AVP对严重创伤/休克血管低反应性的恢复作用与PKC亚型的关系
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摘要
在严重创伤/休克以及临床许多重症都存在血管对血管活性药物治疗的反应减弱甚至不反应的现象(血管低反应性),这严重影响着这些疾病的救治。精氨酸血管加压素(AVP)是下丘脑合成的九肽神经垂体激素,本室既往研究已证实休克后血管平滑肌细胞存在钙失敏,钙失敏在休克血管低反应性的发生中起重要作用,AVP对休克后血管低反应性和钙失敏有一定的恢复作用,但具体机制尚未完全阐明。本实验室前期研究表明,蛋白激酶C(PKC)和Rho激酶是重要的调节休克后血管反应性和血管平滑肌细胞钙敏感性的激酶分子;并且Rho激酶参与了AVP的抗休克作用,但是我们发现用Rho激酶的抑制剂Fasudil和Y-27632预处理仅部分拮抗了AVP调节休克后血管反应性和钙敏感性的作用,提示可能有其它机制参与AVP的作用。PKC是一类由多种同工酶组成的丝氨酸/苏氨酸蛋白激酶家族,存在多种组织分布和功能不同的亚型。而AVP是否通过一种或几种PKC亚型来发挥恢复血管平滑肌细胞钙敏感性和血管反应性的作用,具体调节机制如何,尚不清楚。据此,我们利用大鼠失血性休克模型和缺氧损伤体外培养血管平滑肌细胞(VSMC)模型,研究AVP对休克血管反应性和血管平滑肌细胞钙敏感性的调节作用,并从钙敏感性调节分子PKC途径入手研究其机制。主要内容包括三部分:①进一步明确AVP恢复失血性休克血管低反应性的作用;②AVP调节休克血管反应性和钙敏感性的作用与PKCα、δ、ε亚型的关系;③AVP激活PKC的机制,包括AVP激活PKC亚型与V_(1a)、V_2受体的关系,以及PLC、PLD和PLA2在AVP这一信号传导途径中的作用。
主要实验方法:
第一部分,进一步明确AVP对失血性休克血管反应性的恢复作用
1.整体实验,采用失血性休克大鼠模型(30 mmHg,2 h,下同),观察大鼠失血性休克后AVP(0.04、0.1、0.4 U/kg)对去甲肾上腺素(NE)诱导肠系膜上动脉(SMA)血管收缩反应和升压效应的影响。
2.离体血管环实验,取失血性休克大鼠肠系膜上动脉,利用离体血管环张力测定技术,观察AVP(5×10~(-11)、5×10~(-10)、5×10~(-9) mol/L)对休克大鼠SMA血管反应性的影响(用血管环对梯度浓度NE的收缩反应反映血管反应性)。
3. VSMC实验,贴块法取大鼠SMA血管平滑肌细胞原代培养,传代至第3-5代接种于Transwell小室建立VSMC双室培养模型,观察缺氧1.5 h后VSMC对NE的收缩反应变化以及AVP对缺氧VSMC收缩反应性的影响(通过观察荧光素标记的牛血清白蛋白在Transwell小室中的渗透率变化反映VSMC的收缩反应性)。
第二部分,AVP改善失血性休克血管反应性和血管平滑肌细胞钙敏感性的作用与PKCα、δ和ε亚型的关系
1.血管环实验,取失血性休克大鼠SMA,观察AVP处理后,休克血管环反应性和钙敏感性的变化,以及特异性的PKCα、δ、ε亚型抑制剂预处理对AVP这一作用的影响(以去极化状态下[120 mmol/L K~+]血管环对梯度浓度Ca~(2+)的收缩反应来反映钙敏感性)。同时取肠系膜动脉检测血管平滑肌肌球蛋白轻链(MLC_(20))磷酸化的变化,分析PKCα、δ和ε亚型在AVP调节失血性休克血管反应性和钙敏感性中的作用及其与MLC_(20)之间的关系。
2. VSMC实验,采用培养的大鼠肠系膜动脉VSMC,观察在各PKC亚型(α、δ、ε)抑制剂预处理缺氧培养的VSMC下,AVP对VSMC收缩反应性的影响;同时观察AVP对缺氧VSMC胞浆和胞膜成分中PKCα、δ、ε亚型蛋白表达的影响,研究AVP是通过哪一种或几种PKC亚型来调节休克血管反应性。观察AVP和PKC亚型抑制剂对缺氧VSMC肌球蛋白轻链激酶(MLCK)和肌球蛋白轻链磷酸酶(MLCP)活性的影响,探讨AVP恢复血管反应性和血管平滑肌细胞钙敏感性与MLCK/MLCP的关系以及PKC亚型在其中的作用。
第三部分,研究AVP激活PKC的机制
1.血管环实验,取失血性休克大鼠SMA,观察V_(1a)、V_2受体拮抗剂预处理对AVP改善休克血管反应性和钙敏感性的影响,同时检测肠系膜动脉平滑肌MLC_(20)磷酸化的变化,研究AVP诱导PKC激活与V_(1a)和V_2受体的关系及其机制。
2. VSMC实验,包括:①采用培养的大鼠肠系膜动脉VSMC,观察V_(1a)、V_2受体拮抗剂对AVP调节PKCα、δ、ε亚型表达的影响,同时观察VSMC收缩反应性以及MLCK/MLCP活性的变化,分析AVP诱导PKC激活与V_(1a)和V_2受体的关系及其机制;②观察缺氧后血管平滑肌细胞三种磷脂酶(PLC、PLD、PLA_2)的活性变化以及AVP对其的作用,并进一步观察V_(1a)、V_2受体拮抗剂预处理对AVP调节PLC、PLD、PLA_2活性的影响,探讨PLC、PLD、PLA_2是否参与了休克后AVP诱导PKC激活调节钙敏感性的信号传导过程。
主要结果:
一、AVP对失血性休克血管反应性的恢复作用
失血性休克后大鼠对NE的升压反应和肠系膜上动脉对NE诱导的收缩反应明显降低(P<0.01),三个剂量的AVP(0.04、0.1、0.4 U/kg)处理均使失血性休克大鼠对NE的升压反应和肠系膜上动脉对NE的收缩反应升高(P<0.05～0.01);在离体血管环实验中,AVP(5×10~(-11)、5×10~(-10)、5×10~(-9) mol/L)处理后可明显恢复休克诱导的血管反应性降低,使SMA对NE的量-效曲线明显左移,Emax升高(P<0.01);缺氧处理使VSMC对NE的收缩反应明显降低,AVP可升高VSMC对NE的收缩反应性,其荧光标记物累计渗透率分别在给NE后的45 min、60 min、75 min明显高于缺氧1.5 h组(P<0.05～P<0.01)。结果提示,AVP对严重失血性休克/缺氧处理的整体动物、离体血管和血管平滑肌细胞对NE的反应性均有明显的改善作用。
二、AVP改善失血性休克血管反应性和血管平滑肌细胞钙敏感性的作用与PKCα、δ和ε亚型的关系
1. AVP(5×10~(-10) mol/L)可显著升高休克大鼠血管环对NE的反应性和钙敏感性,使NE和Ca2+的量-效曲线明显左移,Emax升高(P<0.01)。特异性的PKCα、δ和ε亚型抑制剂或抑制肽可拮抗AVP对休克后血管反应性和钙敏感性的恢复作用,其中PKCε亚型抑制肽表现出较强的拮抗作用。结果初步证明,PKCα、δ和ε亚型都参与AVP对休克后血管反应性和钙敏感性的改善作用,但它们的作用强度并不相同。
2.缺氧1.5 h可明显降低VSMC对NE的收缩反应性,AVP可显著升高缺氧处理VSMC对NE的收缩反应性(P<0.05~P<0.01),PKCα亚型的特异性抑制剂G? 6976和PKCε亚型的抑制肽预处理可明显抑制AVP对缺氧处理VSMC收缩反应的恢复作用(P<0.01);PKCδ亚型的特异性拮抗剂Rottlerin预处理也部分抑制AVP的这一作用(P<0.05)。缺氧后VMSC胞膜成分中PKCα和ε亚型的表达明显升高,而胞浆成分中蛋白表达降低。AVP处理进一步升高胞膜PKCα和ε亚型的表达,与缺氧组相比有显著差异(P<0.05~P<0.01);但AVP对胞浆PKCα和ε的表达量无明显影响。而胞浆和胞膜PKCδ亚型显示了相似的变化趋势,但无显著差异。结果显示,AVP可能通过促进VSMC胞浆中的PKC向胞膜转位而激活,来调节失血性休克大鼠血管平滑肌细胞的钙敏感性和血管反应性,其主要亚型为PKCα和ε亚型。
3.休克大鼠肠系膜动脉血管平滑肌的MLC_(20)磷酸化水平明显低于正常对照组(P<0.01),AVP预处理可显著升高MLC_(20)磷酸化水平(P<0.01),PKCα和ε亚型的抑制剂对AVP诱导MLC_(20)磷酸化水平的升高有显著抑制作用(P<0.01),而PKCδ亚型抑制剂无明显抑制作用。结果提示,AVP可通过调节血管平滑肌的MLC_(20)磷酸化水平来改善休克后血管反应性和钙敏感性,PKCα和ε亚型在其中发挥了重要作用。
4.缺氧处理VSMC MLCP活性明显升高,MLCK活性明显降低(P<0.01),AVP处理可抑制缺氧VSMC的MLCP活性的升高(P<0.05),使MLCK活性略有升高,但与缺氧组相比无显著差异;PKCα亚型的抑制剂G? 6976和PKCε亚型的抑制肽预处理可拮抗由AVP引起的MLCP活性的降低(P<0.05),PKCδ亚型的抑制剂Rottlerin预处理使AVP诱导的MLCP活性降低有所升高,但无显著差异(P>0.05);三种抑制剂对细胞MLCK活性变化无明显影响。结果提示AVP激活PKC后,主要通过抑制MLCP活性,升高MLC_(20)磷酸化水平,升高VSMC的钙敏感性发挥改善休克血管反应性的作用。
三、AVP激活PKC的机制
1.血管加压素V_(1a)受体拮抗剂[d(CH2)5-Tyr2(Me)]AVP预处理可明显抑制AVP诱导的SMA对NE和Ca2+的反应性升高(P<0.01),使NE和Ca2+的量-效曲线明显右移,Emax降低(P<0.01);V_2受体拮抗剂[d(CH2)(d-Ile2Abu4)]AVP预处理也部分抑制了AVP的作用(P<0.05~P<0.01)。在缺氧VSMC收缩反应性的变化中也显示了相似的趋势,V_(1a)受体拮抗剂明显拮抗AVP升高缺氧VSMC收缩反应性的作用(P<0.01),V_2受体拮抗剂预处理组的细胞反应性也有轻度降低,但无显著差异。结果说明,AVP恢复失血性休克动物血管反应性和钙敏感性的机制与其V_(1a)和V_2受体有关,其中V_(1a)受体可能发挥着更为重要的作用。
2.缺氧处理VMSC胞膜中PKCα和ε亚型的蛋白表达量明显升高,AVP进一步升高胞膜PKCα和ε的表达,V_(1a)受体拮抗剂预处理可明显拮抗AVP诱导的胞膜PKCα和ε亚型的蛋白表达升高(P<0.05~P<0.01),而V_2受体拮抗剂无明显作用。而胞浆成分和胞膜成分中PKCδ亚型的蛋白表达也显示了相似的变化趋势,但各组间无统计学差异。V_(1a)受体拮抗剂预处理可拮抗由AVP引起的缺氧处理VSMC MLCP活性的降低和休克血管平滑肌MLC_(20)磷酸化水平升高(P<0.05～0.01),而V_2受体拮抗剂无明显作用; AVP及其V_(1a)、V_2受体拮抗剂对缺氧细胞MLCK活性无明显影响。结果提示,AVP通过激活PKC激活来调节血管反应性和血管平滑肌细胞钙敏感性的作用可能是通过V_(1a)受体介导的,V_2受体在这一信号传导途径中可能并不起主要作用。
3.缺氧后PLC和PLD活性升高,AVP处理可使PLC和PLD活性进一步升高,明显高于缺氧组(P<0.05)。V_(1a)受体拮抗剂预处理可明显拮抗AVP诱导PLC和PLD活性升高的作用(P<0.01),V_2受体拮抗剂无明显作用。各组PLA_2活性均无明显差异。结果提示,PLC和PLD参与了休克后AVP通过V_(1a)受体介导的PKC激活过程。
结论:
1.失血性休克后血管反应性显著降低,AVP对休克后全身和局部的血管反应性以及缺氧血管平滑肌细胞的收缩反应性都有较好的恢复作用。
2. AVP可通过激活PKCα和ε亚型,来调节失血性休克大鼠血管平滑肌细胞的钙敏感性和血管反应性,其机制是AVP首先促进血管平滑肌细胞胞浆中无活性的PKC向胞膜转位、并激活,进而抑制MLCP活性,使MLC_(20)磷酸化水平升高,最后增加血管平滑肌细胞的钙敏感性,升高血管反应性。
3. V_(1a)受体拮抗剂预处理可抑制AVP诱导的胞膜PKCα和ε的蛋白表达升高、MCLP活性降低、MLC_(20)磷酸化水平升高和血管反应性升高,同时也可抑制AVP诱导的PLC和PLD活性升高。提示AVP诱导PKC激活的机制可能与V_(1a)受体-PLC/PLD途径有关。
The occurrence of vascular hyporeactivity after severe trauma or shock has been shown to have important roles in the incidence, development, and the outcome of shock and interfered with the therapy of shock. Arginine vasopressin (AVP) is a 9-amino-acid neurohypophysial peptide hormone synthesized in the hypothalamus. Our previous studies have demonstrated that hemorrhagic shock could also cause calcium desensitization of blood vessels, which played important roles in vascular hyporeactivity following hemorrhagic shock, and protein kinase C (PKC) and Rho-kinase can regulate the calcium sensitivity of vascular smooth muscle cell (VSMC) by induced the inhibition of myosin light chain phosphatase (MLCP). And recent observations from our laboratory showed that AVP is beneficial to hemorrhagic shock, which may be related to AVP-induce increase of vascular reactivity and calcium sensitivity of vascular smooth muscle cell via the activation of Rho-kinase. However, Rho-kinase antagonist, Fasudil and Y-27632 only partially blocked this effect of AVP, it’s suggested that there may be other mechanisms involved in the effect of AVP. PKC was lipid-regulated serine/threonine kinases, included multiple isozymes with distinct tissue distributions and regulatory properties. However, little is known about which isoforms of PKC might be involved in modulating vascular reactivity and calcium sensitivity of vascular smooth muscle after hemorrhagic shock induced by AVP and the precise mechanisms. So with hemorrhagic shock model of rats and hypoxia-treated VSMC, we observed the effects of AVP on vascular reactivity amd calcium sensitivity following hemorrhagic shock in rats and explore its relations withα,δandεisoforms of PKC.
Methods:
The experiments were conducted in three parts.
Part I. The effects of AVP on vascular reactivity following hemorrhagic shock in rats
1. In vivo—The hemorrhagic shock (30 mmHg for 2 hours) model of rats was adopted to observe the effects of AVP(0.04、0.1、0.4 U/kg) on the contractile response of SMA to norepinephrine(NE) and pressor effect of NE.
2. In isolated SMA—Superior mesenteric artery (SMA) rings from rats were used to observe the effects of AVP(5×10~(-11)、5×10~(-10)、5×10~(-9) mol/L) on vascular reactivity of SMA with isolated organ perfusion system (The vascular reactivity was observed by measuring the contraction initiated by accumulative NE).
