Abstract：
UNASSIGNED: Hyporeactivity to vasopressors leading to multiple organ failure is a serious clinical implication in sepsis. Though the regulatory role of purinoceptors in inflammation is reported, their involvement in sepsis-induced vasoplegia is still unknown. Thus we investigated the effect of sepsis on vascular AT1 and P2Y6 receptors.
UNASSIGNED: Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Vascular reactivity was assessed by organ bath study and aortic mRNA expression of AT1 and P2Y6 was quantified by qRT-PCR.
UNASSIGNED: Both angiotensin-II and UDP produced higher contractions in the absence of endothelium as well as following inhibition of nitric oxide synthase. Angiotensin-II mediated aortic contraction was antagonized by losartan (AT1 antagonist), but not by PD123319 (AT2 antagonist) whereas UDP-induced aortic contraction was significantly inhibited by MRS2578 (P2Y6 antagonist). In addition, MRS2578 significantly inhibited the contractile response of Ang-II. Compared to SO mice, angiotensin-II and UDP-induced maximum contraction were found to be significantly attenuated in sepsis. Accordingly, aortic mRNA expression of AT1a receptors was significantly down-regulated while that of P2Y6 receptors was significantly increased in sepsis. 1400 W (a selective iNOS inhibitor) significantly reversed angiotensin-II-induced vascular hyporeactivity in sepsis without affecting UDP-induced hypo-reactivity.
UNASSIGNED: Sepsis-induced vascular hyporeactivity to angiotensin-II is mediated by enhanced expression of iNOS. Moreover, AT1R-P2Y6 cross talk/heterodimerization could be a novel target for regulating vascular dysfunction in sepsis.
UNASSIGNED: Polymicrobial sepsis was induced by cecal ligation and puncture in mice. Vascular reactivity was assessed by organ bath study and aortic mRNA expression of AT1 and P2Y6 was quantified by qRT-PCR.
UNASSIGNED: Both angiotensin-II and UDP produced higher contractions in the absence of endothelium as well as following inhibition of nitric oxide synthase. Angiotensin-II mediated aortic contraction was antagonized by losartan (AT1 antagonist), but not by PD123319 (AT2 antagonist) whereas UDP-induced aortic contraction was significantly inhibited by MRS2578 (P2Y6 antagonist). In addition, MRS2578 significantly inhibited the contractile response of Ang-II. Compared to SO mice, angiotensin-II and UDP-induced maximum contraction were found to be significantly attenuated in sepsis. Accordingly, aortic mRNA expression of AT1a receptors was significantly down-regulated while that of P2Y6 receptors was significantly increased in sepsis. 1400 W (a selective iNOS inhibitor) significantly reversed angiotensin-II-induced vascular hyporeactivity in sepsis without affecting UDP-induced hypo-reactivity.
UNASSIGNED: Sepsis-induced vascular hyporeactivity to angiotensin-II is mediated by enhanced expression of iNOS. Moreover, AT1R-P2Y6 cross talk/heterodimerization could be a novel target for regulating vascular dysfunction in sepsis.
摘要：
■对血管加压药的低反应性导致多器官衰竭是脓毒症的严重临床意义。尽管有报道称嘌呤受体在炎症中的调节作用，他们是否参与脓毒症诱导的血管停搏液尚不清楚.因此，我们研究了脓毒症对血管AT1和P2Y6受体的影响。
■在小鼠中通过盲肠结扎和穿刺诱导多微生物败血症。通过器官浴研究评估血管反应性，并通过qRT-PCR定量AT1和P2Y6的主动脉mRNA表达。
■血管紧张素II和UDP在没有内皮的情况下以及在一氧化氮合酶的抑制之后都产生更高的收缩。血管紧张素II介导的主动脉收缩被氯沙坦（AT1拮抗剂）拮抗，但不是通过PD123319（AT2拮抗剂），而UDP诱导的主动脉收缩被MRS2578（P2Y6拮抗剂）显着抑制。此外,MRS2578显著抑制Ang-II的收缩反应。与SO小鼠相比，发现血管紧张素II和UDP诱导的最大收缩在脓毒症中显著减弱.因此，在脓毒症中,AT1a受体的主动脉mRNA表达显著下调,而P2Y6受体的表达显著升高。1400W（一种选择性iNOS抑制剂）可显着逆转脓毒症中血管紧张素II诱导的血管低反应性，而不影响UDP诱导的低反应性。
■脓毒症诱导的血管对血管紧张素II的低反应性是由iNOS表达增强介导的。此外，AT1R-P2Y6串扰/异二聚化可能是脓毒症血管功能障碍调控的新靶点。
■在小鼠中通过盲肠结扎和穿刺诱导多微生物败血症。通过器官浴研究评估血管反应性，并通过qRT-PCR定量AT1和P2Y6的主动脉mRNA表达。
■血管紧张素II和UDP在没有内皮的情况下以及在一氧化氮合酶的抑制之后都产生更高的收缩。血管紧张素II介导的主动脉收缩被氯沙坦（AT1拮抗剂）拮抗，但不是通过PD123319（AT2拮抗剂），而UDP诱导的主动脉收缩被MRS2578（P2Y6拮抗剂）显着抑制。此外,MRS2578显著抑制Ang-II的收缩反应。与SO小鼠相比，发现血管紧张素II和UDP诱导的最大收缩在脓毒症中显著减弱.因此，在脓毒症中,AT1a受体的主动脉mRNA表达显著下调,而P2Y6受体的表达显著升高。1400W（一种选择性iNOS抑制剂）可显着逆转脓毒症中血管紧张素II诱导的血管低反应性，而不影响UDP诱导的低反应性。
■脓毒症诱导的血管对血管紧张素II的低反应性是由iNOS表达增强介导的。此外，AT1R-P2Y6串扰/异二聚化可能是脓毒症血管功能障碍调控的新靶点。
