exenatide and Ischemia

The inotropic effects of glucagon have been recognized for many years, but it has remained unclear whether glucagon signaling is beneficial to cardiac function. We evaluated the effects of glucagon alone and in combination with the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide in the isolated perfused rat heart. The isolated perfused rat heart was used to investigate the initial inotropic and chronotropic effects of glucagon and exenatide during aerobic perfusion, and recovery of contractile function following ischaemia/reperfusion. Glucagon, but not exenatide, elicited an acute chronotropic and inotropic response during aerobic perfusion of the rat heart. Compared with control, glucagon improved recovery of left ventricular developed pressure (LVDP) by 33% (p < 0.05) and rate-pressure product (RPP) by 66% (p < 0.001) following ischaemia/reperfusion and amplified the mild recovery enhancement elicited by exenatide in a dose-dependent manner. Glucagon shows inotropic properties in the isolated perfused rat heart and improves contractile recovery following ischaemia/reperfusion, both alone and when co-administered with a GLP-1 receptor agonist. Glucagon and exenatide, a GLP-1 receptor agonist, combine to stimulate greater recovery of postischaemic contractile function in the Langendorff heart. Glucagon was inotropic and chronotropic, yet this initial effect decreased over time and did not account for the increased contractility observed postischaemia/reperfusion.

Topics: Animals; Exenatide; Glucagon; Glucagon-Like Peptide-1 Receptor; Heart; Ischemia; Myocardial Contraction; Rats; Reperfusion

Inflammation associated with blood-retinal barrier (BRB) breakdown is a common feature of several retinal diseases. Therefore, the development of novel nonsteroidal anti-inflammatory approaches may provide important therapeutic options. Previous studies demonstrated that inhibition of dipeptidyl peptidase-IV, the enzyme responsible for the degradation of glucagon-like peptide-1 (GLP-1), led to insulin-independent prevention of diabetes-induced increases in BRB permeability, suggesting that incretin-based drugs may have beneficial pleiotropic effects in the retina. In the current study, the barrier protective and anti-inflammatory properties of exendin-4 (Ex-4), an analog of GLP-1, after ischemia-reperfusion (IR) injury were examined.. Ischemia-reperfusion injury was induced in rat retinas by increasing the intraocular pressure for 45 minutes followed by 48 hours of reperfusion. Rats were treated with Ex-4 prior to and following IR. Blood-retinal barrier permeability was assessed by Evans blue dye leakage. Retinal inflammatory gene expression and leukocytic infiltration were measured by qRT-PCR and immunofluorescence, respectively. A microglial cell line was used to determine the effects of Ex-4 on lipopolysaccharide (LPS)-induced inflammatory response.. Exendin-4 dramatically reduced the BRB permeability induced by IR injury, which was associated with suppression of inflammatory gene expression. Moreover, in vitro studies showed that Ex-4 also reduced the inflammatory response to LPS and inhibited NF-κB activation.. The present work suggests that Ex-4 can prevent IR injury-induced BRB breakdown and inflammation through inhibition of inflammatory cytokine production by activated microglia and may provide a novel option for therapeutic intervention in diseases involving retinal inflammation.

Topics: Animals; Blood-Retinal Barrier; Cattle; Cells, Cultured; Disease Models, Animal; Exenatide; Glucagon-Like Peptide 1; Immunoblotting; Immunohistochemistry; Incretins; Inflammation; Ischemia; Male; Peptides; Rats; Rats, Long-Evans; Reperfusion Injury; Retinal Diseases; Venoms

Remote ischaemic conditioning (RIC) has been shown to reduce myocardial infarct size in patients. Our objective was to investigate whether the combination of RIC with either exenatide or glucose-insulin-potassium (GIK) is more effective than RIC alone.. Pigs were submitted to 40 min of coronary occlusion followed by reperfusion, and received (i) no treatment, (ii) one of the following treatments: RIC (5 min ischemia/5 min reperfusion × 4), GIK, or exenatide (at doses reducing infarct size in clinical trials), or (iii) a combination of two of these treatments (RIC + GIK or RIC + exenatide). After 5 min of reperfusion (n = 4/group), prominent phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) was observed, both in control and reperfused myocardium, in animals receiving GIK, and mitochondria from these hearts showed reduced ADP-stimulated respiration. (1)H NMR-based metabonomics disclosed a shift towards increased glycolysis in GIK and exenatide groups. In contrast, oxidative stress (myocardial nitrotyrosine levels) and eNOS uncoupling were significantly reduced only by RIC. In additional experiments (n = 7-10/group), ANOVA demonstrated a significant effect of the number of treatments after 2 h of reperfusion on infarct size (triphenyltetrazolium, % of the area at risk; 59.21 ± 3.34, 36.64 ± 3.03, and 21.04 ± 2.38% for none, one, and two treatments, respectively), and significant differences between one and two treatments (P = 0.004) but not among individual treatments or between RIC + GIK and RIC + exenatide.. GIK and exenatide activate cardioprotective pathways different from those of RIC, and have additive effects with RIC on infarct size reduction in pigs.

