GLP-1(7-36) and GLP-1(9-36) Protect Murine Hearts from Post-Ischemic Contractile Dysfunction

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Background: Increasing evidence suggests that glycemic control is necessary but insufficient to alter cardiovascular complications in Type 2 DM. Glucagon like peptide-1(GLP-1) is a novel anti-glycemic agent that possesses both insulinotropic and insulinomimetic actions and has been shown to be cardio-protective in both animals and humans. However, it is uncertain as to whether the protective effects are mediated by the native peptide, GLP-1(7-36) or its active metabolite, GLP-1(9-36). The goal of the present study was to determine the effects of GLP-1 (7-36) versus GLP-1(9-36) on post-ischemic contractile dysfunction. Methods: Thirty C57BL/6 mice (age 8–12 weeks) were anesthetized and hearts were extracted, immediately suspended in a Langendorff preparation and perfused at constant flow (3.3ml/min) with a standard KH buffer containing 11mM glucose and 5mM pyruvate. A pressure transducing balloon was placed in the LV and filled to generate 5 mmHg in LVEDP and hearts were paced at 480min^–1. After a 15min stabilization period, GLP-1(7-36) [400 pM] or GLP-1 (9-36) [800 pM] were added to the perfusate for 10min before low flow ischemia was induced for 20min followed by 40min of reperfusion. LV developed pressure (LVDev), LVdP/dt, and LVEDP were monitored and compared to buffer alone. Results: GLP-1(7-36) had a more rapid (Con:40min; GLP-1(7-36): 10min, p<0.01) and complete recovery of function (Con:54±12%; GLP-1(7-36):78±5%, p<0.001). The effect was abolished by pre-treatment with the GLP-1 receptor antagonist, exendin(9-39) [30nM]. Notably, GLP-1(9-36) was also associated with a similar rapid (Con: 40min; GLP-1 (9-36): 10min, p<0.01) and more complete recovery (Con: 41±8%; GLP-1 (9-36):67±6%, p<0.001). Conclusion: Both GLP-1(7-36) and GLP-1(9-36) mitigate post-ischemic contractile dysfunction in isolated mouse hearts. GLP-1 appears to act independent of the GLP–1 receptor.

LV Functional Recovery GLP-1(7-36) vs Control

			Ischemia	Reperfusion
	Baseline	Drug Run-in	10% Flow	10min	20min	40min	% recovery
GLP-1(7-36) n=6	96	94	4	79	80	75	78%
SEM	±5	±5	±1	±6	±6	±5	±5
Control n=7	102	94	8	49	53	55	54%
SEM	±7	±8	±3	±9	±11	±9	±12

LVDev mmHg

LV Functional Recovery GLP-1(9-36) vs Control

			Ischemia	Reperfusion
	Baseline	Drug Run-in	10% Flow	10min	20min	40min	% Recovery
GLP-1(9-36) n=6	95	89	0.9	71	72	64	67%
SEM	±7	±4	±.2	±5	±6	±5	±6
Control n=7	96	95	0.9	54	47	40	41%
SEM	±8	±8	±8	±8	±8	±8	±8

LVDev mmHg