The cardioprotective and inotropic components of the postconditioning effects of GLP-1 and GLP-1(9-36)a in an isolated rat heart.
GLP-1 and its metabolite GLP-1(9-36)a have been shown to exert cardiotropic effects, and were demonstrated to be cardioprotective agents in isolated, postischemic rat or mouse hearts. An agent's total effect on myocardial performance in a postconditioning paradigm is a sum of its myocyte-preserving (cardioprotective) and contractility-affecting (negative or positive inotropic) action components. These components may not always be explicitly separated by the experimental protocol. We propose an analytical approach to identify and quantify the cardioprotective and inotropic components in a postconditioning protocol, as exemplified by use of GLP-1 and GLP-1(9-36)a following a global ischemia in isolated rat hearts. Peptides were administered during the first 15min of 120min reperfusion. GLP-1 0.3nM reduced infarct size from 23.2+/-2.4% to 14.1+/-2.3% of area-at-risk (n=15, P=0.0223), an effect abolished by the GLP-1 receptor antagonist, exendin(9-39) 5nM. GLP-1 showed only a small, non-significant tendency to increase mechanical performance (increase of LVDP by 26.7%, P=0.1621; RPP 33.5%, P=0.0858; dP/dt(max) 28.5%, P=0.1609). This could be accounted for by the cardioprotective component of GLP-1 action, rather than any true inotropic effect. In contrast, GLP-1(9-36)a did not reduce infarct size significantly, but acted as a strong negative inotrope in postischemic hearts, causing a contractility deficit (LVDP 58.8%, P=0.0004; RPP 58.2%, P=0.0007; dP/dt(max)=58.2%, P=0.0012), quantifiable by an analysis of infarct size-mechanical performance plots. These results help resolve certain apparent discrepancies between some of the published effects of GLP-1 and GLP-1(9-36)a.
Ossum
Alvilde
A
Department of Biomedical Sciences and The Danish National Foundation Research Centre for Heart Arrhythmia, University of Copenhagen, Denmark.
van Deurs
Ulla
U
Engstrøm
Thomas
T
Jensen
Jan Skov
JS
Treiman
Marek
M
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D002316:Cardiotonic Agents; D010455:Peptides; C114437:glucagon-like peptide-1 (9-36)-amide; D052216:Glucagon-Like Peptide 1