钙失敏在大鼠失血性休克血管低反应性中的作用

目的观察血管平滑肌钙失敏在大鼠失血性休克(HS)血管低反应性中的作用。方法 取失血 性休克大鼠肠系膜上动脉(SMA),利用离体血管环张力测定技术,以血管环对梯度浓度去甲肾上腺素(NE) 的收缩力反映血管反应性,用去极化状态下(120 mmol／L K+)血管环对梯度浓度Ca2+的收缩力反映血管的 钙敏感性,观察失血性休克低反应血管是否存在钙敏感性降低以及钙敏感性调节剂血管紧张素Ⅱ(Ang Ⅱ)、 胰岛素以及Rho-激酶特异性抑制剂Fasudil是否可以通过调节钙敏感性来调节血管反应性。结果 失血性 休克后SMA对NE的反应性和钙敏感性均显著下降,表现为NE的量-效曲线明显右移,NE的最大收缩力 (Emax)和-lg[EC50](pD2)降低(P<0.05或P<0.01);Ca2+的量一效曲线明显右移,Ca2+的Emax和pD2降低 (P<0.05或P<0.01)。具有钙敏感性增强作用的Ang Ⅱ(10-9mol／L)可使NE和Ca2+的量-效曲线左移,使 NE和Ca2+的Emax增高(P<0.05或P<0.01)。而具有钙敏感性抑制作用的胰岛素(100 nmol／L)可使NE 和Ca2+的量-效曲线右移,NE和Ca2+的Emax降低(P<0.05或P<0.01).Fasudil预处理可消除Ang Ⅱ对 NE诱导的血管收缩反应的增强效果,降低钙敏感性。结论 失血性休克血管平滑肌细胞存在钙敏感性降低. 血管平滑肌细胞钙敏感性降低在失血性休克血管低反应性的     

蛋白激酶C和蛋白激酶G对失血性休克大鼠血管平滑肌细胞钙敏感性的调节作用

目的探讨蛋白激酶C(PKC)、蛋白激酶G(PKG)对失血性休克大鼠血管平滑肌细胞钙敏感性的调节作用。方法经股动脉放血使平均动脉压维持在40mmHg(1mmHg=0.133kPa)2h制备失血性休克大鼠模型。采用离体血管环张力测定技术,测定在失血性休克大鼠肠系膜上动脉(SMA)血管环去极化状态下(120mmol/LK+)对梯度浓度Ca2+的收缩反应性(钙敏感性)变化;同时观察PKC、PKG活性调节剂对钙敏感性的影响。测定大鼠SMA的PKC、PKG活性变化,分析PKC、PKG活性变化与血管钙敏感性变化间的关系。结果休克2hSMA血管环对钙敏感性明显降低,其量-效曲线明显右移,最大收缩力(Emax)明显降低(P均<0.01)。PKC激动剂PMA1×10-7mol/L可明显提高休克血管环对钙敏感性,PKC拮抗剂staurosporine1×10-7mol/L可降低休克血管环对钙敏感性(P<0.05或P<0.01);PKG激动剂8Br-cGMP1×10-4mol/L可使休克血管钙敏感性降低,其拮抗剂KT-58231×10-6mol/L可提高休克血管钙敏感性(P均<0.05)。休克2hSMA的PKC活性明显降低,PKG活性明显升高(P<0.05和P<0.01),分别与休克血管钙敏感性变化呈正相关和负相关(P均<0.01)。结论PKC和PKG参与了失血性休克血管平滑肌细胞钙敏感性的调控,PKC可上调血管平滑肌细胞的钙敏感性,PKG可下调其钙敏感性。     

