TY - JOUR
T1 - Postconditioning with curaglutide, a novel GLP-1 analog, protects against heart ischemia-reperfusion injury in an isolated rat heart
AU - Salling, HK
AU - Döhler, KD
AU - Engstrøm, Thomas
AU - Treiman, Marek
PY - 2012/10/10
Y1 - 2012/10/10
N2 - Aim: GLP-1(7-36)amide (GLP-1) is an intestinal hormone with effects on glucose metabolism and feeding behavior, including insulinotropic, insulinomimetic, glucagonostatic and anorectic actions. In experimental settings, GLP-1 has also been shown to diminish infarct size following heart ischemia-reperfusion. GLP-1 analogs with extended half-lives are continuously being developed against type 2 diabetes mellitus. Of these, only exendin-4 (exenatide, registered as Byetta) has been shown to mimic the infarct size-limiting effect of GLP-1 in a clinically relevant application as a postconditioning agent. The aim of this work was to test, in a postconditioning mode, a novel, proteolysis-resistant GLP-1 analog N-Ac-GLP-1(7-34)amide, herein termed curaglutide, for its cardioprotective ability. Method: Global ischemia (35. min)-reperfusion (120 min) was applied in isolated, retrogradely perfused rat hearts. Peptides were present for 15. min at the onset of reperfusion. Cardiac function parameters (beats per minute, left ventricle developed and diastolic pressures, rate-pressure product) were measured. Infarct size was determined by 2,3,5-tripehyltetrazolium chloride staining and planimetry. Results: Curaglutide did not affect any of the functional heart parameters when administered without preceding ischemia. Curaglutide 0.3. nM diminished significantly the postischemic hypercontracture, with no significant effect on the left ventricle developed pressure or rate-pressure product. Infarct size was reduced by curaglutide postconditioning from 24.8% (SEM 2.8, N = 14) to 11.4% (SEM 3.2, N = 8; P < 0.05). These effects of curaglutide on postischemic hypercontracture and infarct size were similar in magnitude to corresponding effects of GLP-1 receptor agonist exendin-4. The cardioprotective effects of both agents were abolished in the presence of a GLP-1 receptor antagonist exendin(9-39). Conclusion: Curaglutide is a new, proteolysis-resistant GLP-1 analog with a beneficial effect on reperfusion-injury in an isolated rat heart. Curaglutide was here shown to act through GLP-1 receptors. Based on the present results, more extensive experimental studies in vivo, comparing dose-response characteristics and efficacy of curaglutide and exendin-4 appear warranted.
AB - Aim: GLP-1(7-36)amide (GLP-1) is an intestinal hormone with effects on glucose metabolism and feeding behavior, including insulinotropic, insulinomimetic, glucagonostatic and anorectic actions. In experimental settings, GLP-1 has also been shown to diminish infarct size following heart ischemia-reperfusion. GLP-1 analogs with extended half-lives are continuously being developed against type 2 diabetes mellitus. Of these, only exendin-4 (exenatide, registered as Byetta) has been shown to mimic the infarct size-limiting effect of GLP-1 in a clinically relevant application as a postconditioning agent. The aim of this work was to test, in a postconditioning mode, a novel, proteolysis-resistant GLP-1 analog N-Ac-GLP-1(7-34)amide, herein termed curaglutide, for its cardioprotective ability. Method: Global ischemia (35. min)-reperfusion (120 min) was applied in isolated, retrogradely perfused rat hearts. Peptides were present for 15. min at the onset of reperfusion. Cardiac function parameters (beats per minute, left ventricle developed and diastolic pressures, rate-pressure product) were measured. Infarct size was determined by 2,3,5-tripehyltetrazolium chloride staining and planimetry. Results: Curaglutide did not affect any of the functional heart parameters when administered without preceding ischemia. Curaglutide 0.3. nM diminished significantly the postischemic hypercontracture, with no significant effect on the left ventricle developed pressure or rate-pressure product. Infarct size was reduced by curaglutide postconditioning from 24.8% (SEM 2.8, N = 14) to 11.4% (SEM 3.2, N = 8; P < 0.05). These effects of curaglutide on postischemic hypercontracture and infarct size were similar in magnitude to corresponding effects of GLP-1 receptor agonist exendin-4. The cardioprotective effects of both agents were abolished in the presence of a GLP-1 receptor antagonist exendin(9-39). Conclusion: Curaglutide is a new, proteolysis-resistant GLP-1 analog with a beneficial effect on reperfusion-injury in an isolated rat heart. Curaglutide was here shown to act through GLP-1 receptors. Based on the present results, more extensive experimental studies in vivo, comparing dose-response characteristics and efficacy of curaglutide and exendin-4 appear warranted.
U2 - 10.1016/j.regpep.2012.06.007
DO - 10.1016/j.regpep.2012.06.007
M3 - Journal article
SN - 0167-0115
VL - 178
SP - 51
EP - 55
JO - Regulatory Peptides
JF - Regulatory Peptides
ER -
