidylinositol 3-kinase (PI3K), a signaling intermediate of the insulin-responsible pathway, also participates in the ischemia-induced stimulation of glucose. Isolated Langendorff-perfused Sprague-Dawley rat hearts were subjected to 100 nmol/l insulin or 15 min of no-flow ischemia with/without 1 mumol/l wortmannin, an inhibitor of PI3K. After perfusion, relative subcellular glucose transporter GLUT4 distribution was assessed by membrane fractionation and immunoblotting and compared to controls. Uptake kinetics of the glucose analog [18F]fluoro-deoxyglucose (FDG) were also studied during perfusion of rat hearts. GLUT4 translocation to the plasma membrane (PM) was increased by insulin 1.8-fold and by ischemia 2.4-fold (P < 0.05). FDG uptake was increased by insulin 6.0-fold and by ischemia 6.2-fold (P < 0.05). Wortmannin 1 mumol/l inhibited insulin-mediated translocation of GLUT4 and increase in FDG uptake completely. However, it did not show any effect on ischemia-stimulated GLUT4 translocation or on ischemia-induced increase in FDG utilization. A significant correlation was found between relative GLUT4 translocation and FDG uptake in hearts of the insulin series (r = 0.9, P < 0.05) and of the ischemia series (r = 0.8, P < 0.05). Our results demonstrate that wortmannin did not inhibit ischemia-induced stimulation of myocardial glucose transport, supporting the hypothesis of different signaling pathways for ischemia and insulin.