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蛋白激酶C亚型的关系

目的 探讨精氨酸血管加压素(AVP)对失血性休克大鼠血管反应性和钙敏感性的恢复作用与蛋白激酶C(PKC)亚型的关系.方法 取失血性休克大鼠肠系膜上动脉(SMA)并去除内皮,利用离体血管环张力测定技术,观察了AVP(5×10-11、5×10-10和5×10-9 mol/L)调节对休克SMA对去甲肾上腺素(NE)反应性和钙敏感性的作用及其与PKCα、δ亚型的关系.结果 AVP(5×10-11、5×10-10和5×10-9 mol/L)可明显恢复休克后的血管反应性和钙敏感性,使SMA对NE和Ca2+的量一效曲线明显左移,血管环产生的最大收缩张力(Emax)升高(P均＜0.01),且呈一定的剂量依赖关系,各剂量组间比较差异均有统计学意义(P均＜0.05).而特异性的PKCα、δ亚型抑制剂G66976(5×10-6 mol/L)和Rottlerin(10-5 mol/L)均可拮抗AVP(5×10-10 mol/L)诱导的休克后血管反应性和钙敏感性升高,抵消了AVP诱导的NE和Ca2+的量一效曲线左移,使NE的Emax明显降低(P＜0.05或P＜0.01).结论 AVP能剂量依赖性地升高失血性休克大鼠的血管反应性和血管平滑肌钙敏感性,其机制可能与PKCα、δ亚型激活有关.     

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

【目的 探讨新型钙增敏剂MCI-154对失血性休克大鼠血管平滑肌钙敏感性的影响及其可能 的机制。方法取失血性休克大鼠肠系膜上动脉(SMA),利用离体血管环张力测定技术,用去极化状态下 (120 mmol／L K+)血管环对梯度浓度Ca2+的反应来反映钙敏感性。实验分两部分:第一部分观察MCI-154 对失血性休克大鼠血管平滑肌钙敏感性的影响,第二部分观察MCI-154影响失血性休克血管平滑肌钙敏感 性与Rho-激酶、蛋白激酶C(PKC)、蛋白激酶G(PKG)的关系。结果 失血性休克后SMA血管环对Ca2+的 量-效曲线明显右移,最大收缩力(Emax)较正常组显著降低(P<0.01),MCI-154可使休克SMA血管环对 Caz+的量-效曲线进一步右移,且呈一定的剂量依赖关系,提示休克后SMA存在钙失敏,MCI-154进一步降 低休克后SMA血管环的钙敏感性。MCI-154可使具有Rho-激酶激动作用的血管紧张紊Ⅱ(Ang Ⅱ)和 PKC激动剂佛波醇-12-豆蔻酸-13-乙酸酯(PMA)作用下Ca2+的量-效曲线明显右移,Emax显著降低 (P<0.01);PKG的拮抗剂KT-5823可使MCI-154对Ca2+的量-效曲线明显左移,Emax显著升高 (P<0.01),提示MCI-154降低休克后血管平滑肌钙敏感性可能与Rho-激酶、PKC、PKG有关。结论 失血 性休克可使血管平滑肌钙敏感性降低,MCI-154可进一步降低这种钙敏感性。其机制可能通     

失血性休克大鼠PKCα mRNA表达变化规律及对血管低反应性的调节作用

目的 观察PKCot在大鼠失血性休克血管平滑肌中mRNA表达变化规律,及其对失血性休克血管反应性和钙敏感性的调控作用.方法 采用PCR技术测定大鼠肠系膜上动脉不同休克时间点(休克即时、30 min、1 h、2 h、4 h)的PKCct mRNA表达;用离体血管环张力测定技术观察不同休克时间点的肠系膜上动脉一级分支的血管环反应性和钙敏感性变化,以及PKCa激动剂和抑制剂对休克2 h血管反应性、钙敏感性的影响.结果 ①失血性休克后大鼠血管反应性和钙敏感性早期增高、晚期降低,PKCot mRNA表达逐渐增高,于1 h达到峰值(P<0.01),4 h时仍处于较高水平(P<0.01).②PKCa激动剂和抑制剂可分别增高和降低休克2 h大鼠的血管反应性和钙敏感性.结论 PKCct在失血性休克血管反应性和钙敏感性调控中起重要作用,可能是休克血管功能的重要保护性分子.     