3. In VSMC—Primary cultures of VSMCs were obtained from the mesenteric artery of Wistar rats by an explant technique and the third to fifth passage cells were used in the present study. The contractile response of cultured VSMC to NE at different time after 1.5 hours hypoxia and the effects of AVP were observed (The contractile response of VSMC was measured by the ratio of accumulative infiltration of fluorescent isothiocyanate-conjugated bovine serum albumin with transwell).
Part II. The effects of AVP on vascular reactivity and calcium sensitivity of vascular smooth muscle and its relationship to PKCα,δandεisoforms
1. In isolated SMA—With isolated SMA rings from hemorrhagic shock rats, the effects of AVP on vascular reactivity and calcium sensitivity of SMA from hemorrhagic shock rats and and the effects of PKCα,δ,εinhibitor were observed (The calcium sensitivity of SMA were observed by measuring the contraction initiated by accumulative calcium under depolarizing condition (120 mM K+) with an isolated organ perfusion system). And the myosin light chain (MLC20) phosphorylation of mesenteric artery smooth muscle was detected by Western blotting.
2. In VSMC—With hypoxia-treated VSMCs, the contractile response of VSMC to NE after 1.5 h hypoxia and the effects of AVP and PKCα,δ,εinhibitor were observed. And the effect of AVP on the expression of PKC-α,δandεisoforms in the cytosol and particulate fractions of VSMCs, the activity of MLCP and myosin light chain kinase (MLCK) of VSMC were also observed.
Part III. The mechanism of AVP induced the PKC isozymes activation
1. In isolated SMA—The effects of V_(1a) and V_2 receptor inhibitor on AVP improving vascular reactivity and calcium sensitivity of SMA from hemorrhagic shock rats and its relationship to the phosphorylation of MLC_(20) were observed.
2. In VSMC—With hypoxia-treated VSMCs, we observe the effects of V_(1a) and V_2 receptor inhibitor on AVP regulating the expression of PKC-α,δandεisoforms in the cytosol and particulate fractions of VSMCs. At the same time, the activity of MLCP/MLCK and the contractile response of VSMC to NE were assayed. In addition, the activity of phospholipase C (PLC), phospholipase D (PLD), phospholipase A_2 (PLA_2) and the effects of V_(1a) and V_2 receptor inhibitor were observed.
Results:
1. Effects of AVP on vascular reactivity following hemorrhagic shock in rats
In vivo NE-induced pressor response and vasoconstriction of SMA following hemorrhagic shock was significantly decreased (P<0.01), AVP (0.04, 0.1 and 0.4 U/kg) significantly increased the pressor effect of NE and vasoconstriction of SMA to NE in hemorrhagic shock rats (P<0.05~0.01). In vitro, AVP (5×10-11, 5×10-10, 5×10-9 mol/L) pretreatment also improved reactivity of SMA rings to NE following hemorrhagic shock and made the cumulative dose-response curve of NE shift to the left, Emax was increased significantly (P<0.01). After hypoxia for 1.5 h, the contractile response of VSMC to NE significant decreased, AVP pretreatment increased the contractile response of VSMCs, its ratio of accumulative infiltration of fluorescent isothiocyanate-conjugated BSA was significantly increased at 45, 60 and 75 min after NE administration (P<0.05~P<0.01). It was suggested that AVP significantly improved the hypoxia or hemorrhagic shock-induced decrease in contractile reactivity of SMA and VSMC.
2. Effects of AVP on calcium sensitivity of vascular smooth muscle and its relationship with PKCα,δandεisoforms
(1) AVP markedly restored the decreased sensitivity of SMA to NE and Ca2+ following hemorrhagic shock, the concentration-response curve of NE and Ca2+ was shifted to the left and Emax was significantly increased (P<0.01). G? 6976 (the specific PKCαisoform inhibitor), Rottlerin (the specific PKCδisoform inhibitor) and PKCεinhibitor peptide antagonized AVP-induced increase of vascular reactivity and calcium sensitivity of SMA following hemorrhagic shock (P<0.05～P<0.01), in which PKCεinhibitor peptide showed a stronger antagonistic effectiveness than the others. The data suggested that PKCα,δandεisoforms participated in the regulation of AVP on calcium sensitivity and vascular reactivity after shock with different importance.
(2) AVP pretreatment significant increased the contractile response of VSMC to NE (P<0.05～P<0.01), the effects of AVP was significantly blocked by G? 6976 and PKCεinhibitor peptide (P<0.01), while partly inhibited by Rottlerin (P<0.05). The expression of particulate PKCαandεincreased in response to hypoxia, with a concomitant decrease in cytosolic fractions. AVP treatment further increased expression of PKCαandεin the particulate fractions (P<0.05~P<0.01), but the PKCαandεlevels in the cytosolic fractions were not significant changes. While PKCδshowed a similar changes in either the particulate or the cytosolic fractions during the process, but there were no statistical differences among the groups. It was suggested that AVP improved vascular reactivity and calcium sensitivity following hemorrhagic shock through translocating PKCαandεisoforms from a cytosol to a particulate and activation.
(3) The MLC20 phosphorylation of SMA following hemorrhagic shock were significantly decreased (P<0.01), AVP treatment resulted in an increase in MLC20 phosphorylation (P<0.01), which could be inhibited by G? 6976 and PKCεinhibitor peptide, not Rottlerin. The results suggested that PKCαandεisoforms played an important role in AVP regulating vascular reactivity and calcium sensitivity through MLC20 phosphorylation.
(4) Treatment with hypoxia for 1.5 h caused a significant increase in MLCP activity, with a decrease in MLCK activity of VSMC, AVP treatment resulted in an inhibition of MLCP activity (P<0.05), G(o|¨)6976 and PKCεinhibitor peptide (P<0.01), not Rottlerin, abolished AVP-induced decrease of MLCP activity. But there was no significant influence on MLCK activity.. The results of the present study suggested that AVP restores the vascular reactivity and calcium sensitivity of vascular smooth muscle following hemorrhagic shock via an activation of PKCαandεisoforms, and its mechanisms may be related to induce decrease of MLCP activity and MLC20 phosphorylation.
3. Mechanism of AVP induced the PKC isozymes activation
(1) [d(CH2)5-Tyr2(Me)]AVP, the V_(1a) receptor inhibitor, significantly antagonized AVP-induced increase of vascular reactivity and calcium sensitivity of SMA following hemorrhagic shock and V_2 receptor inhibitor ([d(CH_2)(d-Ile~2Abu~4)]AVP) also partly inhibit this effect (P<0.05). And V_(1a) receptor inhibitor also blocked AVP-induced increase of the contractile response of VSMCs to NE (P<0.01), while V_2 receptor inhibitor only slightly inhibited this effect of AVP. The results showed that AVP may restore the decreased vascular reactivity and calcium sensitivity of vascular smooth muscle after hemorrhagic shock through V_(1a) and V_2 receptor, and V_(1a) receptor may play more important roles than V_2 receptor.
(2) The expression of particulate PKCαandεincreased in response to hypoxia, AVP treatment further increased expression of PKCαandεin the particulate fractions, V_(1a) receptor inhibitor significantly antagonized this effect of AVP (P<0.05~P<0.01), but V_2 receptor inhibitor had no effect. While PKCδshowed a similar changes, but there were no statistical differences. AVP treatment resulted in an increase in MLC20 phosphorylation of SMA (P<0.01) and decreased in MLCP activity of VSMC (P<0.05), which could be inhibited by V_(1a) receptor inhibitor, not V_2 receptor inhibitor. MLCK activity of VSMC were significantly decreased after hypoxia (P<0.01), but AVP and V_(1a)/V_2 receptor inhibitor had no effect on it. It was suggested that AVP regulating the calcium sensitivity was mainly related to V_(1a) receptor, not V_2 receptor.
(3) Treatment with hypoxia for 1.5 h caused a significant increase in PLC and PLD activity, AVP further increased the activity of PLC and PLD (P<0.05). V_(1a) receptor inhibitor significantly antagonized AVP-induced increased in PLC and PLD activity (P<0.01). The PLA_2 activity had no significant changes among the groups. The results suggested that PLC and PLD took part in the V_(1a) receptor-mediated effects of AVP.
Conclusions:
1. AVP can restore the decreased vascular reactivity in hemorrhagic shock rats including the systemic responsiveness and local vascular reactivity, and increase the contractile response of vascular smooth muscle cell to NE.
2. AVP restores the vascular reactivity and calcium sensitivity of vascular smooth muscle following hemorrhagic shock via activation of PKCαandεisoforms, and its mechanisms is that AVP firstly induceαandεisoforms of PKC translocation from a cytosol to a particulate and activation, and then inhibits the activity of MLCP and increases MLC20 phosphorylation, followed by improves the calcium sensitivity of VSMC and at last enhances the vascular reactivity.
3. V_(1a) receptor inhibitor antagonized AVP-induced increase expression of PKCαandεin the particulate fractions, decrease in MLCP activity and increase in MLC_(20) phosphorylation of SMA following hemorrhagic shock. At the same time, V_(1a) receptor inhibitor also decreased the increased PLC/PLD activity induced by AVP. These data suggested that AVP induced translocation/activation of PKC in vascular smooth muscle through a V_(1a) receptor dependent mechanism, and PLC or PLD may participate in the signal transduction pathway.
主要实验方法:
第一部分,进一步明确AVP对失血性休克血管反应性的恢复作用
1.整体实验,采用失血性休克大鼠模型(30 mmHg,2 h,下同),观察大鼠失血性休克后AVP(0.04、0.1、0.4 U/kg)对去甲肾上腺素(NE)诱导肠系膜上动脉(SMA)血管收缩反应和升压效应的影响。
2.离体血管环实验,取失血性休克大鼠肠系膜上动脉,利用离体血管环张力测定技术,观察AVP(5×10~(-11)、5×10~(-10)、5×10~(-9) mol/L)对休克大鼠SMA血管反应性的影响(用血管环对梯度浓度NE的收缩反应反映血管反应性)。
3. VSMC实验,贴块法取大鼠SMA血管平滑肌细胞原代培养,传代至第3-5代接种于Transwell小室建立VSMC双室培养模型,观察缺氧1.5 h后VSMC对NE的收缩反应变化以及AVP对缺氧VSMC收缩反应性的影响(通过观察荧光素标记的牛血清白蛋白在Transwell小室中的渗透率变化反映VSMC的收缩反应性)。
第二部分,AVP改善失血性休克血管反应性和血管平滑肌细胞钙敏感性的作用与PKCα、δ和ε亚型的关系
1.血管环实验,取失血性休克大鼠SMA,观察AVP处理后,休克血管环反应性和钙敏感性的变化,以及特异性的PKCα、δ、ε亚型抑制剂预处理对AVP这一作用的影响(以去极化状态下[120 mmol/L K~+]血管环对梯度浓度Ca~(2+)的收缩反应来反映钙敏感性)。同时取肠系膜动脉检测血管平滑肌肌球蛋白轻链(MLC_(20))磷酸化的变化,分析PKCα、δ和ε亚型在AVP调节失血性休克血管反应性和钙敏感性中的作用及其与MLC_(20)之间的关系。
2. VSMC实验,采用培养的大鼠肠系膜动脉VSMC,观察在各PKC亚型(α、δ、ε)抑制剂预处理缺氧培养的VSMC下,AVP对VSMC收缩反应性的影响;同时观察AVP对缺氧VSMC胞浆和胞膜成分中PKCα、δ、ε亚型蛋白表达的影响,研究AVP是通过哪一种或几种PKC亚型来调节休克血管反应性。观察AVP和PKC亚型抑制剂对缺氧VSMC肌球蛋白轻链激酶(MLCK)和肌球蛋白轻链磷酸酶(MLCP)活性的影响,探讨AVP恢复血管反应性和血管平滑肌细胞钙敏感性与MLCK/MLCP的关系以及PKC亚型在其中的作用。
第三部分,研究AVP激活PKC的机制
1.血管环实验,取失血性休克大鼠SMA,观察V_(1a)、V_2受体拮抗剂预处理对AVP改善休克血管反应性和钙敏感性的影响,同时检测肠系膜动脉平滑肌MLC_(20)磷酸化的变化,研究AVP诱导PKC激活与V_(1a)和V_2受体的关系及其机制。
2. VSMC实验,包括:①采用培养的大鼠肠系膜动脉VSMC,观察V_(1a)、V_2受体拮抗剂对AVP调节PKCα、δ、ε亚型表达的影响,同时观察VSMC收缩反应性以及MLCK/MLCP活性的变化,分析AVP诱导PKC激活与V_(1a)和V_2受体的关系及其机制;②观察缺氧后血管平滑肌细胞三种磷脂酶(PLC、PLD、PLA_2)的活性变化以及AVP对其的作用,并进一步观察V_(1a)、V_2受体拮抗剂预处理对AVP调节PLC、PLD、PLA_2活性的影响,探讨PLC、PLD、PLA_2是否参与了休克后AVP诱导PKC激活调节钙敏感性的信号传导过程。
主要结果:
一、AVP对失血性休克血管反应性的恢复作用
失血性休克后大鼠对NE的升压反应和肠系膜上动脉对NE诱导的收缩反应明显降低(P<0.01),三个剂量的AVP(0.04、0.1、0.4 U/kg)处理均使失血性休克大鼠对NE的升压反应和肠系膜上动脉对NE的收缩反应升高(P<0.05～0.01);在离体血管环实验中,AVP(5×10~(-11)、5×10~(-10)、5×10~(-9) mol/L)处理后可明显恢复休克诱导的血管反应性降低,使SMA对NE的量-效曲线明显左移,Emax升高(P<0.01);缺氧处理使VSMC对NE的收缩反应明显降低,AVP可升高VSMC对NE的收缩反应性,其荧光标记物累计渗透率分别在给NE后的45 min、60 min、75 min明显高于缺氧1.5 h组(P<0.05～P<0.01)。结果提示,AVP对严重失血性休克/缺氧处理的整体动物、离体血管和血管平滑肌细胞对NE的反应性均有明显的改善作用。
二、AVP改善失血性休克血管反应性和血管平滑肌细胞钙敏感性的作用与PKCα、δ和ε亚型的关系
1. AVP(5×10~(-10) mol/L)可显著升高休克大鼠血管环对NE的反应性和钙敏感性,使NE和Ca2+的量-效曲线明显左移,Emax升高(P<0.01)。特异性的PKCα、δ和ε亚型抑制剂或抑制肽可拮抗AVP对休克后血管反应性和钙敏感性的恢复作用,其中PKCε亚型抑制肽表现出较强的拮抗作用。结果初步证明,PKCα、δ和ε亚型都参与AVP对休克后血管反应性和钙敏感性的改善作用,但它们的作用强度并不相同。
2.缺氧1.5 h可明显降低VSMC对NE的收缩反应性,AVP可显著升高缺氧处理VSMC对NE的收缩反应性(P<0.05~P<0.01),PKCα亚型的特异性抑制剂G? 6976和PKCε亚型的抑制肽预处理可明显抑制AVP对缺氧处理VSMC收缩反应的恢复作用(P<0.01);PKCδ亚型的特异性拮抗剂Rottlerin预处理也部分抑制AVP的这一作用(P<0.05)。缺氧后VMSC胞膜成分中PKCα和ε亚型的表达明显升高,而胞浆成分中蛋白表达降低。AVP处理进一步升高胞膜PKCα和ε亚型的表达,与缺氧组相比有显著差异(P<0.05~P<0.01);但AVP对胞浆PKCα和ε的表达量无明显影响。而胞浆和胞膜PKCδ亚型显示了相似的变化趋势,但无显著差异。结果显示,AVP可能通过促进VSMC胞浆中的PKC向胞膜转位而激活,来调节失血性休克大鼠血管平滑肌细胞的钙敏感性和血管反应性,其主要亚型为PKCα和ε亚型。
3.休克大鼠肠系膜动脉血管平滑肌的MLC_(20)磷酸化水平明显低于正常对照组(P<0.01),AVP预处理可显著升高MLC_(20)磷酸化水平(P<0.01),PKCα和ε亚型的抑制剂对AVP诱导MLC_(20)磷酸化水平的升高有显著抑制作用(P<0.01),而PKCδ亚型抑制剂无明显抑制作用。结果提示,AVP可通过调节血管平滑肌的MLC_(20)磷酸化水平来改善休克后血管反应性和钙敏感性,PKCα和ε亚型在其中发挥了重要作用。
4.缺氧处理VSMC MLCP活性明显升高,MLCK活性明显降低(P<0.01),AVP处理可抑制缺氧VSMC的MLCP活性的升高(P<0.05),使MLCK活性略有升高,但与缺氧组相比无显著差异;PKCα亚型的抑制剂G? 6976和PKCε亚型的抑制肽预处理可拮抗由AVP引起的MLCP活性的降低(P<0.05),PKCδ亚型的抑制剂Rottlerin预处理使AVP诱导的MLCP活性降低有所升高,但无显著差异(P>0.05);三种抑制剂对细胞MLCK活性变化无明显影响。结果提示AVP激活PKC后,主要通过抑制MLCP活性,升高MLC_(20)磷酸化水平,升高VSMC的钙敏感性发挥改善休克血管反应性的作用。
三、AVP激活PKC的机制
