Antidiabetic Drug Voglibose Is Protective Against Ischemia—Reperfusion Injury Through Glucagon-Like Peptide 1 Receptors and the Phosphoinositide 3-Kinase-Akt-Endothelial Nitric Oxide Synthase Pathway in Rabbits

Abstract

Glucagon-like peptide 1 (GLP-1) reportedly exerts a protective effect against cardiac ischemia. We hypothesized that the alpha-glucosidase inhibitor voglibose, an unabsorbable antidiabetic drug with cardioprotective effects, may act through stimulation of GLP-1 receptors. The results of the present study suggest oral administration of voglibose reduces myocardial infarct size and mitigates cardiac dysfunction in rabbits after 30 minutes of coronary occlusion and 48 hours of reperfusion. Voglibose increased basal and postprandial plasma GLP-1 levels and reduced postprandial plasma glucose levels. The infarct size-reducing effect of voglibose was abolished by treatment with exendin(9-39), wortmannin, Nomega-nitro-L-arginine methylester, or 5-hydroxydecanoate), which inhibit GLP-1 receptors, phosphoinositide 3-kinase, nitric oxide synthase, and K(ATP) channels, respectively. Western blot analysis showed that treatment with voglibose upregulated myocardial levels of phospho-Akt, phosphoendothelial nitric oxide synthase after myocardial infarction. The upregulation of phospho-Akt was inhibited by exendin(9-39) and wortmannin. These findings suggest that voglibose reduces myocardial infarct size through stimulation of GLP-1 receptors, activation of the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathways, and the opening of mitochondrial K(ATP) channels. These findings may provide new insight into therapeutic strategies for the treatment of patients with coronary artery disease.

Elevated plasma GLP-1 levels and enhanced expression of cardiac GLP-1 receptors as markers of left ventricular systolic dysfunction: a cross-sectional study

“…However, the expression of GLP-1 receptor protein was significantly enhanced in patients with impaired LV function as compared with those in patients with preserved LV function. This was supported by our previous animal studies demonstrating that the expression of GLP-1 receptors in the LV myocardium was upregulated in a rabbit model of myocardial infarction,15 16 and other report that the cardiac GLP-1 receptors were upregulated in a heart failure dog model of dilated cardiomyopathy 25. This may support the concept that GLP-1-GLP-1 receptor system may serve as a compensatory mechanism for LV dysfunction.…”

“…7 We previously reported that oral administration of voglibose and miglitol significantly increased basal and postprandial plasma levels of GLP-1 and the increased endogenous GLP-1 significantly improved cardiac function and reduced the myocardial infarct size 1516 Furthermore, the expression of GLP-1 receptors was enhanced in the myocardium of rabbits with myocardial infarction 1516 These results suggest that endogenous GLP-1 as well as exogenous GLP-1 has a cardioprotective effect.…”

“…14 In an in vivo rat or porcine model of myocardial infarction, intravenous infusion of GLP-1 or GLP-1 agonist exenatide significantly reduced the infarct size 57 We previously reported that oral administration of voglibose and miglitol significantly increased basal and postprandial plasma levels of GLP-1 and the increased endogenous GLP-1 significantly improved cardiac function and reduced the myocardial infarct size 1516 Furthermore, the expression of GLP-1 receptors was enhanced in the myocardium of rabbits with myocardial infarction 15…”

Effects of 24-week treatment with acarbose on glucagon-like peptide 1 in newly diagnosed type 2 diabetic patients: a preliminary report

“…In a recent animal study, it has reported that orally administered voglibose, another AGI, protects the myocardium against ischemia–reperfusion injury through the stimulation of GLP-1 receptors, the activation of PI3K-Akt endothelial NOS pathways, and the opening of mitochondrial KATP channels in rabbits after 30 minutes of coronary occlusion and 48 hours of reperfusion [12]. In the present study, the observed changes in CIMT were not significantly different pre- and post-acarbose treatment.…”

“…GLP-1 can elevate levels of nitric oxide (NO), which is the most important endothelium-derived vasodilator and has a potent anti-atherosclerotic effect [9,10] in the coronary effluent from mouse hearts [11]. Moreover, a recent animal study suggests that voglibose (another AGI) can reduce myocardial infarct size through the stimulation of GLP-1 receptors and the activation of the phosphoinositide 3-kinase-Akt-endothelial NOS pathways [12]. …”