Protective effects of GLP-1 analogues exendin-4 and GLP-1(9–36) amide against ischemia–reperfusion injury in rat heart David P. Sonne a , Thomas Engstrøm b , Marek Treiman a, ⁎ a Department of Biomedical Sciences and The Danish National Research, Foundation Centre for Heart Arrhythmia, University of Copenhagen, The Panum Institute 12.5, Blegdamsvej 3, DK-2200 Copenhagen, Denmark b Cardiac Catheterization Laboratory, The Heart Centre, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark Received 28 September 2007; accepted 4 October 2007 Available online 13 October 2007 Abstract Glucagon-Like Peptide-1 (GLP-1) is an incretin peptide secreted from intestinal L-cells, whose potent plasma glucose-lowering action has prompted intense efforts to develop GLP-1 receptor-targeting drugs for treatment of diabetic hyperglycemia. More recently, GLP-1 and its analogues have been shown to exert cardiovascular effects in a number of experimental models. Here we tested exendin-4 (Exe-4), a peptide agonist at GLP-1 receptors, and GLP-1(9–36) amide, the primary endogenous metabolite of GLP-1 (both in the concentration range 0.03– 3.0 nM), for their protective effects against ischemia–reperfusion injury (IRI) in an isolated rat heart preparation. When administered, the agents were only present for the first 15 min of a 120 min reperfusion period (postconditioning protocol). Exe-4, but not GLP-1(9–36) amide, showed a strong infarct-limiting action (from 33.2% ± 2.7% to 14.5% ± 2.2% of the ischemic area, p b 0.05). This infarct size-limiting effect of Exe-4 was abolished by exendin(9–39) (Exe(9–39)), a GLP-1 receptor antagonist. In contrast, both Exe-4 and GLP-1(9–36) amide were able to augment left ventricular performance (left ventricular developed pressure and rate-pressure product) during the last 60 min of reperfusion. These effects were only partially antagonized by Exe(9–39). We suggest that Exe-4, in addition to being currently exploited in treatment of diabetes, may present a suitable candidate for postconditioning trials in clinical settings of IRI. The divergent agonist effects of Exe-4 and GLP-1(9–36), along with correspondingly divergent antagonistic efficacy of Exe(9–39), seem consistent with the presence of more than one type of GLP-1 receptor in this system. © 2007 Elsevier B.V. All rights reserved. Keywords: Myocardial; Infarction; Postconditioning; Pharmacological; Cardioprotection; Ischemia 1. Introduction Glucagon-Like Peptide-1 (GLP-1) is one of several products of posttranslational processing of the proglucagon gene transcript in the intestinal L-cells, the other products comprising glicentin, oxyntomodulin, intervening peptides and Glucagon- Like Peptide-2 [1]. Physiology and pharmacology of GLP-1 have been researched extensively, with a major emphasis on its incretin actions and consequently its application in the treatment of type-2 diabetes [2]. GLP-1 occurs in two biologically active isoforms: GLP-1(7–36) amide and a glycine-extended isoform GLP-1(7–37) [3], with the amidated peptide being the most prevalent form in man. However, both forms are rapidly degraded in circulation at the N-terminus by dipeptidyl peptidase IV (DPPIV), resulting in a short plasma half-life for the intact peptides (approximately 1–2 min) [4]. This cleavage by DPPIV generates metabolites (GLP-1(9-36) amide and GLP- 1(9–37), respectively) which are unable to activate the GLP-1 receptor (GLP-1R) [5] and which lack insulinotropic activity [6]. Ischemia–reperfusion injury (IRI) of the heart refers to a range of pathophysiological phenomena spanning from revers- ible dysfunction to cell death, as induced by reperfusion after a period of major ischemia of an area of myocardium, such as seen when angioplasty or thrombolysis is applied for treatment of acute myocardial infarction (AMI) [7,8]. In the last two decades, a host of experimental studies have brought a Available online at www.sciencedirect.com Regulatory Peptides 146 (2008) 243 – 249 www.elsevier.com/locate/regpep ⁎ Corresponding author. Tel.: +45 3532 7510 or +45 5120 1601; fax: +45 3532 7418. E-mail address: M.Treiman@mfi.ku.dk (M. Treiman). 0167-0115/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2007.10.001