1.血管加压素V_(1a)受体拮抗剂[d(CH2)5-Tyr2(Me)]AVP预处理可明显抑制AVP诱导的SMA对NE和Ca2+的反应性升高(P<0.01),使NE和Ca2+的量-效曲线明显右移,Emax降低(P<0.01);V_2受体拮抗剂[d(CH2)(d-Ile2Abu4)]AVP预处理也部分抑制了AVP的作用(P<0.05~P<0.01)。在缺氧VSMC收缩反应性的变化中也显示了相似的趋势,V_(1a)受体拮抗剂明显拮抗AVP升高缺氧VSMC收缩反应性的作用(P<0.01),V_2受体拮抗剂预处理组的细胞反应性也有轻度降低,但无显著差异。结果说明,AVP恢复失血性休克动物血管反应性和钙敏感性的机制与其V_(1a)和V_2受体有关,其中V_(1a)受体可能发挥着更为重要的作用。
2.缺氧处理VMSC胞膜中PKCα和ε亚型的蛋白表达量明显升高,AVP进一步升高胞膜PKCα和ε的表达,V_(1a)受体拮抗剂预处理可明显拮抗AVP诱导的胞膜PKCα和ε亚型的蛋白表达升高(P<0.05~P<0.01),而V_2受体拮抗剂无明显作用。而胞浆成分和胞膜成分中PKCδ亚型的蛋白表达也显示了相似的变化趋势,但各组间无统计学差异。V_(1a)受体拮抗剂预处理可拮抗由AVP引起的缺氧处理VSMC MLCP活性的降低和休克血管平滑肌MLC_(20)磷酸化水平升高(P<0.05～0.01),而V_2受体拮抗剂无明显作用; AVP及其V_(1a)、V_2受体拮抗剂对缺氧细胞MLCK活性无明显影响。结果提示,AVP通过激活PKC激活来调节血管反应性和血管平滑肌细胞钙敏感性的作用可能是通过V_(1a)受体介导的,V_2受体在这一信号传导途径中可能并不起主要作用。
3.缺氧后PLC和PLD活性升高,AVP处理可使PLC和PLD活性进一步升高,明显高于缺氧组(P<0.05)。V_(1a)受体拮抗剂预处理可明显拮抗AVP诱导PLC和PLD活性升高的作用(P<0.01),V_2受体拮抗剂无明显作用。各组PLA_2活性均无明显差异。结果提示,PLC和PLD参与了休克后AVP通过V_(1a)受体介导的PKC激活过程。
结论:
1.失血性休克后血管反应性显著降低,AVP对休克后全身和局部的血管反应性以及缺氧血管平滑肌细胞的收缩反应性都有较好的恢复作用。
2. AVP可通过激活PKCα和ε亚型,来调节失血性休克大鼠血管平滑肌细胞的钙敏感性和血管反应性,其机制是AVP首先促进血管平滑肌细胞胞浆中无活性的PKC向胞膜转位、并激活,进而抑制MLCP活性,使MLC_(20)磷酸化水平升高,最后增加血管平滑肌细胞的钙敏感性,升高血管反应性。
3. V_(1a)受体拮抗剂预处理可抑制AVP诱导的胞膜PKCα和ε的蛋白表达升高、MCLP活性降低、MLC_(20)磷酸化水平升高和血管反应性升高,同时也可抑制AVP诱导的PLC和PLD活性升高。提示AVP诱导PKC激活的机制可能与V_(1a)受体-PLC/PLD途径有关。
The occurrence of vascular hyporeactivity after severe trauma or shock has been shown to have important roles in the incidence, development, and the outcome of shock and interfered with the therapy of shock. Arginine vasopressin (AVP) is a 9-amino-acid neurohypophysial peptide hormone synthesized in the hypothalamus. Our previous studies have demonstrated that hemorrhagic shock could also cause calcium desensitization of blood vessels, which played important roles in vascular hyporeactivity following hemorrhagic shock, and protein kinase C (PKC) and Rho-kinase can regulate the calcium sensitivity of vascular smooth muscle cell (VSMC) by induced the inhibition of myosin light chain phosphatase (MLCP). And recent observations from our laboratory showed that AVP is beneficial to hemorrhagic shock, which may be related to AVP-induce increase of vascular reactivity and calcium sensitivity of vascular smooth muscle cell via the activation of Rho-kinase. However, Rho-kinase antagonist, Fasudil and Y-27632 only partially blocked this effect of AVP, it’s suggested that there may be other mechanisms involved in the effect of AVP. PKC was lipid-regulated serine/threonine kinases, included multiple isozymes with distinct tissue distributions and regulatory properties. However, little is known about which isoforms of PKC might be involved in modulating vascular reactivity and calcium sensitivity of vascular smooth muscle after hemorrhagic shock induced by AVP and the precise mechanisms. So with hemorrhagic shock model of rats and hypoxia-treated VSMC, we observed the effects of AVP on vascular reactivity amd calcium sensitivity following hemorrhagic shock in rats and explore its relations withα,δandεisoforms of PKC.
Methods:
The experiments were conducted in three parts.
Part I. The effects of AVP on vascular reactivity following hemorrhagic shock in rats
1. In vivo—The hemorrhagic shock (30 mmHg for 2 hours) model of rats was adopted to observe the effects of AVP(0.04、0.1、0.4 U/kg) on the contractile response of SMA to norepinephrine(NE) and pressor effect of NE.
2. In isolated SMA—Superior mesenteric artery (SMA) rings from rats were used to observe the effects of AVP(5×10~(-11)、5×10~(-10)、5×10~(-9) mol/L) on vascular reactivity of SMA with isolated organ perfusion system (The vascular reactivity was observed by measuring the contraction initiated by accumulative NE).
3. In VSMC—Primary cultures of VSMCs were obtained from the mesenteric artery of Wistar rats by an explant technique and the third to fifth passage cells were used in the present study. The contractile response of cultured VSMC to NE at different time after 1.5 hours hypoxia and the effects of AVP were observed (The contractile response of VSMC was measured by the ratio of accumulative infiltration of fluorescent isothiocyanate-conjugated bovine serum albumin with transwell).
Part II. The effects of AVP on vascular reactivity and calcium sensitivity of vascular smooth muscle and its relationship to PKCα,δandεisoforms
1. In isolated SMA—With isolated SMA rings from hemorrhagic shock rats, the effects of AVP on vascular reactivity and calcium sensitivity of SMA from hemorrhagic shock rats and and the effects of PKCα,δ,εinhibitor were observed (The calcium sensitivity of SMA were observed by measuring the contraction initiated by accumulative calcium under depolarizing condition (120 mM K+) with an isolated organ perfusion system). And the myosin light chain (MLC20) phosphorylation of mesenteric artery smooth muscle was detected by Western blotting.
2. In VSMC—With hypoxia-treated VSMCs, the contractile response of VSMC to NE after 1.5 h hypoxia and the effects of AVP and PKCα,δ,εinhibitor were observed. And the effect of AVP on the expression of PKC-α,δandεisoforms in the cytosol and particulate fractions of VSMCs, the activity of MLCP and myosin light chain kinase (MLCK) of VSMC were also observed.
Part III. The mechanism of AVP induced the PKC isozymes activation
1. In isolated SMA—The effects of V_(1a) and V_2 receptor inhibitor on AVP improving vascular reactivity and calcium sensitivity of SMA from hemorrhagic shock rats and its relationship to the phosphorylation of MLC_(20) were observed.
2. In VSMC—With hypoxia-treated VSMCs, we observe the effects of V_(1a) and V_2 receptor inhibitor on AVP regulating the expression of PKC-α,δandεisoforms in the cytosol and particulate fractions of VSMCs. At the same time, the activity of MLCP/MLCK and the contractile response of VSMC to NE were assayed. In addition, the activity of phospholipase C (PLC), phospholipase D (PLD), phospholipase A_2 (PLA_2) and the effects of V_(1a) and V_2 receptor inhibitor were observed.
Results:
1. Effects of AVP on vascular reactivity following hemorrhagic shock in rats
In vivo NE-induced pressor response and vasoconstriction of SMA following hemorrhagic shock was significantly decreased (P<0.01), AVP (0.04, 0.1 and 0.4 U/kg) significantly increased the pressor effect of NE and vasoconstriction of SMA to NE in hemorrhagic shock rats (P<0.05~0.01). In vitro, AVP (5×10-11, 5×10-10, 5×10-9 mol/L) pretreatment also improved reactivity of SMA rings to NE following hemorrhagic shock and made the cumulative dose-response curve of NE shift to the left, Emax was increased significantly (P<0.01). After hypoxia for 1.5 h, the contractile response of VSMC to NE significant decreased, AVP pretreatment increased the contractile response of VSMCs, its ratio of accumulative infiltration of fluorescent isothiocyanate-conjugated BSA was significantly increased at 45, 60 and 75 min after NE administration (P<0.05~P<0.01). It was suggested that AVP significantly improved the hypoxia or hemorrhagic shock-induced decrease in contractile reactivity of SMA and VSMC.
2. Effects of AVP on calcium sensitivity of vascular smooth muscle and its relationship with PKCα,δandεisoforms
(1) AVP markedly restored the decreased sensitivity of SMA to NE and Ca2+ following hemorrhagic shock, the concentration-response curve of NE and Ca2+ was shifted to the left and Emax was significantly increased (P<0.01). G? 6976 (the specific PKCαisoform inhibitor), Rottlerin (the specific PKCδisoform inhibitor) and PKCεinhibitor peptide antagonized AVP-induced increase of vascular reactivity and calcium sensitivity of SMA following hemorrhagic shock (P<0.05～P<0.01), in which PKCεinhibitor peptide showed a stronger antagonistic effectiveness than the others. The data suggested that PKCα,δandεisoforms participated in the regulation of AVP on calcium sensitivity and vascular reactivity after shock with different importance.
(2) AVP pretreatment significant increased the contractile response of VSMC to NE (P<0.05～P<0.01), the effects of AVP was significantly blocked by G? 6976 and PKCεinhibitor peptide (P<0.01), while partly inhibited by Rottlerin (P<0.05). The expression of particulate PKCαandεincreased in response to hypoxia, with a concomitant decrease in cytosolic fractions. AVP treatment further increased expression of PKCαandεin the particulate fractions (P<0.05~P<0.01), but the PKCαandεlevels in the cytosolic fractions were not significant changes. While PKCδshowed a similar changes in either the particulate or the cytosolic fractions during the process, but there were no statistical differences among the groups. It was suggested that AVP improved vascular reactivity and calcium sensitivity following hemorrhagic shock through translocating PKCαandεisoforms from a cytosol to a particulate and activation.
(3) The MLC20 phosphorylation of SMA following hemorrhagic shock were significantly decreased (P<0.01), AVP treatment resulted in an increase in MLC20 phosphorylation (P<0.01), which could be inhibited by G? 6976 and PKCεinhibitor peptide, not Rottlerin. The results suggested that PKCαandεisoforms played an important role in AVP regulating vascular reactivity and calcium sensitivity through MLC20 phosphorylation.
(4) Treatment with hypoxia for 1.5 h caused a significant increase in MLCP activity, with a decrease in MLCK activity of VSMC, AVP treatment resulted in an inhibition of MLCP activity (P<0.05), G(o|¨)6976 and PKCεinhibitor peptide (P<0.01), not Rottlerin, abolished AVP-induced decrease of MLCP activity. But there was no significant influence on MLCK activity.. The results of the present study suggested that AVP restores the vascular reactivity and calcium sensitivity of vascular smooth muscle following hemorrhagic shock via an activation of PKCαandεisoforms, and its mechanisms may be related to induce decrease of MLCP activity and MLC20 phosphorylation.
3. Mechanism of AVP induced the PKC isozymes activation
(1) [d(CH2)5-Tyr2(Me)]AVP, the V_(1a) receptor inhibitor, significantly antagonized AVP-induced increase of vascular reactivity and calcium sensitivity of SMA following hemorrhagic shock and V_2 receptor inhibitor ([d(CH_2)(d-Ile~2Abu~4)]AVP) also partly inhibit this effect (P<0.05). And V_(1a) receptor inhibitor also blocked AVP-induced increase of the contractile response of VSMCs to NE (P<0.01), while V_2 receptor inhibitor only slightly inhibited this effect of AVP. The results showed that AVP may restore the decreased vascular reactivity and calcium sensitivity of vascular smooth muscle after hemorrhagic shock through V_(1a) and V_2 receptor, and V_(1a) receptor may play more important roles than V_2 receptor.
(2) The expression of particulate PKCαandεincreased in response to hypoxia, AVP treatment further increased expression of PKCαandεin the particulate fractions, V_(1a) receptor inhibitor significantly antagonized this effect of AVP (P<0.05~P<0.01), but V_2 receptor inhibitor had no effect. While PKCδshowed a similar changes, but there were no statistical differences. AVP treatment resulted in an increase in MLC20 phosphorylation of SMA (P<0.01) and decreased in MLCP activity of VSMC (P<0.05), which could be inhibited by V_(1a) receptor inhibitor, not V_2 receptor inhibitor. MLCK activity of VSMC were significantly decreased after hypoxia (P<0.01), but AVP and V_(1a)/V_2 receptor inhibitor had no effect on it. It was suggested that AVP regulating the calcium sensitivity was mainly related to V_(1a) receptor, not V_2 receptor.
(3) Treatment with hypoxia for 1.5 h caused a significant increase in PLC and PLD activity, AVP further increased the activity of PLC and PLD (P<0.05). V_(1a) receptor inhibitor significantly antagonized AVP-induced increased in PLC and PLD activity (P<0.01). The PLA_2 activity had no significant changes among the groups. The results suggested that PLC and PLD took part in the V_(1a) receptor-mediated effects of AVP.
Conclusions:
1. AVP can restore the decreased vascular reactivity in hemorrhagic shock rats including the systemic responsiveness and local vascular reactivity, and increase the contractile response of vascular smooth muscle cell to NE.
2. AVP restores the vascular reactivity and calcium sensitivity of vascular smooth muscle following hemorrhagic shock via activation of PKCαandεisoforms, and its mechanisms is that AVP firstly induceαandεisoforms of PKC translocation from a cytosol to a particulate and activation, and then inhibits the activity of MLCP and increases MLC20 phosphorylation, followed by improves the calcium sensitivity of VSMC and at last enhances the vascular reactivity.
