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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 17, 2006; DOI: 10.1124/jpet.106.100982

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Received for publication January 6, 2006.
Revised February 8, 2006.
Accepted for publication February 8, 2006.

The Direct Effects of Glucagon-Like Peptide-1 (GLP-1) on Myocardial Contractility and Glucose Uptake in Normal and Post-Ischemic Isolated Rat Hearts

Tingcun Zhao 1, Pratik Parikh 2, Siva Bhashyam 2, Hakki Bolukoglu 2, Indu G. Poornima 2, You-Tang Shen 3, Richard P. Shannon 2*

1 Brown University School of Medicine 2 Allegheny General Hospital 3 University of Medicine & Dentistry New Jersey

* Address correspondence to: E-mail: rshannon{at}wpahs.org

Abstract

Background: Recent evidence suggests that GLP-1 enhances recovery of LV function following 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. Methods: LV function and myocardial glucose uptake and lactate production were measured under basal conditions and following 30 minutes of low flow ischemia and 30 minutes of reperfusion in the presence and absence of GLP-1 (7-36) amide. The response was compared to standard buffer alone or buffer containing insulin (100µU/ml). Results: GLP-1 decreased the left ventricular developed pressure (Baseline: 100±2 mmHg; GLP-1: 75±3 mmHg, p< 0.05) and LV dP/dt (Baseline: 4,876±65 mmHg/sec; GLP-1: 4,353±76 mmHg/sec, 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 GLUT-1 translocation. GLP-1 enhanced recovery following 30 minutes of low flow ischemia with significant improvements in LVEDP (Con: 13±4 mmHg; GLP-1: 3±2 mmHg, p< 0.05) and LV Dev P (Con: 66±6 mmHg; GLP-1: 98±5 mmHg, p< 0.05). GLP-1 increased L V function, myocardial glucose uptake and GLUT-1 and GLUT-4 translocation during reperfusion to an extent similar to insulin. Conclusions: 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 following low flow ischemia in a fashion similar to insulin.


Key words: Glucagon-like peptide-1, glucose transporters, ischemia/reperfusion, myocardial contractility, myocardial glucose uptake, nitric oxide


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