کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2574389 1561265 2011 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways
موضوعات مرتبط
علوم پزشکی و سلامت پزشکی و دندانپزشکی کاردیولوژی و پزشکی قلب و عروق
پیش نمایش صفحه اول مقاله
Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways
چکیده انگلیسی

Evidence from both clinical and experimental studies indicates that Di-peptidyl peptidase-IV (DPP-4) inhibition may mediate favorable effects on the cardiovascular system. The objective of this study was to examine the acute effects of DPP-4 inhibition on vascular responses and to study the underlying mechanisms of alteration in tone. Aortic segments from C57BL/6 mice were treated with vasoconstrictors and exposed to various doses of alogliptin, a selective DPP-4 inhibitor. Vasodilator responses were evaluated using pathway specific antagonists to elucidate mechanisms of response. In parallel experiments, cultured human umbilical vein endothelial cells (HUVEC) were exposed to varying concentrations of alogliptin to evaluate the effects on candidate vasodilator pathways.Alogliptin relaxed phenylephrine and U46619 pre-constricted aortic segments in a dose dependent manner. Relaxation responses were not affected by the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin fragment 9–39 (88 ± 6 vs. 91 ± 2, p < 0.001). Vascular relaxation to alogliptin was significantly decreased by endothelial denudation, L-NG-monomethyl-arginine citrate (L-NMMA) and by the soluble guanylate cyclase inhibitor ODQ. DPP-4 inhibition induced relaxation was completely abolished by a combination of L-NMMA, charybdotoxin and apamin. Incubation of HUVECs with alogliptin resulted in eNOS and Akt phosphorylation (Ser1177 and Ser473 respectively) paralleled by a rapid increase in nitric oxide. Inhibition of Src kinase decreased eNOS and Akt phosphorylation, in contrast to a lack of any effect on insulin mediated activation of the eNOS-Akt, suggesting that alogliptin mediates vasodilation through Src kinase mediated effects on eNOS-Akt.DPP-4 inhibition by alogliptin mediates rapid vascular relaxation via GLP-1 independent, Src-Akt-eNOS mediated NO release and the activation of vascular potassium channels.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Vascular Pharmacology - Volume 55, Issues 1–3, July–September 2011, Pages 2–9
نویسندگان
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