3. V_(1a) receptor inhibitor antagonized AVP-induced increase expression of PKCαandεin the particulate fractions, decrease in MLCP activity and increase in MLC_(20) phosphorylation of SMA following hemorrhagic shock. At the same time, V_(1a) receptor inhibitor also decreased the increased PLC/PLD activity induced by AVP. These data suggested that AVP induced translocation/activation of PKC in vascular smooth muscle through a V_(1a) receptor dependent mechanism, and PLC or PLD may participate in the signal transduction pathway.
引文
1. Hasan A, McDonough KH. The effects of Escherichia coli sepsis and short-term ischemia on coronary vascular reactivity and myocardial function. Shock 1997, 8:305-310.
2. Liu LM, Ward JA, Dubick MA. Hemorrhagic-induced vascular hyporeactivity to norepinephrine in select vasculatures of rats and the roles of nitric oxide and endothelin. Shock 2003, 19:208-214.
3. Liu LM, Dubick MA: Regional diversity of hemorrhagic shock-induced vascular hyporeactivity and the roles of nitric oxide and endothelin: relationship to gene expression of NO/ET-1 and select cytokines in corresponding organs. J Surg Res 2005, 125:128-136.
4. Suba EA, Mckenna TM, Williams TJ, et al. In vivo and in vitro effects of endotoxin on vascular responsiveness to norepinephrine and signal transdu- ction in the rat. Circ Shock 1992, 36:127-133.
5. Ishimaru S, Shichiri M, Mineshita S, et al. Role of endothelin-1/endothelin receptor system in endotoxic shock rats. Hypertens Res 2001, 24(2):119 -126.
6. Bucher M, Ittner KP, Hobbhahn J, et al. Downregulation of angiotensin II type 1 receptors during sepsis. Hypertension 2001, 38(2):177-182.
7. Chen SJ, Wu CC, Yang SN, et al. Hyperpolarization contributes to vascular hyporeactivity in rats with LPS-induced endotoxic shock. Life Sci 2000, 68(6):659-668.
8. Kai Li, Wang ZF, Hu DY, et al. Opioid receptor antagonists modulate Ca2+-activated K+ channels in mesenteric arterial smooth muscle cells of rats in hemorrhagic shock. Shock 2003, 19:85-90.
9. Zhao KS, Huang XL, Liu J, et al. New approach to treatment of shock—restitution of vasoreactivity. Shock 2002, 18:189-192.
10. Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature 1994, 372: 231-236.
11. Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 1997, 389(6654): 990-994.
12. Kitazawa T, Takizawa N, Ikebe M, et al. Reconstitution of protein kinase C-induced contractile Ca2+ sensitization in triton X-100-demembranated rabbit arterial smooth muscle. J Physiol 1999, 520 Pt 1: 139-152.
13. Xu J, Liu LM. The role of calcium desensitization in vascular hyporeactivity and its regulation after hemorrhagic shock in the rat. Shock 2005, 23:576-581.
14. Oliver G. On the physiological of extracts of the pituitary and certain other glandular organs. J Physiol 1985, 18:27-31.
15.杨光明,刘良明. AVP对失血性休克大鼠血管反应性的影响.中国药理学与毒理学杂志2005, 19(5): 347-352.
16. Yang GM, Liu LM, Xu J, et al. Effect of arginine vasopressin on vascular reactivity and calcium sensitivity after hemorrhagic shock in rats and its relationship to Rho-kinase. J Trauma 2006, 61:1336-1342.
17. Fan JP and Byron KL. Ca2+ signalling in rat vascular smooth muscle cells: a role for protein kinase C at physiological vasoconstrictor concentrations of vasopressin. J. Physiol 2000, 524:821-831.
18. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992, 258:607–614.
19. Shirasawa Y, Rutland TJ, Young JL, et al. Modulation of protein kinase C (PKC)-mediated contraction and the possible role of PKC epsilon in rat mesenteric arteries. Front Biosci 2003, 8: a133-138.
20. Horowitz A, Clement CO, Walsh MP, et al. Epsilon-isoenzyme of protein kinase C induces a Ca2+-independent contraction in vascular smooth muscle. Am J Physiol 1996, 271: C589-594.
21. Holmes CL, Landry DW, Granton JT. Science review: Vasopressin and the cardiovascular system part 1--receptor physiology. Crit Care 2003, 7(6): 427-434.
22. Howl J, Ismail T, Strain AJ, Kirk CJ, Anderson D, Wheatley M. Characterization of the human liver vasopressin receptor. Profound differences between human and ratvasopressin-receptor-mediated responses suggest only a minor role for vasopressin in regulating human hepatic function. Biochem J 1991, 276: 189-195.
23. Wange RL, Smrcka AV, Sternweis PC, Exton JH. Photoaffinity labeling of two rat liver plasma membrane proteins with [32P]gamma-azidoanilido GTP in response to vasopressin. Immunologic identification as alpha subunits of the Gq class of G proteins. J Biol Chem 1991, 266(18): 11409-11412.
24. Force T, Kyriakis JM, Avruch J, Bonventre JV. Endothelin, vasopressin, and angiotensin II enhance tyrosine phosphorylation by protein kinase C-dependent and -independent pathways in glomerular mesangial cells. J Biol Chem 1991, 266(10): 6650-6656.
25. Chen WC, Chen CC. Signal transduction of arginine vasopressin-induced arachidonic acid release in H9c2 cardiac myoblasts: role of Ca2+ and the protein kinase C-dependent activation of p42 mitogen-activated protein kinase. Endocrinology 1999, 140(4): 1639-1648.
26. Kai L, Wang ZF, Shi YL, et al. Opioid receptor antagonists increase [Ca2+]i in rat arterial smooth muscle cells in hemorrhagic shock. Acta Pharmacol Sin 2004, 25(3): 395-400.
27. Li YX, Shiels AJ, Maszak G, et al. Vasopressin-stimulated Ca2+ spiking in vascular smooth muscle cells involves phospholipase D. Am J Physiol Heart Circ Physiol 2001, 280: H2658–2664.
28. Asaoka Y, Oka M, Yoshida K. Role of lysophosphatidylcholine in T-lymphocyte activation: involvement of phospholipase A2 in signal transduction through protein kinase C. Proc Natl Acad Sci USA 1992, 89(14): 6447-6451.
29. Axelrod J. Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem Soc Trans 1990, 18(4): 503-507.
30. Yang GM, Liu LM, Xu j, et al. Effects of MCI-154 on vascular reactivity and its mechanisms after hemorrhagic shock in rats. J Cardiovasc Pharmacol 2006, 47:751-757.
31. Leik CE, Willey A, Graham MF, et al. Isolation and culture of arterial smooth musclecells from human placenta. Hypertension 2004, 43(4):837-840.
32. Lampugnani MG, Resnati M, Dejana E, et al. The role of integrins in the maintenance of endothelial monolayer integrity. J Cell Biol 1991, 112:479-490.
33.蔡文琴,王伯去主编.实用免疫细胞化学与核酸分子杂交技术.四川科学技术出版社1994年第一版, 61-67.
34.陈思锋,吴中立.体液和组织磷脂酶A2简便快速测定法.第二军医大学学报1989, 10(3):254-256.
35. Brackett DJ, Schaefer CF, Tompkins P, et al. Plasma vasopressin and cardiac output changes in awake endotoxic rats. Circ Shock 1984, 13(1): 72-76.
36. Sharshar T, Carlier R, Blanchard A, et al. Depletion of neurohypophyseal content of vasopressin in septic shock. Crit Care Med 2002, 30: 497-500.
37. Joseph E. Parrillo. Septic Shock-Vasopressin, Norepinephrine, and Urgency. N Engl J Med 2008, 358:954-956.
38. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997, 25: 1279-1282.
39. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation 2003, 107(18): 2313-2319.
40. Sirintorn Y, Ehab AA, Cheng YY, et al. The role of arginine vasopressin in diabetes-associated increase in glucagon secretion. Regulatory Peptides 2004, 22(3):157-162.
41. Brackett DJ, Schaefer CF, Tompkins P, et al. Plasma vasopressin and cardiac output changes in awake endotoxic rats. Circ Shock 1984, 13(1): 72-76.
42. Voelckel WG, Lurie KG, Lindner KH, et al. Vasopressin improves survival after cardiac arrest in hypovolemic shock. Anesth Analg 2000, 91:627-634.
43. Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999, 47(4): 699-703.
44. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008, 358:877-887.
45. Takeda K, Meyer-Lehnert H, Kim JK, et al. AVP-induced Ca fluxes and contraction of rat glomerular mesangial cells. Am J Physiol 1988, 255: F142-150.
46. Li T, Liu LM, Xu J, et al. Changes of Rho kinase activity following hemorrhagic shock and its role in shock-induced biphasic response of vascular reactivity and calcium sensitivity. Shock 2006, 26:504-509.
47. Nemenoff RA. Vasopressin signaling pathways in vascular smooth muscle. Front Biosci 1998, d194-207.
48. Shimomura E, Shiraishi M, Iwanaga T, et al. Inhibition of protein kinase C-mediated contraction by Rho kinase inhibitor fasudil in rabbit aorta. Naunyn Schmiedebergs Arch Pharmacol 2004, 370(5): 414-422.
49. Kandabashi T, Shimokawa H, Miyata K, et al. Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioscler Thromb Vasc Biol 2003, 23(12): 2209-2214.
50. Sward K, Mita M, Wilson DP, et al. The role of RhoA and Rho-associated kinase in vascular smooth muscle contraction. Curr Hypertens Rep 2003, 5(1): 66-72.
51. Seko T, Ito M, Kureishi Y, et al. Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle. Circ Res 2003, 92(4): 411-418.
52. Kolosova IA, Ma SF, Adyshev DM, et al. Role of CPI-17 in the regulation of endothelial cytoskeleton. Am J Physiol Lung Cell Mol Physiol 2004, 287(5): L970-980.
53. Hiroki J, Shimokawa H, Higashim M, et al. Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. J Mol Cell Cardiol 2004, 37(2): 537-546.
54.杨光明,刘良明. MCI-154对失血性休克大鼠血管平滑肌钙敏感性的影响及其机制.中国危重病急救医学2005, 17(1):7-11.
55. Kitazawa T, Eto M, Woodsome TP, et al. Agonists trigger G protein-mediated activation of the CPI-17 inhibitor phosphoprotein of myosin light chain phosphatase to enhance vascular smooth muscle contractility. J Biol Chem 2000, 275(14): 9897-9900.
56. Eto M, Kitazawa T, Yazawa M, et al. Histamine-induced vasoconstriction involvesphosphorylation of a specific inhibitor protein for myosin phosphatase by protein kinase C alpha and delta isoforms. J Biol Chem 2001, 276(31): 29072-29078.
57. Yamboliev IA, Hedges JC, Mutnick JL, Adam LP, Gerthoffer WT. Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway. Am J Physiol Heart Circ Physiol 2000, 278(6): H1899-1907.
58. He J, Stephens NL. Calcium and smooth muscle contraction. Mol Cell Biochem 1994, 135: 1-9.
59. Shimizu H, Ito M, Miyahara M, et al. Characterization of the myosin-binding subunit of smooth muscle myosin phosphatase. J Biol Chem 1994, 269:30407-30411.
60. Hartshorne DJ, Hirano K. Interactions of protein phosphatase type 1, with a focus on myosin phosphatase. Mol Cell Biochem 1999, 190: 79-84.
61. Ichikawa K, Ito M, Hartshorne DJ. Phosphorylation of the large subunit of myosin phosphatase and inhibition of phosphatase activity. J Biol Chem 1996b, 271:4733-4740.
62. Hirano K, Hirano M, Kanaide H. Regulation of myosin phosphorylation and myofilament Ca2+ sensitivity in vascular smooth muscle. J Smooth Muscle Res 2004, 40(6): 219-236.
63. Marunaka Y, Eaton DC. Effects of vasopressin and cAMP on single amiloride- blockable Na channels. Am J Physiol 1991, 260: C1071-1084.
64. Ishunina TA, Swaab DF. Vasopressin and oxytocin neurons of the human supraoptic and paraventricular nucleus: size changes in relation to age and sex. J Clin Endocrinol Metab 1999, 84(12): 4637-4644.
65.罗哲,吴肇光.小剂量精氨酸加压素治疗感染性休克的应用.国外医学外科学分册2005, 32(3): 211-214.
66. De Aguilera EM, VilaJM, Irurzun A, et al. Endothelium-independent contractions of human cerebral arteries in response to vasopressin. Stroke 1990, 21(12): 1689-1693.
67. Ohguchi KY, Banno Y, Nakashima S, et al. Regulation of membrane-bound phospholipase D by protein kinase C in HL6 cells. Synergistic action of small GTP-binding protein RhoA. J Biol Chem 1996, 271: 4366~4372.
68. Exton JH. Phospholipase D: Enzymology, mechanisms of regulation, and function. Physiol Rev 1997, 77: 303~320.
69. Vinggaard AM, Hansen HS. Phorbol ester and vasopressin activate phospholipase D in Leydig cells. Mol Cell Endocrinol 1991, 79(1-3): 157-165.
70. Natarajan V, Garcia JG. Agonist-induced activation of phospholipase D in bovine pulmonary artery endothelial cells: regulation by protein kinase C and calcium. J Lab Clin Med 1993, 121(2): 337-347.
71. Araki S, Ito M, Kureishi Y, et al. Arachidonic acid-induced Ca2+ sensitization of smooth muscle contraction through activation of Rho-kinase. Pflugers Arch 2001, 441(5): 596-603.
72. Bauldry SA, Wooten RE. Induction of cytosolic PLA2 activity by phosphatidic acid and diglycerides in permeabilized human neutrophils: interrelationship between PLD and A2. Biochem J 1997, 322:353-363.
73.杨静娴,林原.平滑肌收缩的非钙依赖性调节机制.国外医学生理病理科学与临床分册2004, 24(6): 560-563.
74. Ackermann EJ, Kempner ES, Dennis EA. Ca2+-independent cytosolic phospholipase A2 from macrophage-like P388D1 cells. Isolation and characterization. J Biol Chem 1994, 269(12): 9227-33.
75. Dennis EA. Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem 1994, 269(18): 13057-13060.
1. Hoyle CH. Neuropeptide families and their receptors: evolutionary perspectives. Brain Res 1999, 848:1-25.
2. Oliver H, Schaefer EA. On the physiological action of extracts of the pituitary body and certain other glandular organs. J Physiol (Lond) 1895, 18:277-279.
3. von den Velden R. The renal effects of hypophyseal extract in humans. Berl Klin Wochenscgr 1913, 50:2083-2086.
4. Verney EB. The antidiuretic hormone and the factor which determines its release. Proc R Soc Lond (Biol) 1947, 135:25-106.
5. Du Vigneaud V, Gash DT, Katsoyannis PG. A synthetic preparation possessing biological properties associated with arginine-vasopressin. J Am Chem Soc 1954, 76:4751-4752.
6. Ebert TJ, Cowley AW. Vasopressin reduces cardiac function and augments cardiopulmonary baroreflex resistance increases in man. J Clin Invest 1986, 77: 1136-1142.
7. Albert M, Losser MR, Hayon D, et al. Systemic and renal macro- and microcirculatory responses to arginine vasopressin in endotoxic rabbits. Crit Care Med 2004, 32(9):1891-1898.
8. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation 2003, 107(18): 2313-2319.
9. Dunser MW, Wenzel V, Mayr AJ, et al. Management of vasodilatory shock: defining the role of arginine vasopressin. Drugs 2003, 63: 237-256.
10. Fleisher S, Kagan E, Grossman N, et al. Multiple effects of arginine vasopressin on prostaglandin E2 synthesis in fibroblasts. Eur J Pharmacol 2004, 485(1-3):53-59.
11. Sirintorn Y, Ehab AA, Cheng YY, et al. The role of arginine vasopressin in diabetes-associated increase in glucagon secretion. Regulatory Peptides 2004, 22(3):157-162.
