Protective effects of GLP-1 analogues exendin-4 and GLP-1(9–36) amide against ischemia–reperfusion injury in rat heart

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 < 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.