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J. Pharmacol. Exp. Ther. 317 (3): 1106-1113

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics.

CARDIOVASCULAR

Direct Effects of Glucagon-Like Peptide-1 on Myocardial Contractility and Glucose Uptake in Normal and Postischemic Isolated Rat Hearts

Tingcun Zhao, Pratik Parikh, Siva Bhashyam, Hakki Bolukoglu, Indu Poornima, You-Tang Shen, and Richard P. Shannon

Department of Pediatrics, Brown University School of Medicine, Providence, Rhode Island (T.Z.); Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania, and Drexel University College of Medicine, Philadelphia, Pennsylvania (P.P., S.B., H.B., I.P., R.P.S.); and Department of Molecular and Cellular Cardiology, University of Medicine and Dentistry of New Jersey, Newark, New Jersey (Y.-T.S.)

Abstract: Recent evidence suggests that glucagon-like peptide-1 (GLP-1) enhances recovery of left ventricular (LV) function after transient coronary artery occlusion. However, it is uncertain whether GLP-1 has direct effects on normal or ischemic myocardium and whether the mechanism involves increased myocardial glucose uptake. LV function and myocardial glucose uptake and lactate production were measured under basal conditions and after 30 min of low-flow ischemia and 30 min of reperfusion in the presence and absence of GLP-1-(7–36) amide. The response was compared with standard buffer alone or buffer containing insulin (100 µU/ml). GLP-1 decreased the left ventricular developed pressure (baseline: 100 ± 2 mm Hg; GLP-1: 75 ± 3 mm Hg, p < 0.05) and LV dP/dt (baseline: 4876 ± 65 mm Hg/s; GLP-1: 4353 ± 76 mm Hg/s, p < 0.05) in normal hearts. GLP-1 increased myocardial glucose uptake (baseline: 33 ± 3 µmol/min/g; GLP-1: 81 ± 7 µmol/min/g, p < 0.05) by increasing nitric oxide production and glucose transporter (GLUT)-1 translocation. GLP-1 enhanced recovery after 30 min of low-flow ischemia with significant improvements in LV end-diastolic pressure (control: 13 ± 4 mm Hg; GLP-1: 3 ± 2 mm Hg, p < 0.05) and LV developed pressure (control: 66 ± 6 mm Hg; GLP-1: 98 ± 5 mm Hg, p < 0.05). GLP-1 increased LV function, myocardial glucose uptake, and GLUT-1 and GLUT-4 translocation during reperfusion to an extent similar to that with insulin. GLP-1 has direct effects on the normal heart, reducing contractility, but increasing myocardial glucose uptake through a non-Akt-1-dependent mechanism, distinct from the actions of insulin. However, GLP-1 increased myocardial glucose uptake and enhanced recovery of cardiac function after low-flow ischemia in a fashion similar to that of insulin.

Received for publication January 4, 2006. Accepted for publication February 8, 2006.

Address correspondence to: Dr. Richard P. Shannon, Department of Medicine, Allegheny General Hospital, 320 E. North Ave., Pittsburgh, PA 15212. E-mail: rshannon{at}wpahs.org

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