蛋白激酶Cε对失血性休克大鼠血管反应性和钙敏感性的调节作用

目的 观察蛋白激酶Cε(PKCε)对失血性休克血管反应性和钙敏感性的调节作用.方法 取失血性休克大鼠肠系膜上动脉,利用逆转录一聚合酶链反应(RT-PCR)测定休克即时、0.5、1、2和4 h PKCε mRNA的表达;取大鼠肠系膜上动脉一级分支,利用离体血管张力测定技术,测定不同休克时间点的血管环反应性和钙敏感性,并观察PKCε的激动剂和抑制剂对休克2 h血管反应性和钙敏感性的影响.结果 ①大鼠血管反应性和钙敏感性在休克早期增高,晚期进行性降低;正常组织PKCε mRNA表达量低,失血性休克后表达逐渐增加,于1 h达到峰值(P＜0.01),4 h时仍维持在较高水平(P＜0.01).②PKCε的激动剂可增高休克2 h的血管反应性和钙敏感性,PKCε的抑制剂可降低休克2 h的血管反应性和钙敏感性(P均＜0.01).结论 PKCε对失血性休克血管反应性和钙敏感性有重要的调节作用,可能是一种重要的内源性保护分子.     

ICI174,864对失血性休克大鼠全身及局部血管反应性变化的作用

目的 观察大鼠不同程度失血性休克时全身和局部血管反应性变化及δ阿片受体特异性拮抗剂IC1174,864对失血性休克大鼠血管反应性的影响。方法 56只Wistar大鼠,戊巴比妥钠麻醉(30mg／kg)。实验分两部分。第一部分实验用32只大鼠,随机分为手术对照组、1h低血压组,2h低血压组和3h低血压组,每组8只动物;动物经股动脉插管放血至血压40mmHg(1mmHg=0．133kPa)分别维持1、2和3h,然后回输全部残余失血,观察回输血后1、2和3h血压和肠系膜上动脉(SMA)对去甲肾上腺素(NE,3pg,／kg)的反应性变化。第二部分实验用24只大鼠,随机分为失血性休克对照组、IC1174,864 0．5mg／kg干预组和1．0mg／kg干预组,每组8只动物;动物经股动脉插管放血至血压40mmHg,维持2h,回输残余失血,观察给予IC1174,864后1、2和4h血压和SMA对NE(3μg／kg)的升压和收缩反应。结果 失血性休克后全身(血压对NE的升压反应)和局部(SMA对NE的收缩反应)血管反应性显著降低,且呈一定的程度和时间依赖性,即休克程度越重,时间越长,血管反应性降低越多。单纯回输失血不能纠正血管的低反应性,IC1174,864对休克血管的低反应性有不同程度的恢复作用,且呈一定的剂量依赖关系。结论 失血性休克可诱导全身和局部血管反应性降低,并与休克程度和时间密切相关,全身和局部血管反应性的降低呈现一定的平行关系。δ阿片受体特异性拮抗剂IC1174,864对失血性休克大鼠的血管低反应性有一定的恢复作用。     

聚腺苷二磷酸核糖基聚合酶在大鼠失血性休克后血管低反应性发生中的作用

目的 研究聚腺苷二磷酸核糖基聚合酶(PARP)在大鼠失血性休克后血管低反应性发生中的作用.方法 将SD大鼠随机分为休克组、PARP抑制剂3-氨基苯甲酰胺(3-AB)预处理+休克组和假手术对照组,采用股动脉放血复制失血性休克模型.在体观察给予3 μg/kg去甲肾上腺素(NE)升高血压的幅度;离体测定肠系膜上动脉血管环对NE的反应性;硝酸还原酶法测定血浆和肠系膜上动脉血管环组织匀浆中一氧化氮(NO)的含量.结果 休克模型完成后即刻静脉给NE,休克组血压升高幅度显著低于假手术对照组(P＜0.01);回输血1 h后再次静脉给NE,休克组血压显著低于3-AB预处理+休克组和假手术对照组(P＜0.05和P＜0.01).假手术对照组最大收缩张力[(0.367 1±0.221 3)g/mm]＞3-AB预处理+休克组C(0.286 4±0.153 2)g/mm]＞休克组C(0.185 6±0.11 3)g/mm,P＜0.05或P＜0.01];与休克组比较,3-AB预处理+休克组量一效曲线左移,在NE终浓度为10-7、10-6和10-5 mol/L时其收缩力显著增加(P均＜0.05).3组间血浆NO含量差异均无统计学意义,3-AB预处理+休克组血浆和肠系膜上动脉组织匀浆中NO含量虽较休克组稍有降低,但两组问比较差异无统计学意义.结论 PARP参与了大鼠失血性休克后血管低反应性的发生.     

