隐静脉(SV)是冠状动脉旁路移植术(CABG)患者中应用最广泛的移植材料之一。血栓烷A2(TXA2)通过诱导血管收缩和血小板聚集而参与移植物衰竭。这项研究的目的是研究TXA2诱导的人SV血管收缩的机制。通过使用分离的器官浴系统研究了不同抑制剂和阻断剂对U46619(TXA2模拟物)诱导的血管收缩的作用。在用U46619预收缩的SV中评估对几种介质的松弛反应,并与用去氧肾上腺素预收缩的SV进行比较。我们的结果表明,肌球蛋白轻链激酶抑制剂ML-9或TP受体拮抗剂BAYu3405完全阻断了U46619诱导的收缩。此外,U46619诱导的收缩被磷脂酶C抑制剂U73122、蛋白激酶C抑制剂钙素C、Rho激酶抑制剂Y-27632,L型钙通道阻滞剂硝苯地平,储存操作通道抑制剂SKF96365或去除细胞外钙。对NO供体(硝普钠)的松弛反应,鸟苷酸环化酶(GC)刺激剂(riociguat),磷酸二酯酶(PDE)抑制剂(西地那非,IBMX),当U46619用作预收缩剂时,腺苷酸环化酶(AC)激活剂(毛喉素)和乙酰胆碱(ACh)显着降低。我们的结果表明,细胞外Ca2的流入(通过L型钙通道和储存操作的钙通道)和细胞内Ca2的释放以及Ca2敏化(通过Rho激酶激活)是TXA2诱导的SV血管收缩的必要成分。此外,由几种介质诱导的血管舒张更明显的减少(SNP,Riociguat,西地那非,IBMX,forskolin,和ACh)在U46619的存在下与去氧肾上腺素相比,表明TP受体信号通路与PDE之间存在串扰,AC,GC酶。我们相信,对TXA2诱导的SV血管收缩机制的研究将为预防SV移植物衰竭提供更多信息。
Saphenous vein (SV) is one of the most widely used graft material in patients undergoing coronary artery bypass graft surgery (CABG). Thromboxane A2 (TXA2) is implicated in graft failure by inducing vasoconstriction and platelet aggregation. The aim of this study is to investigate the mechanism involved in TXA2-induced vasoconstriction in human SV. The role of different inhibitors and blockers on
U46619 (TXA2-mimetic)-induced vasoconstriction is investigated by using an isolated organ bath system. Relaxation responses to several mediators are evaluated in SV pre-contracted with
U46619 and compared with those pre-contracted with phenylephrine. Our results demonstrate that
U46619-induced contraction is completely blocked by myosin light chain kinase inhibitor ML-9 or TP receptor antagonist BAY u3405. Furthermore,
U46619-induced contraction is partially inhibited by phospholipase C inhibitor U73122, protein kinase C inhibitor calphostin C, Rho-kinase inhibitor Y-27632, L-type calcium channel blocker nifedipine, store-operated channel inhibitor SKF96365 or removal of extracellular calcium. Relaxation responses to NO donor (sodium nitroprusside), guanylate cyclase (GC) stimulator (riociguat), phosphodiesterase (PDE) inhibitors (sildenafil, IBMX), adenylate cyclase (AC) activator (forskolin) and acetylcholine (ACh) are markedly reduced when
U46619 is used as a pre-contraction agent. Our results demonstrate that influx of extracellular Ca2+ (through L-type calcium channels and store-operated calcium channels) and intracellular Ca2+ release together with Ca2+ sensitization (through Rho-kinase activation) are necessary components for TXA2-induced vasoconstriction in SV. Moreover, more pronounced decrease in vasorelaxation induced by several mediators (SNP, riociguat, sildenafil, IBMX, forskolin, and ACh) in the presence of U46619 when compared with phenylephrine suggests that there is a crosstalk between the TP receptor signaling pathway and PDE, AC, GC enzymes. We believe that the investigation of mechanism of the TXA2-induced vasoconstriction in SV will provide additional information for the prevention of SV graft failure.