Antidiabetic Drug Alogliptin Protects the Heart Against Ischemia-reperfusion Injury Through GLP-1 Receptor-dependent and Receptor-independent Pathways Involving Nitric Oxide Production in Rabbits

Abstract

GLP-1 has been reported to be cardioprotective against ischemia-reperfusion injury. We aimed to examine the effect of alogliptin, which may produce GLP-1, on ischemia-reperfusion injury and its mechanisms. Rabbits were fed a normal chow (control group) and a chow containing alogliptin (2 mg·kg·d: alogliptin-L group and 20 mg·kg·d: alogliptin-H group) for 7 days. The rabbits underwent 30 minutes of coronary occlusion and 48 hours of reperfusion. Exendin (9-39) [5 or 50 μg/kg, i.v., alogliptin-H+exendin (9-39)-L group and alogliptin-H+exendin (9-39)-H group] or L-NAME (10 mg/kg, i.v., alogliptin-H+L-NAME group) was administered to the alogliptin-H group. Alogliptin dose-dependently reduced the infarct size, which was partially blocked by exendin (9-39), but completely blocked by L-NAME. Exendin (9-39) or L-NAME alone did not affect the infarct size for themselves. The left ventricular ejection fraction and ±dP/dt were higher in the alogliptin-L group and alogliptin-H group than in the control group. Alogliptin increased the serum NOx and plasma GLP-1 levels, and those levels inversely correlated with the infarct size. Alogliptin upregulated the expressions of phosphorylated (p)-Akt and p-eNOS, which were inhibited by exendin (9-39) and L-NAME, respectively. In conclusion, alogliptin protects the heart against ischemia-reperfusion injury through GLP-1 receptor-dependent and receptor-independent pathways which involve nitric oxide production in rabbits.

Exendin‐4, a GLP‐1 receptor agonist regulates retinal capillary tone and restores microvascular patency after ischaemia–reperfusion injury

“…It is also considered that the activation of eNOS plays a protective role on blood vessels and may be damaged under I/R conditions (Brunner et al, 2003). Our present study shows that the level of phosphorylated eNOS decreased due to I/R injury but was significantly increased by exendin‐4 administration, which was consistent with the previous studies of GLP‐1 receptor agonists on other organs such as kidney and heart after I/R injury (Abdel‐Latif, Heeba, Taye, & Khalifa, 2018; Baba et al, 2017; Chang et al, 2015; Chen et al, 2017). To further investigate whether the exendin‐4 improved the endothelial dysfunction during I/R injury through increasing NO production, the intracellular NO levels were evaluated in cultured primary HRMECs.…”

Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists

“…The NO-synthase (NOS) inhibitor completely abolished the infarctlimiting effect of alogliptin. Exendin (9-39) significantly reduced, but did not eliminate, the infarct-reducing effect of alogliptin [40].…”

“…The drug increased exercise tolerance in mice with MI, which indirectly indicates a decrease in postinfarction cardiac remodeling [37]. Alogliptin (2 or 20 mg/kg/day per os) was administered to rabbits for 7 days before CAO (30 min) and reperfusion (48 h) [40]. Alogliptin dose-dependently reduced infarct size and increased the plasma GLP-1 level [40].…”

“…Alogliptin (2 or 20 mg/kg/day per os) was administered to rabbits for 7 days before CAO (30 min) and reperfusion (48 h) [40]. Alogliptin dose-dependently reduced infarct size and increased the plasma GLP-1 level [40]. The NO-synthase (NOS) inhibitor completely abolished the infarctlimiting effect of alogliptin.…”

Glucagon-like peptide-1 (GLP-1) mediates the protective effects of dipeptidyl peptidase IV inhibition on pulmonary hypertension

“…Mounting evidence indicate that GLP-1 exert a broad range of protective effects on cardiovascular diseases, including hypertension [22], chronic heart failure [23, 24], and ischemia-reperfusion injury [25]. Not only in preconstricted systemic circulation arteries, but also in pulmonary arteries, GLP-1 receptor agonist could induce a relaxation in endothelium-dependent manner [16, 26].…”