12. Barberis C, Mouillac B, Durroux T. Structural bases of vasopressin/oxytocin receptor function. J Endocrinol 1998, 156:223-229.
13. Swaab DF, Nijveldt F, Pool CW. Distribution of oxytocin and vasopressin in the rat supraoptic and paraventricular nucleus. J Endocrinol 1975, 67:461-462.
14. Giovannucci DR, Stuenkel EL. Regulation of secretory granule recruitment and exocytosis at rat neurohypophysial nerve endings. J Physiol 1997, 498 (Pt 3):735-751.
15. Nowycky MC, Seward EP, Chernevskaya NI. Excitation-secretion coupling in mammalian neurohypophysial nerve terminals. Cell Mol Neurobiol 1998, 18(1):65-80.
16. Deleuze C, Duvoid A, Hussy N. Properties and glial origin of osmoticdependent release of taurine from the rat supraoptic nucleus. J Physiol 1998, 507(Pt 2):463-471.
17. Stern JE, Armstrong WE. Reorganization of the dendritic trees of oxytocin and vasopressin neurons of the rat supraoptic nucleus during lactation. J Neurosci 1998, 18(3):841-853.
18. Majzoub JA, Rich A, van Boom J, et al. Vasopressin and oxytocin mRNA regulation in the rat assessed by hybridization with synthetic oligonucleotides. J Biol Chem 1983, 258(23):14061-14064.
19. Zingg HH, Lefebvre D, Almazan G. Regulation of vasopressin gene expression in rat hypothalamic neurons. Response to osmotic stimulation. J Biol Chem 1986, 261(28):12956-12959.
20. Tang AH. A specific antagonist of vasopressin produced plasma hyperosomolality and reduce ischemic-induced cerebral edema in rats. Lif Sci 1988, 43: 399-403.
21. Czaczkes JW. Physiologic studies of antidiuretic hormone by its direct measurement in human plasma. J Clin Invest 1964, 43:1625-1640.
22. Brackett DJ, Schaefer CF, Tompkins P, et al. Plasma vasopressin and cardiac output changes in awake endotoxic rats. Circ Shock, 1984, 13(1): 72-76.
23. Arnauld E, Czernichow P, Fumoux F, et al. The effects of hypotension and hypovolaemia on the liberation of vasopressin during haemorrhage in the unanaesthe- tized monkey (Macaca mulatta). Pflugers Arch 1977, 371(3):193-200.
24. Cowley AW Jr, Switzer SJ, Guinn MM. Evidence and quantification of the vasopressinarterial pressure control system in the dog. Circ Res 1980, 46(1):58-67.
25. Wang BC, Flora-Ginter G, Leadley RJ Jr, et al. Ventricular receptors stimulate vasopressin release during hemorrhage. Am J Physiol 1988, 254:R204-211.
26. Fitzsimmons MD, Roberts MM, Sherman TG, et al. Models of neurohypophyseal homeostasis. Am J Physiol 1992, 262(6 Pt 2):R1121-1130.
27. Sharshar T, Carlier R, Blanchard A, et al. Depletion of neurohypophyseal content of vasopressin in septic shock. Crit Care Med, 2002, 30: 497-500.
28. Zerbe RL, Henry DP, Robertson GL. Vasopressin response to orthostatic hypotension. Etiologic and clinical implications. Am J Med 1983, 74(2):265-271.
29. Reid IA. Role of nitric oxide in the regulation of renin and vasopressin secretion. Front Neuroendocrinol 1994, 15(4):351-383.
30. Holmes CL, Landry DW, Granton JT. Science review: Vasopressin and the cardiova- scular system part 1--receptor physiology. Crit Care, 2003, 7(6): 427-434.
31. Zenteno-Savin T, Sada-Ovalle I, Ceballos G, et al. Effects of arginine vasopressin in the heart are mediated by specific intravascular endothelial receptors. Eur J Pharmacol 2000, 410:15-23.
32. Berrada K, Plesnicher CL, Luo X, et al. Dynamic interaction of human vasopressin/oxytocin receptor subtypes with g protein-coupled receptor kinases and protein kinase C after agonist stimulation. J Biol Chem 2000, 275:27229-27237.
33. Ross EM, Gilman AG. Biochemical properties of hormone-sensitive adenylate cyclase. Annu Rev Biochem 1980, 49:533-564.
34. Neves SR, Ram PT, Iyengar R. G protein pathways. Science 2002, 296:1636-1639.
35. Thibonnier M, Graves MK, Wagner MS, et al. Structure, sequence, expression, and chromosomal localization of the human V1a vasopressin receptor gene. Genomics 1996, 31:327-334.
36. Briley EM, Lolait SJ, Axelrod J, et al. The cloned vasopressin V1a receptor stimulates phospholipase A2, phospholipase C, and phospholipase D through activation of receptor-operated calcium channels. Neuropeptides 1994, 27: 63-74.
37. Bankir L. Antidiuretic action of vasopressin: quantitative aspects and interactionbetween V1a and V2 receptor-mediated effects. Cardiovasc Res 2001, 51:372-390.
38. Edwards RM, Trizna W, et al. Renal microvascular effects of vasopressin and vasopressin antagonists. Am J Physiol 1989, 256:F274-278.
39. Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on hemodyn- amics and renal function in severe septic shock: a case series. Intensive Care Med 2001, 27:1416-1421.
40. Patel B, Chittock D, Walley K. Vasopressin infusion in SIRS and septic shock: a randomized controlled trial. Am J Respir Crit Care Med 1999, 159:A608.
41. Howl J, Ismail T, Strain AJ, et al. Characterization of the human liver vasopressin receptor. Profound differences between human and rat vasopressin-receptor-mediated responses suggest only a minor role for vasopressin in regulating human hepatic function. Biochem J, 1991; 276: 189-195.
42. Wange RL, Smrcka AV, Sternweis PC, et al. Photoaffinity labeling of two rat liver plasma membrane proteins with [32P]gamma-azidoanilido GTP in response to vasopressin. Immunologic identification as alpha subunits of the Gq class of G proteins. J Biol Chem, 1991, 266(18): 11409-11412.
43. Force T, Kyriakis JM, Avruch J, et al. Endothelin, vasopressin, and angiotensin II enhance tyrosine phosphorylation by protein kinase C-dependent and -independent pathways in glomerular mesangial cells. J Biol Chem, 1991, 266(10): 6650-6656.
44. Thibonnier M, Bayer AL, Simonson MS, et al. Reconstitution of solubilized V1 vasopressin receptors of human platelets. Am J Physiol, 1990, 259: E751-756.
45. Erlenbach I, Wess J. Molecular basis of V2 vasopressin receptor/Gs coupling selectivity. J Biol Chem 1998, 273:26549-26558.
46. Liu J, Wess J. Different single receptor domains determine the distinct G protein coupling profiles of members of the vasopressin receptor family. J Biol Chem 1996, 271:8772-8778.
47. Birnbaumer M. Vasopressin receptors. Trends Endocrinol Metab 2000, 11:406-410.
48. Rosenthal W, Antaramian A, Gilbert S, et al. Nephrogenic diabetes insipidus. A V2 vasopressin receptor unable to stimulate adenylyl cyclase. J Biol Chem 1993,268:13030-13033.
49. Bichet DG, Razi M, Lonergan M, et al. Hemodynamic and coagulation responses to 1-desamino[8-D-arginine] vasopressin in patients with congenital nephrogenic diabetes insipidus. N Engl J Med 1988, 318: 881-887.
50. Phillips PA, Abrahams JM, Kelly JM, et al. Localization of vasopressin binding sites in rat tissues using specific V1 and V2 selective ligands. Endocrinology 1990, 126:1478-1484.
51. Sugimoto T, Saito M, Mochizuki S, et al. Molecular cloning and functional expression of a cDNA encoding the human V1b vasopressin receptor. J Biol Chem 1994, 269:27088-27092.
52. Thibonnier M, Preston JA, Dulin N, et al. The human V3 pituitary vasopressin receptor: ligand binding profile and density-dependent signaling pathways. Endocrinology 1997, 138:4109-4122.
53. Thibonnier M, Berti-Mattera LN, Dulin N, et al. Signal transduction pathways of the human V1-vascular, V2-renal, V3-pituitary vasopressin and oxytocin receptors. Prog Brain Res 1998, 119:147-161.
54. Peter J, Burbach H, Adan RA, et al. Molecular neurobiology and pharmacology of the vasopressin/oxytocin receptor family. Cell Mol Neurobiol 1995, 15:573-595.
55. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev 2001, 81:629-683.
56. Thibonnier M, Conarty DM, Preston JA, et al. Human vascular endothelial cells express oxytocin receptors. Endocrinology 1999, 140:1301-1309.
57. Sanborn BM, Dodge K, Monga M, et al. Molecular mechanisms regulating the effects of oxytocin on myometrial intracellular calcium. Adv Exp Med Biol 1998, 449: 277-286.
58. Gutkowska J, Jankowski M, Lambert C, et al. Oxytocin releases atrial natriuretic peptide by combining with oxytocin receptors in the heart. Proc Natl Acad Sci USA 1997, 94:11704-11709.
59. Diaz Brinton R, Brownson EA. Vasopressin-induction of cyclic AMP in culturedhippocampal neurons. Brain Res Dev Brain Res 1993, 71:101-105.
60. de Wied D, Elands J, Kovacs G. Interactive effects of neurohypophyseal neuropeptides with receptor antagonists on passive avoidance behavior: mediation by a cerebral neurohypophyseal hormone receptor? Proc Natl Acad Sci USA 1991, 88:1494-1498.
61. Katusic ZS, Shepherd JT, Vanhoutte PM. Vasopressin causes endotheliumdependent relaxations of the canine basilar artery. Circ Res 1984, 55(5):575-579.
62. Tagawa T, Imaizumi T, Endo T, et al. Vasodilatory effect of arginine vasopressin is mediated by nitric oxide in human forearm vessels. J Clin Invest 1993, 92(3): 1483-1490.
63. Garcia-Villalon AL, Garcia JL, Fernandez N, et al. Regional differences in the arterial response to vasopressin: role of endothelial nitric oxide. Br J Pharmacol 1996, 118:1848-1854.
64. Holmes CL, Patel BM, Russell JA, et al. Physiology of vasopressin relevant to management of septic shock. Chest 2001, 120:989-1002.
65. Liard JF. Does vasopressin-induced vasoconstriction persist during prolonged infusion in dogs? Am J Physiol 1987, 252: R668-673.
66. Gold JA, Cullinane S, Chen J, et al. Vasopressin as an alternative to norepinephrine in the treatment of milrinone-induced hypotension. Crit Care Med 2000, 28:249-252.
67. Nemenoff RA. Vasopressin signaling pathways in vascular smooth muscle. Front Biosci 1998, d194-207.
68. Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature 1994, 372: 231-236.
69. Fukata Y, Aman M, Kaibuchi K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cell . Pharmcol Sci 2001, 22(1): 33-39.
70. Ogut Z, Brozovich FV. Regulation of force in vascular smooth muscle. J Mol Cell Cardiol 2003, 35(4): 347-355.
71. Maturi MF, Martin SE, Markle D, et al. Coronary vasoconstriction induced by vasopressin. Production of myocardial ischemia in dogs by constriction of nondiseasedsmall vessels. Circulation 1991, 83:2111-2121.
72. Boyle WA III, Segel LD. Direct cardiac effects of vasopressin and their reversal by a vascular antagonist. Am J Physiol 1986, 251:H734-741.
73. Okamura T, Ayajiki K, Fujioka H, et al. Mechanisms underlying arginine vasopressin-induced relaxation in monkey isolated coronary arteries. J Hypertens 1999, 17:673-678.
74. Wenzel V, Kern KB, Hilwig RW, et al. The left anterior descending coronary artery dilates after arginine vasopressin during normal sinus rhythm, and ventricular fibrillation with cardiopulmonary resuscitation. Circulation 2001, 104:2974.
75. Boyle WA III, Segel LD. Attenuation of vasopressin-mediated coronary constriction and myocardial depression in the hypoxic heart. Circ Res 1990, 66:710-721.
76. Walker BR, Childs ME, Adams EM. Direct cardiac effects of vasopressin: role of V1- and V2-vasopressinergic receptors. Am J Physiol 1988, 255:H261-265.
77. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997, 95:1122-1125.
78. Dunser MW, Mayr AJ, Stallinger A, et al. Cardiac performance during vasopressin infusion in postcardiotomy shock. Intensive Care Med 2002, 28:746-751.
79. Xu Y, Hopfner RL, McNeill JR, et al. Vasopressin accelerates protein synthesis in neonatal rat cardiomyocytes. Mol Cell Biochem 1999, 195:183-190.
80. De Aguilera EM, Vila JM, Irurzun A, et al. Endothelium-independent contractions of human cerebral arteries in response to vasopressin. Stroke 1990, 21(12):1689-1693.
81. Prengel AW, Maiere, Wwnzel V, et a1. Vasopressin improve vatal organ blood flow after prolonged cardiac arrest with postcounterskock pulseless electrical activity in pigs. Crit Care Med Stroke 1999, 27(3): 486-489.
82. Qahwash IM, Cassar CA, Radcliff RP, et al. Bacterial lipopolysaccharide-induced coordinate downregulation of arginine vasopressin receptor V3 and corticotropin- releasing factor receptor 1 messenger ribonucleic acids in the anterior pituitary of endotoxemic steers. Endocrine 2002, 18(1):13-20.
83. Evora PR, Pearson PJ, Schaff HV. Arginine vasopressin induces endotheliumdependentvasodilatation of the pulmonary artery. V1-receptor-mediated production of nitric oxide. Chest 1993, 103(4):1241-5.
84. Sai Y, Okamura T, Amakata Y, et al. Comparison of responses of canine pulmonary artery and vein to angiotensin II, bradykinin and vasopressin. Eur J Pharmacol 1995, 282(1-3):235-241.
85. Leather HA, Segers P, Berends N, et al. Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension. Crit Care Med 2002, 30(11):2548-2552.
86. Yang GM, Liu LM, Xu J, et al. Effect of arginine vasopressin on vascular reactivity and calcium sensitivity after hemorrhagic shock in rats and its relationship to Rho-kinase. J Trauma 2006, 61:1336-1342.
87. Amano M, Chihara K, Kimura K, et al. Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science 1997, 275(5304): 1308-1311.
88. Essler M, Staddon JM, Weber PC, et al. Cyclic AMP blocks bacterial lipopolysacc- haride-induced myosin light chain phosphorylation in endothelial cells through inhibition of Rho/Rho kinase signaling. J Immunol 2000, 164(12): 6543-6549.
89. Kreisberg JI, Ghosh-Choudhury N, Radnik RA, et al. Role of Rho and myosin phosphorylation in actin stress fiber assembly in mesangial cells. Am J Physiol 1997, 273: F283-288.
90. Eto M, Kitazawa T, Yazawa M, et al. Histamine-induced vasoconstriction involves phosphorylation of a specific inhibitor protein for myosin phosphatase by protein kinase C alpha and delta isoforms. J Biol Chem 2001, 276(31): 29072-29078.
91. Horowitz A, Clement CO, Walsh MP, et al. Epsilon-isoenzyme of protein kinase C induces a Ca2+-independent contraction in vascular smooth muscle. Am J Physiol 1996, 271: C589-594.
92. Walsh MP, Horowitz A, Clement-Chomienne O, et al. Protein kinase C mediation of Ca2+-independent contractions of vascular smooth muscle. Biochem Cell Biol 1996, 74(4): 485-502.
93. Kitazawa T, Eto M, Woodsome TP, et al. Agonists trigger G protein-mediated activationof the CPI-17 inhibitor phosphoprotein of myosin light chain phosphatase to enhance vascular smooth muscle contractility. J Biol Chem 2000, 275(14): 9897-9900.