Topics: Aging; Animals; Exenatide; Glucose; Insulin; Ischemia; Myocardial Infarction; Myocardial Reperfusion; Myocardial Reperfusion Injury; Peptides; Potassium; Swine; Venoms

Exendin-4, an analog of glucagon-like peptide-1, has shown to have beneficial effects on endothelial function, and was recently approved for the treatment of diabetes. In previous studies, we showed that exendin-4 induces angiogenesis in in vitro and ex vivo assays; in this study, we assessed the proangiogenic effects of exendin-4 in vivo using a mouse hindlimb ischemia model. Treatment with exendin-4 for three days mitigated hindlimb and gastrocnemius muscle fiber necrosis. Hindlimb perfusion was determined using indocyanine green fluorescence dynamics that showed, significantly higher blood flow rate to the ischemic hindlimbs in an exendin-4-treated group. Immunohistochemistry assay showed that exendin-4 increased CD31-positive areas in the gastrocnemius muscle of ischemic limbs. Furthermore, treatment of the hindlimbs of ischemic mice with exendin-4 increased vascular endothelial growth factor (VEGF) and phospho-extracellular signal-related kinase (ERK) on western blot analysis. Our data demonstrate that exendin-4 prevents hindlimb ischemic injury by inducing vessels via VEGF angiogenic-related pathways. These findings suggest that exendin-4 has potential as a therapeutic agent for vascular diseases that stimulate angiogenesis.

Topics: Angiogenesis Inducing Agents; Animals; Disease Models, Animal; Exenatide; Hemodynamics; Hindlimb; Ischemia; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Neovascularization, Physiologic; Peptides; Vascular Endothelial Growth Factor A; Venoms

Exendin-4, an exogenous glucagon-like peptide-1 receptor (GLP-1R) agonist, protects the heart from ischemia/reperfusion injury. However, the mechanisms for this protection are poorly understood. Caveolae, sarcolemmal invaginations, and caveolins, scaffolding proteins in caveolae, localize molecules involved in cardiac protection. We tested the hypothesis that caveolae and caveolins are essential for exendin-4 induced cardiac protection using in vitro and in vivo studies in control and caveolin-3 (Cav-3) knockout mice (Cav-3 KO).. Myocytes were treated with exendin-4 and then incubated with methyl-β-cyclodextrin (MβCD) to disrupt caveolae formation. This was then followed by simulated ischemia/reperfusion (SI/R). In addition, cardiac protection in vivo was assessed by measuring infarct size and cardiac troponin levels.. Exendin-4 protected cardiac myocytes (CM) from SI/R [35.6 ± 12.6% vs. 64.4 ± 18.0% cell death, P = 0.034] and apoptosis but this protection was abolished by MβCD (71.8 ± 10.8% cell death, P = 0.004). Furthermore, Cav-3/GLP-1R co-localization was observed and membrane fractionation by sucrose density gradient centrifugation of CM treated with MβCD + exendin-4 revealed that buoyant (caveolae enriched) fractions decreased Cav-3 compared to CM treated with exendin-4 exclusively. Furthermore, exendin-4 induced a reduction in infarct size and cardiac troponin relative to control (infarct size: 25.1 ± 8.2% vs. 41.4 ± 4.1%, P < 0.001; troponin: 36.9 ± 14.2 vs. 101.1 ± 22.3 ng/ml, P < 0.001). However, exendin-4 induced cardiac protection was abolished in Cav-3 KO mice (infarct size: 43.0 ± 6.4%, P < 0.001; troponin: 96.8 ± 26.6 ng/ml, P = 0.001).. We conclude that caveolae and caveolin-3 are critical for exendin-4 induced protection of the heart from ischemia/reperfusion injury.

Topics: Animals; Caveolae; Caveolin 3; Exenatide; Hypoglycemic Agents; Ischemia; Male; Mice, Inbred C57BL; Mice, Knockout; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Peptides; Rats, Wistar; Venoms

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Exenatide; Female; Humans; Hypoglycemic Agents; Ischemia; Kidney Glomerulus; Male; Middle Aged; Peptides; Renal Insufficiency; Venoms