预处理对失血性休克大鼠肠系膜上动脉收缩反应性的影响

目的评价不同条件预处理对失血性休克血管功能的保护作用机制。方法采用大鼠失血性休克模型，观察不同条件预处理（失血预处理及吡哪地尔预处理）对由激动剂[去甲肾上腺素（NE）]诱导在体大鼠肠系膜上动脉（SMA）收缩反应性的影响。结果5％～10％失血预处理对休克大鼠存活率无显著改善，而吡哪地尔可明显改善休克后120min的大鼠存活率。5％失血预处理30min可上调大鼠休克后0min使用NE前后的股动脉压变化，而预处理24h可降低大鼠休克前股动脉压变化，但对休克后使用NE前后的股动脉压变化无明显影响；吡哪地尔预处理1h可降低大鼠休克前使用NE前后的股动脉压变化，而预处理24h对大鼠休克后的股动脉压变化均无影响。5％失血预处理24h可改善休克后120min大鼠SMA对NE的收缩反应性，使用NE后的管径变化显著增加（P〈0．01）；吡哪地尔预处理1h和24h可明显降低大鼠休克前SMA对NE的收缩反应性，使用NE后的管径变化显著降低（P均〈0．05），但吡哪地尔预处理（1h和24h）均可改善休克后120min大鼠SMA对NE的收缩反应性，使用NE后的管径变化显著增加（P均〈0．05）；而格列苯脲可部分取消吡哪地尔的这一作用。结论吡哪地尔预处理24h可降低休克前大鼠SMA对NE的收缩反应性，并可改善休克后120min大鼠SMA对NE的收缩反应性，且使休克大鼠存活率明显提高。吡哪地尔预处理24h对失血性休克大鼠血管功能的保护作用可能与ATP敏感性钾通道有关。     

血管生成素-1,2经p38丝裂原活化蛋白激酶调节失血性休克血管低反应性

目的 观察p38丝裂原活化蛋白激酶(p38MAPK)在血管生成素-1(Ang-1)、血管生成素-2(Ang-2)调节失血性休克大鼠血管反应性双相变化中的作用.方法 观察失血性休克后不同时间点肠系膜上动脉(SMA)中p38MAPK蛋白表达和磷酸化变化,p38MAPK抑制剂对Ang-1和Ang-2调节缺氧早期和晚期血管反应性作用的影响,以及给予Ang-1、Ang-2和Tie-1抑制剂后缺氧血管内皮细胞(VEC)和血管平滑肌细胞(VSMC)混合细胞中p38MAPK蛋白表达和磷酸化变化.结果 失血性休克后p38MAPK磷酸化水平显著增高;p38MAPK抑制剂可显著改善缺氧4 h血管低反应性并拮抗Ang-2进一步降低缺氧4 h血管低反应性的作用;Ang-1和Tie-2抑制剂可显著抑制缺氧4 h的p38MAPK磷酸化增高(P<0.01).结论 p38MAPK参与了Ang-1和Ang-2对休克晚期血管低反应性的调节,但不是休克早期血管高反应性的主要调节分子.     