94.杨光明,李涛,徐竞,等.精氨酸血管加压素恢复失血性休克大鼠血管反应性和钙敏感性与PKC亚型的关系.中国危重病急救医学2008, 20(3): 133-137.
95. Standen NB, Quayle JM. K+ channel modulation in arterial smooth muscle. Acta Physiol Scand 1998, 164:549-557.
96. Davies NW. Modulation of ATP-sensitive K+ channels in skeletal muscle by intracellular protons. Nature 1990, 343:375-377.
97. Landry DW, Oliver JA: The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog. J Clin Invest 1992, 89:2071-2074.
98. Geisen K, Vegh A, Krause E, et al. Cardiovascular effects of conventional sulfonylureas and glimepiride. Horm Metab Res 1996, 28:496-507.
99. Gardiner SM, Kemp PA, March JE, et al. Regional haemodynamic responses to infusion of lipopolysaccharide in conscious rats: effects of pre- or post-treatment with glibenclamide. Br J Pharmacol 1999, 128:1772-1778.
100. Salzman AL, Vromen A, Denenberg A, et al. KATP-channel inhibition improves hemodynamics and cellular energetics in hemorrhagic shock. Am J Physiol 1997, 272:H688-H694.
101. Wakatsuki T, Nakaya Y, Inoue I. Vasopressin modulates K+-channel activities of cultured smooth muscle cells from porcine coronary artery. Am J Physiol 1992, 263:H491-H496.
102. Bolotina VM, Najibi S, Palacino JJ, et al. Nitric oxide directly activates calcium- dependent potassium channels in vascular smooth muscle. Nature 1994, 368:850-853.
103. Umino T, Kusano E, Muto S, et al. AVP inhibits LPS- and IL-1beta-stimulated NO and cGMP via V1 receptor in cultured rat mesangial cells. Am J Physiol 1999, 276:F433- F441.
104. JM, Lluch S. Potentiation by vasopressin of adrenergic vasoconstriction in the rat isolated mesenteric artery. Br J Pharmacol 1997, 122:431-438.
105. Iversen BM, Arendshorst WJ. ANG II and vasopressin stimulate calcium entry indispersed smooth muscle cells of preglomerular arterioles. Am J Physiol 1998, 274:F498-F508.
106. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997, 25:1279-1282.
107. Malay MB, Ashton RC Jr, Landry DW, et al. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999, 47:699-703.
108. Rosenzweig EB, Starc TJ, Chen JM, et al. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation 1999, 100:II182-186.
109. Chen JM, Cullinane S, Spanier TB, et al. Vasopressin deficiency and pressor hypersensitivity in hemodynamically unstable organ donors. Circulation 1999, 100:II 244-246.
110. Morales D, Madigan J, Cullinane S, et al. Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock. Circulation 1999, 100:226-229.
111. Voelckel WG, Raedler C, Wenzel V, et al. Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs. Crit Care Med, 2003, 31(4):1160-1165.
112. Raedler C, Voelckel WG, Wenzel V, et al. Treatment of uncontrolled hemorrhagic shock after liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin. Anesth Analg, 2004, 98(6): 1759-1766.
113. Voelckel WG, Lurie KG, Lindner KH, et al. Vasopressin improves survival after cardiac arrest in hypovolemic shock. Anesth Analg, 2000, 91:627-634.
114. Shelly MP, Greatorex R, Calne RY, et al. The physiological effects of vasopressin when used to control intra-abdominal bleeding. Intensive Care Med 1988, 14:526–531.
115. Morales DL, Gregg D, Helman DN, et al. Arginine vasopressin in the treatment of 50 patients with postcardiotomy vasodilatory shock. Ann Thorac Surg 2000, 69(1):102-106.
116. Patel BM, Chittock DR, Russell JA, et al. Beneficial effects of shortterm vasopressin infusion during severe septic shock. Anesthesiology 2002, 96(3):576-582.
117. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion inpatients with septic shock. N Engl J Med 2008, 358:877-887.
118. Suba EA, Mckenna TM, Williams TJ, et al. In vivo and in vitro effects of endotoxin on vascular responsiveness to norepinephrine and signal transduction in the rat. Circ Shock 1992, 36:127-133.
119. Ekelund U, Bjornberg J, Mellander S.α2 adrenoceptor activation may trigger the:increased production of endothelium-derived nitric oxide in skeletal muscle during acute hemorrhage. Acta Physiol Scand 1988, 164: 285-292.
120. Ishimaru S, Shichiri M, Mineshita S, et al. Role of endothelin-1/endothelin receptor system in endotoxic shock rats. Hypertens Res 2001, 24(2): 119- 126.
121. Bucher M, Ittner KP, Hobbhahn J, et al. Downregulation of angiotensinⅡtype 1 receptors during sepsis. Hypertension 2001, 38(2):177-182.
122. Bucher M, Hobbhahn J, Taeger K, et al. Cytokine-mediated downregulation of vasopressin V(1A) receptors during acute endotoxemia in rats. Am J Physiol Regul Integr Comp Physiol 2002, 282(4):R979-984.
123. Chen SJ, Wu CC, Yang SN, et al. Hyperpolarization contributes to vascular hyporea- ctivity in rats with LPS-induced endotoxic shock. Life Sci 2000, 68(6):659-668.
124.开丽,胡德耀,王中峰,等.失血性休克引起大鼠肠系膜动脉血管平滑肌钾通道活动变化.生理学报2001, 53(4):291-295.
125. Zhao KS, Liu J, Yang GY, et al. Peroxynitrite leads to arteriolar smooth muscle cell membrane hyperpolarization and low vasoreactivity in severe shock. Clin Hemorheol Microcirc. 2000; 23(2-4):259-267.
126.刘杰,赵克森,王雪梅,等.血管平滑肌细胞内酸中毒在重症休克血管反应性降低中的作用.中华创伤杂志1999, 15:11-14.
127. Kai L, Wang ZF, Shi YL, et al. Opioid receptor antagonists increase [Ca2+]i in rat arterial smooth muscle cells in hemorrhagic shock. Acta Pharmacol Sin 2004, 25(3): 395-400.
128. Liu LM, Dubick MA. Regional diversity of hemorrhagic shock-induced vascular hyporeactivity and the roles of nitric oxide and endothelin: relationship to gene expression of NO/ET-1 and select cytokines in corresponding organs. J Surg Res 2005,125:128-136.
129. Xu J, Liu LM. The role of calcium desensitization in vascular hyporeactivity and its regulation after hemorrhagic shock in the rat. Shock 2005, 23:576-581.
130. Yang GM, Liu LM, Xu j, et al. Effects of MCI-154 on vascular reactivity and its mechanisms after hemorrhagic shock in rats. J Cardiovasc Pharmacol 2006, 47: 751-757.
131. Johansson J, Gedeborg R, Rubertsson S. Vasopressin versus continuous adrenaline during experi-mental cardiopulmonary resuscitation. Resuscitation 2004, 62(1): 61-69.
132. Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomized controlled trial. Lancet 2001, 358(9276):105-109.
133. Mayr VD, Readler C, Wenzel V, et al. A comparision of epinephrine and vasopressin in a porcine model of cardiac arrest after rapid in travenous injection of bupivacaine. Anesth Analg 2004, 98(5): 1426-1431.
134. Stadlbauer KH, Wagner-Berger HG, Wenzel V, et al. Survival will full neurologic recovery after prolonged cardiopulmonary resuscitation with a combination of vasopressin and epinephrine in pigs. Anesth Analg 2003, 96(6):1743-1749.
135. Udelson JE, Smith WB, Henrix GH, et al. Acute hemodynamic effects of conivaptan, a dual V1a and V2 vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001, 104:2417-2423.
136. Dunser MW, Mayr AJ, Tur A, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med 2003, 31(5):1394-1398.
137. Klinzing S, Simon M, Reinhart K, et al. High-dose vasopressin is not superior to norepinephrine in septic shock. Crit Care Med 2003, 31(11):2646-2650.
2. Liu LM, Ward JA, Dubick MA. Hemorrhagic-induced vascular hyporeactivity to norepinephrine in select vasculatures of rats and the roles of nitric oxide and endothelin. Shock 2003, 19:208-214.
3. Liu LM, Dubick MA: Regional diversity of hemorrhagic shock-induced vascular hyporeactivity and the roles of nitric oxide and endothelin: relationship to gene expression of NO/ET-1 and select cytokines in corresponding organs. J Surg Res 2005, 125:128-136.
4. Suba EA, Mckenna TM, Williams TJ, et al. In vivo and in vitro effects of endotoxin on vascular responsiveness to norepinephrine and signal transdu- ction in the rat. Circ Shock 1992, 36:127-133.
5. Ishimaru S, Shichiri M, Mineshita S, et al. Role of endothelin-1/endothelin receptor system in endotoxic shock rats. Hypertens Res 2001, 24(2):119 -126.
6. Bucher M, Ittner KP, Hobbhahn J, et al. Downregulation of angiotensin II type 1 receptors during sepsis. Hypertension 2001, 38(2):177-182.
7. Chen SJ, Wu CC, Yang SN, et al. Hyperpolarization contributes to vascular hyporeactivity in rats with LPS-induced endotoxic shock. Life Sci 2000, 68(6):659-668.
8. Kai Li, Wang ZF, Hu DY, et al. Opioid receptor antagonists modulate Ca2+-activated K+ channels in mesenteric arterial smooth muscle cells of rats in hemorrhagic shock. Shock 2003, 19:85-90.
9. Zhao KS, Huang XL, Liu J, et al. New approach to treatment of shock—restitution of vasoreactivity. Shock 2002, 18:189-192.
10. Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature 1994, 372: 231-236.
11. Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 1997, 389(6654): 990-994.
12. Kitazawa T, Takizawa N, Ikebe M, et al. Reconstitution of protein kinase C-induced contractile Ca2+ sensitization in triton X-100-demembranated rabbit arterial smooth muscle. J Physiol 1999, 520 Pt 1: 139-152.
13. Xu J, Liu LM. The role of calcium desensitization in vascular hyporeactivity and its regulation after hemorrhagic shock in the rat. Shock 2005, 23:576-581.
14. Oliver G. On the physiological of extracts of the pituitary and certain other glandular organs. J Physiol 1985, 18:27-31.
15.杨光明,刘良明. AVP对失血性休克大鼠血管反应性的影响.中国药理学与毒理学杂志2005, 19(5): 347-352.
16. Yang GM, Liu LM, Xu J, et al. Effect of arginine vasopressin on vascular reactivity and calcium sensitivity after hemorrhagic shock in rats and its relationship to Rho-kinase. J Trauma 2006, 61:1336-1342.
17. Fan JP and Byron KL. Ca2+ signalling in rat vascular smooth muscle cells: a role for protein kinase C at physiological vasoconstrictor concentrations of vasopressin. J. Physiol 2000, 524:821-831.
18. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992, 258:607–614.
19. Shirasawa Y, Rutland TJ, Young JL, et al. Modulation of protein kinase C (PKC)-mediated contraction and the possible role of PKC epsilon in rat mesenteric arteries. Front Biosci 2003, 8: a133-138.
20. Horowitz A, Clement CO, Walsh MP, et al. Epsilon-isoenzyme of protein kinase C induces a Ca2+-independent contraction in vascular smooth muscle. Am J Physiol 1996, 271: C589-594.
21. Holmes CL, Landry DW, Granton JT. Science review: Vasopressin and the cardiovascular system part 1--receptor physiology. Crit Care 2003, 7(6): 427-434.
22. Howl J, Ismail T, Strain AJ, Kirk CJ, Anderson D, Wheatley M. Characterization of the human liver vasopressin receptor. Profound differences between human and ratvasopressin-receptor-mediated responses suggest only a minor role for vasopressin in regulating human hepatic function. Biochem J 1991, 276: 189-195.
23. Wange RL, Smrcka AV, Sternweis PC, Exton JH. Photoaffinity labeling of two rat liver plasma membrane proteins with [32P]gamma-azidoanilido GTP in response to vasopressin. Immunologic identification as alpha subunits of the Gq class of G proteins. J Biol Chem 1991, 266(18): 11409-11412.
24. Force T, Kyriakis JM, Avruch J, Bonventre JV. Endothelin, vasopressin, and angiotensin II enhance tyrosine phosphorylation by protein kinase C-dependent and -independent pathways in glomerular mesangial cells. J Biol Chem 1991, 266(10): 6650-6656.
25. Chen WC, Chen CC. Signal transduction of arginine vasopressin-induced arachidonic acid release in H9c2 cardiac myoblasts: role of Ca2+ and the protein kinase C-dependent activation of p42 mitogen-activated protein kinase. Endocrinology 1999, 140(4): 1639-1648.
26. Kai L, Wang ZF, Shi YL, et al. Opioid receptor antagonists increase [Ca2+]i in rat arterial smooth muscle cells in hemorrhagic shock. Acta Pharmacol Sin 2004, 25(3): 395-400.
27. Li YX, Shiels AJ, Maszak G, et al. Vasopressin-stimulated Ca2+ spiking in vascular smooth muscle cells involves phospholipase D. Am J Physiol Heart Circ Physiol 2001, 280: H2658–2664.
28. Asaoka Y, Oka M, Yoshida K. Role of lysophosphatidylcholine in T-lymphocyte activation: involvement of phospholipase A2 in signal transduction through protein kinase C. Proc Natl Acad Sci USA 1992, 89(14): 6447-6451.
29. Axelrod J. Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem Soc Trans 1990, 18(4): 503-507.
30. Yang GM, Liu LM, Xu j, et al. Effects of MCI-154 on vascular reactivity and its mechanisms after hemorrhagic shock in rats. J Cardiovasc Pharmacol 2006, 47:751-757.
31. Leik CE, Willey A, Graham MF, et al. Isolation and culture of arterial smooth musclecells from human placenta. Hypertension 2004, 43(4):837-840.
32. Lampugnani MG, Resnati M, Dejana E, et al. The role of integrins in the maintenance of endothelial monolayer integrity. J Cell Biol 1991, 112:479-490.
33.蔡文琴,王伯去主编.实用免疫细胞化学与核酸分子杂交技术.四川科学技术出版社1994年第一版, 61-67.
34.陈思锋,吴中立.体液和组织磷脂酶A2简便快速测定法.第二军医大学学报1989, 10(3):254-256.
35. Brackett DJ, Schaefer CF, Tompkins P, et al. Plasma vasopressin and cardiac output changes in awake endotoxic rats. Circ Shock 1984, 13(1): 72-76.
36. Sharshar T, Carlier R, Blanchard A, et al. Depletion of neurohypophyseal content of vasopressin in septic shock. Crit Care Med 2002, 30: 497-500.
37. Joseph E. Parrillo. Septic Shock-Vasopressin, Norepinephrine, and Urgency. N Engl J Med 2008, 358:954-956.
38. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997, 25: 1279-1282.
39. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation 2003, 107(18): 2313-2319.
40. Sirintorn Y, Ehab AA, Cheng YY, et al. The role of arginine vasopressin in diabetes-associated increase in glucagon secretion. Regulatory Peptides 2004, 22(3):157-162.
41. Brackett DJ, Schaefer CF, Tompkins P, et al. Plasma vasopressin and cardiac output changes in awake endotoxic rats. Circ Shock 1984, 13(1): 72-76.
42. Voelckel WG, Lurie KG, Lindner KH, et al. Vasopressin improves survival after cardiac arrest in hypovolemic shock. Anesth Analg 2000, 91:627-634.
43. Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999, 47(4): 699-703.
44. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008, 358:877-887.
45. Takeda K, Meyer-Lehnert H, Kim JK, et al. AVP-induced Ca fluxes and contraction of rat glomerular mesangial cells. Am J Physiol 1988, 255: F142-150.
