Effects of sitagliptin on ß-adrenoceptor mediated relaxation in streptozotocin-diabetic rat aorta

Authors: AYHANIM ELİF MÜDERRİSOĞLU, BETÜL RABİA ERDOĞAN, ZEYNEP ELİF YEŞİLYURT, CEREN UYAR BOZTAŞ, İREM KARAÖMERLİOĞLU, VECDİ MELİH ALTAN, EBRU ARIOĞLU İNAN

Abstract: Background/aim: Dipeptidyl peptidase-4 (DPP4) inhibitors, a class of oral antidiabetic drugs, have been shown to be protective on the vascular system because of their antiinflammatory, antiatherosclerotic, and vasodilatory effects. ß2 -adrenoceptors (ß2 -ARs) mediate the vasorelaxation in the aorta. However, ß3 -adrenoceptor-mediated relaxation has not been studied in diabetic aorta yet. Thus, we aimed to study the effect of sitagliptin treatment on ß2 - and ß3 -adrenoceptor-mediated relaxations in the diabetic rat aorta. Materials and methods: Eight-week old Sprague Dawley rats were divided into three groups: control, diabetic, sitagliptin treated diabetic. Diabetes was induced by injection of streptozotocin (35 or 40 mg/kg, intraperitoneally). After 10 weeks of diabetes, some of the diabetic rats were treated with sitagliptin (orally, 10mg/kg/day). ß2 - and ß3 -AR-mediated relaxation responses were evaluated by using isoprenaline and CL 316,243, respectively. ß3-AR-mediated relaxation experiments were repeated in presence of L-NAME. Western blotting and immunohistochemistry were performed to determine the abundance of ß3 -adrenoceptor and endothelial nitric oxide synthase (eNOS). Results: The isoprenaline-mediated relaxation response was impaired in the diabetic group and sitagliptin treatment did not improve it. There was no significant change in CL316,243 mediated-relaxation or protein expression of ß3 -ARs among the groups. However, the ratio of phosphorylated eNOS/NOS protein was increased markedly in the sitagliptin treated group, which points the stimulating effect of this drug towards the eNOS pathway. Conclusion: Our results indicate that sitagliptin treatment does not alter ß-AR-mediated relaxation in streptozotocin-diabetic rat aorta; however, it significantly stimulates the eNOS pathway. Future studies are needed to clarify the relationship between the eNOS pathway and DPP-4 inhibition.

Keywords: ß-adrenoceptors, aorta, streptozotocin induced diabetes, sitagliptin, endothelial nitric oxide synthase

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