title: Tirofiban induces vasorelaxation of the coronary artery via an endothelium-dependent NO-cGMP signaling by activating the PI3K/Akt/eNOS pathway.
abstract: Tirofiban, a glycoprotein IIb/IIIa inhibitor, is an antiplatelet drug extensively used in patients with acute coronary syndrome (ACS) and exerts an therapeutic effect on no-reflow phenomenon during percutaneous coronary intervention (PCI). Previous studies elucidated the vasodilation caused by tirofiban in the peripheral artery. However, whether tirofiban exerts a vasodilator effect on the coronary artery is unclear. Our present study found that tirofiban induced endothelium-dependent vasodilation in a concentration- and time-dependent manner in the isolated rat coronary artery pre-constricted by 5-hydroxytryptamine (5-HT). Further study showed that incubation of human umbilical venous endothelial cells (HUVECs) with tirofiban increased NO production, which was ascribed to the increased eNOS phosphorylation. This was confirmed by the loss of the vasorelaxant effect of tirofiban in the presence of l-NAME (eNOS inhibitor) and L-NMMA (NOS inhibitor) but not SMT (iNOS inhibitor) on isolated rat coronary arteries. The vasorelaxation was also blocked by the PI3K inhibitors, wortmannin and LY294002, as well as the Akt inhibitor SH-5, indicating the role of PI3K and Akt in tirofiban-mediated vasodilation. Moreover, further study showed that soluble guanylyl cyclase (sGC) inhibitor ODQ, or blockers of potassium channel (big-conductance calcium-activated potassium channel) blocked tirofiban-induced vasodilation of the coronary artery. These findings suggest that tirofiban induces vasorelaxation via an endothelium-dependent NO-cGMP signaling through the activation of the Akt/eNOS/sGC pathway.
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
authors.forename: Tianyang
authors.initials: T
authors.lastname: Xia
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Guan
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
authors.forename: Jinjuan
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
authors.forename: Caiyu
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China. Electronic address: chunyuzeng01@163.com.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China. Electronic address: weiericwang@163.com.
authors.forename: Wei Eric
authors.initials: WE
authors.lastname: Wang
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077466:Tirofiban; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000008:administration & dosage
chemical_list: D014665:Vasodilator Agents; D009569:Nitric Oxide; D014443:Tyrosine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D000077466:Tirofiban; D006152:Cyclic GMP
keywords: Coronary artery; No-reflow; PI3K/Akt/eNOS; Tirofiban; Vasorelaxation