46. Li T, Liu LM, Xu J, et al. Changes of Rho kinase activity following hemorrhagic shock and its role in shock-induced biphasic response of vascular reactivity and calcium sensitivity. Shock 2006, 26:504-509.
47. Nemenoff RA. Vasopressin signaling pathways in vascular smooth muscle. Front Biosci 1998, d194-207.
48. Shimomura E, Shiraishi M, Iwanaga T, et al. Inhibition of protein kinase C-mediated contraction by Rho kinase inhibitor fasudil in rabbit aorta. Naunyn Schmiedebergs Arch Pharmacol 2004, 370(5): 414-422.
49. Kandabashi T, Shimokawa H, Miyata K, et al. Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioscler Thromb Vasc Biol 2003, 23(12): 2209-2214.
50. Sward K, Mita M, Wilson DP, et al. The role of RhoA and Rho-associated kinase in vascular smooth muscle contraction. Curr Hypertens Rep 2003, 5(1): 66-72.
51. Seko T, Ito M, Kureishi Y, et al. Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle. Circ Res 2003, 92(4): 411-418.
52. Kolosova IA, Ma SF, Adyshev DM, et al. Role of CPI-17 in the regulation of endothelial cytoskeleton. Am J Physiol Lung Cell Mol Physiol 2004, 287(5): L970-980.
53. Hiroki J, Shimokawa H, Higashim M, et al. Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. J Mol Cell Cardiol 2004, 37(2): 537-546.
54.杨光明,刘良明. MCI-154对失血性休克大鼠血管平滑肌钙敏感性的影响及其机制.中国危重病急救医学2005, 17(1):7-11.
55. Kitazawa T, Eto M, Woodsome TP, et al. Agonists trigger G protein-mediated activation of the CPI-17 inhibitor phosphoprotein of myosin light chain phosphatase to enhance vascular smooth muscle contractility. J Biol Chem 2000, 275(14): 9897-9900.
56. Eto M, Kitazawa T, Yazawa M, et al. Histamine-induced vasoconstriction involvesphosphorylation of a specific inhibitor protein for myosin phosphatase by protein kinase C alpha and delta isoforms. J Biol Chem 2001, 276(31): 29072-29078.
57. Yamboliev IA, Hedges JC, Mutnick JL, Adam LP, Gerthoffer WT. Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway. Am J Physiol Heart Circ Physiol 2000, 278(6): H1899-1907.
58. He J, Stephens NL. Calcium and smooth muscle contraction. Mol Cell Biochem 1994, 135: 1-9.
59. Shimizu H, Ito M, Miyahara M, et al. Characterization of the myosin-binding subunit of smooth muscle myosin phosphatase. J Biol Chem 1994, 269:30407-30411.
60. Hartshorne DJ, Hirano K. Interactions of protein phosphatase type 1, with a focus on myosin phosphatase. Mol Cell Biochem 1999, 190: 79-84.
61. Ichikawa K, Ito M, Hartshorne DJ. Phosphorylation of the large subunit of myosin phosphatase and inhibition of phosphatase activity. J Biol Chem 1996b, 271:4733-4740.
62. Hirano K, Hirano M, Kanaide H. Regulation of myosin phosphorylation and myofilament Ca2+ sensitivity in vascular smooth muscle. J Smooth Muscle Res 2004, 40(6): 219-236.
63. Marunaka Y, Eaton DC. Effects of vasopressin and cAMP on single amiloride- blockable Na channels. Am J Physiol 1991, 260: C1071-1084.
64. Ishunina TA, Swaab DF. Vasopressin and oxytocin neurons of the human supraoptic and paraventricular nucleus: size changes in relation to age and sex. J Clin Endocrinol Metab 1999, 84(12): 4637-4644.
65.罗哲,吴肇光.小剂量精氨酸加压素治疗感染性休克的应用.国外医学外科学分册2005, 32(3): 211-214.
66. De Aguilera EM, VilaJM, Irurzun A, et al. Endothelium-independent contractions of human cerebral arteries in response to vasopressin. Stroke 1990, 21(12): 1689-1693.
67. Ohguchi KY, Banno Y, Nakashima S, et al. Regulation of membrane-bound phospholipase D by protein kinase C in HL6 cells. Synergistic action of small GTP-binding protein RhoA. J Biol Chem 1996, 271: 4366~4372.
68. Exton JH. Phospholipase D: Enzymology, mechanisms of regulation, and function. Physiol Rev 1997, 77: 303~320.
69. Vinggaard AM, Hansen HS. Phorbol ester and vasopressin activate phospholipase D in Leydig cells. Mol Cell Endocrinol 1991, 79(1-3): 157-165.
70. Natarajan V, Garcia JG. Agonist-induced activation of phospholipase D in bovine pulmonary artery endothelial cells: regulation by protein kinase C and calcium. J Lab Clin Med 1993, 121(2): 337-347.
71. Araki S, Ito M, Kureishi Y, et al. Arachidonic acid-induced Ca2+ sensitization of smooth muscle contraction through activation of Rho-kinase. Pflugers Arch 2001, 441(5): 596-603.
72. Bauldry SA, Wooten RE. Induction of cytosolic PLA2 activity by phosphatidic acid and diglycerides in permeabilized human neutrophils: interrelationship between PLD and A2. Biochem J 1997, 322:353-363.
73.杨静娴,林原.平滑肌收缩的非钙依赖性调节机制.国外医学生理病理科学与临床分册2004, 24(6): 560-563.
74. Ackermann EJ, Kempner ES, Dennis EA. Ca2+-independent cytosolic phospholipase A2 from macrophage-like P388D1 cells. Isolation and characterization. J Biol Chem 1994, 269(12): 9227-33.
75. Dennis EA. Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem 1994, 269(18): 13057-13060.
1. Hoyle CH. Neuropeptide families and their receptors: evolutionary perspectives. Brain Res 1999, 848:1-25.
2. Oliver H, Schaefer EA. On the physiological action of extracts of the pituitary body and certain other glandular organs. J Physiol (Lond) 1895, 18:277-279.
3. von den Velden R. The renal effects of hypophyseal extract in humans. Berl Klin Wochenscgr 1913, 50:2083-2086.
4. Verney EB. The antidiuretic hormone and the factor which determines its release. Proc R Soc Lond (Biol) 1947, 135:25-106.
5. Du Vigneaud V, Gash DT, Katsoyannis PG. A synthetic preparation possessing biological properties associated with arginine-vasopressin. J Am Chem Soc 1954, 76:4751-4752.
6. Ebert TJ, Cowley AW. Vasopressin reduces cardiac function and augments cardiopulmonary baroreflex resistance increases in man. J Clin Invest 1986, 77: 1136-1142.
7. Albert M, Losser MR, Hayon D, et al. Systemic and renal macro- and microcirculatory responses to arginine vasopressin in endotoxic rabbits. Crit Care Med 2004, 32(9):1891-1898.
8. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation 2003, 107(18): 2313-2319.
9. Dunser MW, Wenzel V, Mayr AJ, et al. Management of vasodilatory shock: defining the role of arginine vasopressin. Drugs 2003, 63: 237-256.
10. Fleisher S, Kagan E, Grossman N, et al. Multiple effects of arginine vasopressin on prostaglandin E2 synthesis in fibroblasts. Eur J Pharmacol 2004, 485(1-3):53-59.
11. Sirintorn Y, Ehab AA, Cheng YY, et al. The role of arginine vasopressin in diabetes-associated increase in glucagon secretion. Regulatory Peptides 2004, 22(3):157-162.
12. Barberis C, Mouillac B, Durroux T. Structural bases of vasopressin/oxytocin receptor function. J Endocrinol 1998, 156:223-229.
13. Swaab DF, Nijveldt F, Pool CW. Distribution of oxytocin and vasopressin in the rat supraoptic and paraventricular nucleus. J Endocrinol 1975, 67:461-462.
14. Giovannucci DR, Stuenkel EL. Regulation of secretory granule recruitment and exocytosis at rat neurohypophysial nerve endings. J Physiol 1997, 498 (Pt 3):735-751.
15. Nowycky MC, Seward EP, Chernevskaya NI. Excitation-secretion coupling in mammalian neurohypophysial nerve terminals. Cell Mol Neurobiol 1998, 18(1):65-80.
16. Deleuze C, Duvoid A, Hussy N. Properties and glial origin of osmoticdependent release of taurine from the rat supraoptic nucleus. J Physiol 1998, 507(Pt 2):463-471.
17. Stern JE, Armstrong WE. Reorganization of the dendritic trees of oxytocin and vasopressin neurons of the rat supraoptic nucleus during lactation. J Neurosci 1998, 18(3):841-853.
18. Majzoub JA, Rich A, van Boom J, et al. Vasopressin and oxytocin mRNA regulation in the rat assessed by hybridization with synthetic oligonucleotides. J Biol Chem 1983, 258(23):14061-14064.
19. Zingg HH, Lefebvre D, Almazan G. Regulation of vasopressin gene expression in rat hypothalamic neurons. Response to osmotic stimulation. J Biol Chem 1986, 261(28):12956-12959.
20. Tang AH. A specific antagonist of vasopressin produced plasma hyperosomolality and reduce ischemic-induced cerebral edema in rats. Lif Sci 1988, 43: 399-403.
21. Czaczkes JW. Physiologic studies of antidiuretic hormone by its direct measurement in human plasma. J Clin Invest 1964, 43:1625-1640.
22. Brackett DJ, Schaefer CF, Tompkins P, et al. Plasma vasopressin and cardiac output changes in awake endotoxic rats. Circ Shock, 1984, 13(1): 72-76.
23. Arnauld E, Czernichow P, Fumoux F, et al. The effects of hypotension and hypovolaemia on the liberation of vasopressin during haemorrhage in the unanaesthe- tized monkey (Macaca mulatta). Pflugers Arch 1977, 371(3):193-200.
24. Cowley AW Jr, Switzer SJ, Guinn MM. Evidence and quantification of the vasopressinarterial pressure control system in the dog. Circ Res 1980, 46(1):58-67.
25. Wang BC, Flora-Ginter G, Leadley RJ Jr, et al. Ventricular receptors stimulate vasopressin release during hemorrhage. Am J Physiol 1988, 254:R204-211.
26. Fitzsimmons MD, Roberts MM, Sherman TG, et al. Models of neurohypophyseal homeostasis. Am J Physiol 1992, 262(6 Pt 2):R1121-1130.
27. Sharshar T, Carlier R, Blanchard A, et al. Depletion of neurohypophyseal content of vasopressin in septic shock. Crit Care Med, 2002, 30: 497-500.
28. Zerbe RL, Henry DP, Robertson GL. Vasopressin response to orthostatic hypotension. Etiologic and clinical implications. Am J Med 1983, 74(2):265-271.
29. Reid IA. Role of nitric oxide in the regulation of renin and vasopressin secretion. Front Neuroendocrinol 1994, 15(4):351-383.
30. Holmes CL, Landry DW, Granton JT. Science review: Vasopressin and the cardiova- scular system part 1--receptor physiology. Crit Care, 2003, 7(6): 427-434.
31. Zenteno-Savin T, Sada-Ovalle I, Ceballos G, et al. Effects of arginine vasopressin in the heart are mediated by specific intravascular endothelial receptors. Eur J Pharmacol 2000, 410:15-23.
32. Berrada K, Plesnicher CL, Luo X, et al. Dynamic interaction of human vasopressin/oxytocin receptor subtypes with g protein-coupled receptor kinases and protein kinase C after agonist stimulation. J Biol Chem 2000, 275:27229-27237.
33. Ross EM, Gilman AG. Biochemical properties of hormone-sensitive adenylate cyclase. Annu Rev Biochem 1980, 49:533-564.
34. Neves SR, Ram PT, Iyengar R. G protein pathways. Science 2002, 296:1636-1639.
35. Thibonnier M, Graves MK, Wagner MS, et al. Structure, sequence, expression, and chromosomal localization of the human V1a vasopressin receptor gene. Genomics 1996, 31:327-334.
36. Briley EM, Lolait SJ, Axelrod J, et al. The cloned vasopressin V1a receptor stimulates phospholipase A2, phospholipase C, and phospholipase D through activation of receptor-operated calcium channels. Neuropeptides 1994, 27: 63-74.
37. Bankir L. Antidiuretic action of vasopressin: quantitative aspects and interactionbetween V1a and V2 receptor-mediated effects. Cardiovasc Res 2001, 51:372-390.
38. Edwards RM, Trizna W, et al. Renal microvascular effects of vasopressin and vasopressin antagonists. Am J Physiol 1989, 256:F274-278.
39. Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on hemodyn- amics and renal function in severe septic shock: a case series. Intensive Care Med 2001, 27:1416-1421.
40. Patel B, Chittock D, Walley K. Vasopressin infusion in SIRS and septic shock: a randomized controlled trial. Am J Respir Crit Care Med 1999, 159:A608.
41. Howl J, Ismail T, Strain AJ, et al. Characterization of the human liver vasopressin receptor. Profound differences between human and rat vasopressin-receptor-mediated responses suggest only a minor role for vasopressin in regulating human hepatic function. Biochem J, 1991; 276: 189-195.
42. Wange RL, Smrcka AV, Sternweis PC, et al. Photoaffinity labeling of two rat liver plasma membrane proteins with [32P]gamma-azidoanilido GTP in response to vasopressin. Immunologic identification as alpha subunits of the Gq class of G proteins. J Biol Chem, 1991, 266(18): 11409-11412.
43. Force T, Kyriakis JM, Avruch J, et al. Endothelin, vasopressin, and angiotensin II enhance tyrosine phosphorylation by protein kinase C-dependent and -independent pathways in glomerular mesangial cells. J Biol Chem, 1991, 266(10): 6650-6656.
44. Thibonnier M, Bayer AL, Simonson MS, et al. Reconstitution of solubilized V1 vasopressin receptors of human platelets. Am J Physiol, 1990, 259: E751-756.
45. Erlenbach I, Wess J. Molecular basis of V2 vasopressin receptor/Gs coupling selectivity. J Biol Chem 1998, 273:26549-26558.
46. Liu J, Wess J. Different single receptor domains determine the distinct G protein coupling profiles of members of the vasopressin receptor family. J Biol Chem 1996, 271:8772-8778.
47. Birnbaumer M. Vasopressin receptors. Trends Endocrinol Metab 2000, 11:406-410.
48. Rosenthal W, Antaramian A, Gilbert S, et al. Nephrogenic diabetes insipidus. A V2 vasopressin receptor unable to stimulate adenylyl cyclase. J Biol Chem 1993,268:13030-13033.
49. Bichet DG, Razi M, Lonergan M, et al. Hemodynamic and coagulation responses to 1-desamino[8-D-arginine] vasopressin in patients with congenital nephrogenic diabetes insipidus. N Engl J Med 1988, 318: 881-887.
50. Phillips PA, Abrahams JM, Kelly JM, et al. Localization of vasopressin binding sites in rat tissues using specific V1 and V2 selective ligands. Endocrinology 1990, 126:1478-1484.
51. Sugimoto T, Saito M, Mochizuki S, et al. Molecular cloning and functional expression of a cDNA encoding the human V1b vasopressin receptor. J Biol Chem 1994, 269:27088-27092.
52. Thibonnier M, Preston JA, Dulin N, et al. The human V3 pituitary vasopressin receptor: ligand binding profile and density-dependent signaling pathways. Endocrinology 1997, 138:4109-4122.
53. Thibonnier M, Berti-Mattera LN, Dulin N, et al. Signal transduction pathways of the human V1-vascular, V2-renal, V3-pituitary vasopressin and oxytocin receptors. Prog Brain Res 1998, 119:147-161.
