To overcome this hurdle exenatide and liraglutide have been selleck chemicals introduced as more stable peptidic GLP 1 receptor agonists. Both share amino acid sequence homology to GLP 1 and display prolonged half life in humans allowing twice daily or once daily dosing. A third analog, lixisenatide is a new potent and selective peptidic GLP 1 receptor agonist for once daily s. c. injection cur rently in late stage clinical development. European market approval was recently granted under the trade name Lyxumia. In animal models of diabetes lixisenatide im proved basal blood glucose and metabolic dysfunction with a rapid onset and sustained duration Inhibitors,Modulators,Libraries of action, prevented the deterioration of pancreatic responsiveness, delayed gastric emptying and reduced food intake.

Dose dependent effects of lixisenatide in T2DM patients in adequately controlled with metformin were demonstrated in a randomized, double blind, placebo controlled trial. Despite currently Inhibitors,Modulators,Libraries ongoing cardiovascular outcome stud ies in more than 26,000 T2DM patients directly treated with exenatide, liraglutide, or lixisenatide, basic mechanis tic questions regarding the cardiac mode of action of these GLP 1 receptor agonists remain puzzling. All analogs have been tested in only a limited set of pre clinical cardiovas cular studies, and here with a strong focus on infarct size reduction and acute cardioprotection. So far none of the GLP 1 analogs has been administered Inhibitors,Modulators,Libraries in chronic studies only after the onset of myocardial infarction. Hence the efficacy on cardiac remodeling beyond an acute anti ischemic effect with infarct size reduction is Inhibitors,Modulators,Libraries not clear.

Finally specificity of expression measurements of GLP1R in cardiac tissues has been recently challenged. Some GLP 1 peptide analogs exert GLP 1 receptor independent effects in the myocardium. Here, we first investigated the acute effects of lixisenatide on acute infarct size reduction in an isolated Langendorff heart preparation. In a second chronic Inhibitors,Modulators,Libraries rat study, with a transient ischemia setting designed to match closer to the clinical situation, lixisenatide administration was started clearly after the acute damage. A clinically established ACE inhibitor, ramipril, served as calibrator in this study proto col. In addition several mechanistic and cellular studies were performed to spread light on underlying signaling pathways and molecular mechanisms.

Methods All animal studies conformed to the German law for the protection of animal guidelines and the guide for the care and use of laboratory animals published by the US National Institutes of Health as well as to Sanofi Ethical Committee guidelines. Approval was granted by a local animal stud ies ethic review board. Specific materials Ramipril thereby and lixisenatide were synthesized in chemical departments of Sanofi.