54. Peter J, Burbach H, Adan RA, et al. Molecular neurobiology and pharmacology of the vasopressin/oxytocin receptor family. Cell Mol Neurobiol 1995, 15:573-595.
55. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev 2001, 81:629-683.
56. Thibonnier M, Conarty DM, Preston JA, et al. Human vascular endothelial cells express oxytocin receptors. Endocrinology 1999, 140:1301-1309.
57. Sanborn BM, Dodge K, Monga M, et al. Molecular mechanisms regulating the effects of oxytocin on myometrial intracellular calcium. Adv Exp Med Biol 1998, 449: 277-286.
58. Gutkowska J, Jankowski M, Lambert C, et al. Oxytocin releases atrial natriuretic peptide by combining with oxytocin receptors in the heart. Proc Natl Acad Sci USA 1997, 94:11704-11709.
59. Diaz Brinton R, Brownson EA. Vasopressin-induction of cyclic AMP in culturedhippocampal neurons. Brain Res Dev Brain Res 1993, 71:101-105.
60. de Wied D, Elands J, Kovacs G. Interactive effects of neurohypophyseal neuropeptides with receptor antagonists on passive avoidance behavior: mediation by a cerebral neurohypophyseal hormone receptor? Proc Natl Acad Sci USA 1991, 88:1494-1498.
61. Katusic ZS, Shepherd JT, Vanhoutte PM. Vasopressin causes endotheliumdependent relaxations of the canine basilar artery. Circ Res 1984, 55(5):575-579.
62. Tagawa T, Imaizumi T, Endo T, et al. Vasodilatory effect of arginine vasopressin is mediated by nitric oxide in human forearm vessels. J Clin Invest 1993, 92(3): 1483-1490.
63. Garcia-Villalon AL, Garcia JL, Fernandez N, et al. Regional differences in the arterial response to vasopressin: role of endothelial nitric oxide. Br J Pharmacol 1996, 118:1848-1854.
64. Holmes CL, Patel BM, Russell JA, et al. Physiology of vasopressin relevant to management of septic shock. Chest 2001, 120:989-1002.
65. Liard JF. Does vasopressin-induced vasoconstriction persist during prolonged infusion in dogs? Am J Physiol 1987, 252: R668-673.
66. Gold JA, Cullinane S, Chen J, et al. Vasopressin as an alternative to norepinephrine in the treatment of milrinone-induced hypotension. Crit Care Med 2000, 28:249-252.
67. Nemenoff RA. Vasopressin signaling pathways in vascular smooth muscle. Front Biosci 1998, d194-207.
68. Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature 1994, 372: 231-236.
69. Fukata Y, Aman M, Kaibuchi K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cell . Pharmcol Sci 2001, 22(1): 33-39.
70. Ogut Z, Brozovich FV. Regulation of force in vascular smooth muscle. J Mol Cell Cardiol 2003, 35(4): 347-355.
71. Maturi MF, Martin SE, Markle D, et al. Coronary vasoconstriction induced by vasopressin. Production of myocardial ischemia in dogs by constriction of nondiseasedsmall vessels. Circulation 1991, 83:2111-2121.
72. Boyle WA III, Segel LD. Direct cardiac effects of vasopressin and their reversal by a vascular antagonist. Am J Physiol 1986, 251:H734-741.
73. Okamura T, Ayajiki K, Fujioka H, et al. Mechanisms underlying arginine vasopressin-induced relaxation in monkey isolated coronary arteries. J Hypertens 1999, 17:673-678.
74. Wenzel V, Kern KB, Hilwig RW, et al. The left anterior descending coronary artery dilates after arginine vasopressin during normal sinus rhythm, and ventricular fibrillation with cardiopulmonary resuscitation. Circulation 2001, 104:2974.
75. Boyle WA III, Segel LD. Attenuation of vasopressin-mediated coronary constriction and myocardial depression in the hypoxic heart. Circ Res 1990, 66:710-721.
76. Walker BR, Childs ME, Adams EM. Direct cardiac effects of vasopressin: role of V1- and V2-vasopressinergic receptors. Am J Physiol 1988, 255:H261-265.
77. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997, 95:1122-1125.
78. Dunser MW, Mayr AJ, Stallinger A, et al. Cardiac performance during vasopressin infusion in postcardiotomy shock. Intensive Care Med 2002, 28:746-751.
79. Xu Y, Hopfner RL, McNeill JR, et al. Vasopressin accelerates protein synthesis in neonatal rat cardiomyocytes. Mol Cell Biochem 1999, 195:183-190.
80. De Aguilera EM, Vila JM, Irurzun A, et al. Endothelium-independent contractions of human cerebral arteries in response to vasopressin. Stroke 1990, 21(12):1689-1693.
81. Prengel AW, Maiere, Wwnzel V, et a1. Vasopressin improve vatal organ blood flow after prolonged cardiac arrest with postcounterskock pulseless electrical activity in pigs. Crit Care Med Stroke 1999, 27(3): 486-489.
82. Qahwash IM, Cassar CA, Radcliff RP, et al. Bacterial lipopolysaccharide-induced coordinate downregulation of arginine vasopressin receptor V3 and corticotropin- releasing factor receptor 1 messenger ribonucleic acids in the anterior pituitary of endotoxemic steers. Endocrine 2002, 18(1):13-20.
83. Evora PR, Pearson PJ, Schaff HV. Arginine vasopressin induces endotheliumdependentvasodilatation of the pulmonary artery. V1-receptor-mediated production of nitric oxide. Chest 1993, 103(4):1241-5.
84. Sai Y, Okamura T, Amakata Y, et al. Comparison of responses of canine pulmonary artery and vein to angiotensin II, bradykinin and vasopressin. Eur J Pharmacol 1995, 282(1-3):235-241.
85. Leather HA, Segers P, Berends N, et al. Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension. Crit Care Med 2002, 30(11):2548-2552.
86. Yang GM, Liu LM, Xu J, et al. Effect of arginine vasopressin on vascular reactivity and calcium sensitivity after hemorrhagic shock in rats and its relationship to Rho-kinase. J Trauma 2006, 61:1336-1342.
87. Amano M, Chihara K, Kimura K, et al. Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science 1997, 275(5304): 1308-1311.
88. Essler M, Staddon JM, Weber PC, et al. Cyclic AMP blocks bacterial lipopolysacc- haride-induced myosin light chain phosphorylation in endothelial cells through inhibition of Rho/Rho kinase signaling. J Immunol 2000, 164(12): 6543-6549.
89. Kreisberg JI, Ghosh-Choudhury N, Radnik RA, et al. Role of Rho and myosin phosphorylation in actin stress fiber assembly in mesangial cells. Am J Physiol 1997, 273: F283-288.
90. Eto M, Kitazawa T, Yazawa M, et al. Histamine-induced vasoconstriction involves phosphorylation of a specific inhibitor protein for myosin phosphatase by protein kinase C alpha and delta isoforms. J Biol Chem 2001, 276(31): 29072-29078.
91. Horowitz A, Clement CO, Walsh MP, et al. Epsilon-isoenzyme of protein kinase C induces a Ca2+-independent contraction in vascular smooth muscle. Am J Physiol 1996, 271: C589-594.
92. Walsh MP, Horowitz A, Clement-Chomienne O, et al. Protein kinase C mediation of Ca2+-independent contractions of vascular smooth muscle. Biochem Cell Biol 1996, 74(4): 485-502.
93. Kitazawa T, Eto M, Woodsome TP, et al. Agonists trigger G protein-mediated activationof the CPI-17 inhibitor phosphoprotein of myosin light chain phosphatase to enhance vascular smooth muscle contractility. J Biol Chem 2000, 275(14): 9897-9900.
94.杨光明,李涛,徐竞,等.精氨酸血管加压素恢复失血性休克大鼠血管反应性和钙敏感性与PKC亚型的关系.中国危重病急救医学2008, 20(3): 133-137.
95. Standen NB, Quayle JM. K+ channel modulation in arterial smooth muscle. Acta Physiol Scand 1998, 164:549-557.
96. Davies NW. Modulation of ATP-sensitive K+ channels in skeletal muscle by intracellular protons. Nature 1990, 343:375-377.
97. Landry DW, Oliver JA: The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog. J Clin Invest 1992, 89:2071-2074.
98. Geisen K, Vegh A, Krause E, et al. Cardiovascular effects of conventional sulfonylureas and glimepiride. Horm Metab Res 1996, 28:496-507.
99. Gardiner SM, Kemp PA, March JE, et al. Regional haemodynamic responses to infusion of lipopolysaccharide in conscious rats: effects of pre- or post-treatment with glibenclamide. Br J Pharmacol 1999, 128:1772-1778.
100. Salzman AL, Vromen A, Denenberg A, et al. KATP-channel inhibition improves hemodynamics and cellular energetics in hemorrhagic shock. Am J Physiol 1997, 272:H688-H694.
101. Wakatsuki T, Nakaya Y, Inoue I. Vasopressin modulates K+-channel activities of cultured smooth muscle cells from porcine coronary artery. Am J Physiol 1992, 263:H491-H496.
102. Bolotina VM, Najibi S, Palacino JJ, et al. Nitric oxide directly activates calcium- dependent potassium channels in vascular smooth muscle. Nature 1994, 368:850-853.
103. Umino T, Kusano E, Muto S, et al. AVP inhibits LPS- and IL-1beta-stimulated NO and cGMP via V1 receptor in cultured rat mesangial cells. Am J Physiol 1999, 276:F433- F441.
104. JM, Lluch S. Potentiation by vasopressin of adrenergic vasoconstriction in the rat isolated mesenteric artery. Br J Pharmacol 1997, 122:431-438.
105. Iversen BM, Arendshorst WJ. ANG II and vasopressin stimulate calcium entry indispersed smooth muscle cells of preglomerular arterioles. Am J Physiol 1998, 274:F498-F508.
106. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997, 25:1279-1282.
107. Malay MB, Ashton RC Jr, Landry DW, et al. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999, 47:699-703.
108. Rosenzweig EB, Starc TJ, Chen JM, et al. Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation 1999, 100:II182-186.
109. Chen JM, Cullinane S, Spanier TB, et al. Vasopressin deficiency and pressor hypersensitivity in hemodynamically unstable organ donors. Circulation 1999, 100:II 244-246.
110. Morales D, Madigan J, Cullinane S, et al. Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock. Circulation 1999, 100:226-229.
111. Voelckel WG, Raedler C, Wenzel V, et al. Arginine vasopressin, but not epinephrine, improves survival in uncontrolled hemorrhagic shock after liver trauma in pigs. Crit Care Med, 2003, 31(4):1160-1165.
112. Raedler C, Voelckel WG, Wenzel V, et al. Treatment of uncontrolled hemorrhagic shock after liver trauma: fatal effects of fluid resuscitation versus improved outcome after vasopressin. Anesth Analg, 2004, 98(6): 1759-1766.
113. Voelckel WG, Lurie KG, Lindner KH, et al. Vasopressin improves survival after cardiac arrest in hypovolemic shock. Anesth Analg, 2000, 91:627-634.
114. Shelly MP, Greatorex R, Calne RY, et al. The physiological effects of vasopressin when used to control intra-abdominal bleeding. Intensive Care Med 1988, 14:526–531.
115. Morales DL, Gregg D, Helman DN, et al. Arginine vasopressin in the treatment of 50 patients with postcardiotomy vasodilatory shock. Ann Thorac Surg 2000, 69(1):102-106.
116. Patel BM, Chittock DR, Russell JA, et al. Beneficial effects of shortterm vasopressin infusion during severe septic shock. Anesthesiology 2002, 96(3):576-582.
117. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion inpatients with septic shock. N Engl J Med 2008, 358:877-887.
118. Suba EA, Mckenna TM, Williams TJ, et al. In vivo and in vitro effects of endotoxin on vascular responsiveness to norepinephrine and signal transduction in the rat. Circ Shock 1992, 36:127-133.
119. Ekelund U, Bjornberg J, Mellander S.α2 adrenoceptor activation may trigger the:increased production of endothelium-derived nitric oxide in skeletal muscle during acute hemorrhage. Acta Physiol Scand 1988, 164: 285-292.
120. Ishimaru S, Shichiri M, Mineshita S, et al. Role of endothelin-1/endothelin receptor system in endotoxic shock rats. Hypertens Res 2001, 24(2): 119- 126.
121. Bucher M, Ittner KP, Hobbhahn J, et al. Downregulation of angiotensinⅡtype 1 receptors during sepsis. Hypertension 2001, 38(2):177-182.
122. Bucher M, Hobbhahn J, Taeger K, et al. Cytokine-mediated downregulation of vasopressin V(1A) receptors during acute endotoxemia in rats. Am J Physiol Regul Integr Comp Physiol 2002, 282(4):R979-984.
123. Chen SJ, Wu CC, Yang SN, et al. Hyperpolarization contributes to vascular hyporea- ctivity in rats with LPS-induced endotoxic shock. Life Sci 2000, 68(6):659-668.
124.开丽,胡德耀,王中峰,等.失血性休克引起大鼠肠系膜动脉血管平滑肌钾通道活动变化.生理学报2001, 53(4):291-295.
125. Zhao KS, Liu J, Yang GY, et al. Peroxynitrite leads to arteriolar smooth muscle cell membrane hyperpolarization and low vasoreactivity in severe shock. Clin Hemorheol Microcirc. 2000; 23(2-4):259-267.
126.刘杰,赵克森,王雪梅,等.血管平滑肌细胞内酸中毒在重症休克血管反应性降低中的作用.中华创伤杂志1999, 15:11-14.
127. Kai L, Wang ZF, Shi YL, et al. Opioid receptor antagonists increase [Ca2+]i in rat arterial smooth muscle cells in hemorrhagic shock. Acta Pharmacol Sin 2004, 25(3): 395-400.
128. Liu LM, Dubick MA. Regional diversity of hemorrhagic shock-induced vascular hyporeactivity and the roles of nitric oxide and endothelin: relationship to gene expression of NO/ET-1 and select cytokines in corresponding organs. J Surg Res 2005,125:128-136.
129. Xu J, Liu LM. The role of calcium desensitization in vascular hyporeactivity and its regulation after hemorrhagic shock in the rat. Shock 2005, 23:576-581.
130. Yang GM, Liu LM, Xu j, et al. Effects of MCI-154 on vascular reactivity and its mechanisms after hemorrhagic shock in rats. J Cardiovasc Pharmacol 2006, 47: 751-757.
131. Johansson J, Gedeborg R, Rubertsson S. Vasopressin versus continuous adrenaline during experi-mental cardiopulmonary resuscitation. Resuscitation 2004, 62(1): 61-69.
132. Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomized controlled trial. Lancet 2001, 358(9276):105-109.
133. Mayr VD, Readler C, Wenzel V, et al. A comparision of epinephrine and vasopressin in a porcine model of cardiac arrest after rapid in travenous injection of bupivacaine. Anesth Analg 2004, 98(5): 1426-1431.
134. Stadlbauer KH, Wagner-Berger HG, Wenzel V, et al. Survival will full neurologic recovery after prolonged cardiopulmonary resuscitation with a combination of vasopressin and epinephrine in pigs. Anesth Analg 2003, 96(6):1743-1749.
135. Udelson JE, Smith WB, Henrix GH, et al. Acute hemodynamic effects of conivaptan, a dual V1a and V2 vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001, 104:2417-2423.
136. Dunser MW, Mayr AJ, Tur A, et al. Ischemic skin lesions as a complication of continuous vasopressin infusion in catecholamine-resistant vasodilatory shock: incidence and risk factors. Crit Care Med 2003, 31(5):1394-1398.
137. Klinzing S, Simon M, Reinhart K, et al. High-dose vasopressin is not superior to norepinephrine in septic shock. Crit Care Med 2003, 31(11):2646-2650.