Changes of Rho kinase activity after hemorrhagic shock and its role in shock-induced biphasic response of vascular reactivity and calcium sensitivity

The purpose of the present study is to investigate the changes of Rho kinase activity and its role in biphasic response of vascular reactivity and calcium sensitivity after hemorrhagic shock. The vascular reactivity and calcium sensitivity of superior mesenteric artery (SMA) from hemorrhagic shock rats were determined via observing the contraction initiated by norepinephrine (NE) and Ca under depolarizing conditions (120 mmol/L K) with isolated organ perfusion system. At same time, Rho kinase activity in mesenteric artery was measured, and the effects of Rho kinase activity-regulating agents, angiotensin II (Ang-II), insulin, and Y-27632, on vascular reactivity and calcium sensitivity were also observed. The results indicated that the vascular reactivity and calcium sensitivity were increased at early shock (immediate and 30 min after shock) and decreased at late shock (1 and 2 h after shock). The maximal contractions of NE and Ca were significantly increased (P < 0.05 or P < 0.01) at early shock. But they were significantly decreased at late shock (P < 0.05 or P < 0.01). Rho kinase activity was significantly increased at early shock (immediate after shock) (P < 0.05) but significantly decreased at 1 and 2 h after shock (P < 0.05 or P < 0.01). It was positively correlated with the changes of vascular reactivity and calcium sensitivity. Insulin decreased the increased contractile response of SMA to NE and Caat early shock (P < 0.05 or P < 0.01). Angiotensin II increased the decreased contractile response of SMA to NE and Ca at 2-h shock (P < 0.05 or P < 0.01); Y-27632, Rho kinase-specific antagonist, decreased the contractile response of SMA to NE and Ca at 2-h shock, and abolished Ang-II induced the increase of vascular reactivity and calcium sensitivity. The results suggest that Rho kinase may be involved in the biphasic change of vascular reactivity and calcium sensitivity after hemorrhagic shock. Rho kinase may regulate vascular reactivity through the regulation of calcium sensitivity. Rho kinase-regulating agents may have some beneficial effects on shock-induced vascular hyporeactivity.     

The role of calcium desensitization in vascular hyporeactivity and its regulation after hemorrhagic shock in the rat

The objectives of the present study were to investigate the role of calcium desensitization in vascular hyporeactivity, and the regulatory effects of Rho-kinase, protein kinase C (PKC), and protein kinase G (PKG) on calcium sensitivity. The vascular reactivity and calcium sensitivity with superior mesenteric artery (SMA) from hemorrhagic shock rat were observed by measuring the contraction initiated by norepinephrine (NE) and Ca2+ under depolarizing conditions (120 mmol/L K) in an isolated organ perfusion system. Angiotensin II (Ang-II) and Fasudil, the Rho-kinase agonist and inhibitor, phorbol 12-myristate 13-acetate (PMA) and staurosporine, the PKC agonist and inhibitor, 8Br-cGMP and KT-5823, the PKG agonist and inhibitor, and Calyculin A, myosin light chain phosphatase (MLCP) inhibitor were used as tool agents. The results indicated that vascular reactivity and calcium sensitivity were decreased after hemorrhagic shock. The cumulative dose-response curve of SMA to NE and Ca2+ after shock was shifted to the right. Ang-II (10 mol/L) could improve the decreased vascular reactivity by increasing the calcium sensitivity of SMA, and insulin (100 nmol/L) could further decrease the vascular reactivity by decreasing the calcium sensitivity of SMA. These results suggested that the vasculature after shock was desensitized to calcium, which played an important role in the onset of vascular hyporeactivity after shock. PMA and KT-5823 could increase the sensitivity of SMA to Ca2+ and made the cumulative dose-response curve shift to the left. In contrast, Fasudil, staurosporine, and 8Br-cGMP decreased the sensitivity of SMA to Ca2+ and made the cumulative dose-response curve of Ca2+ shift to the right. Calyculin A (10 mol/L) pretreatment further enhanced Ang-II, and PMA induced increase of calcium sensitivity, yet weakened the 8Br-cGMP-induced decrease of calcium sensitivity. Taken together, the data suggest that Rho-kinase, PKC, and PKG are involved in the regulation of calcium sensitivity of vascular smooth muscle after hemorrhagic shock, and their regulatory effects on calcium sensitivity of vasculature are possibly related to MLCP.     

羟乙基淀粉对失血性休克血管反应性的影响

目的 观察羟乙基淀粉（HEs）对失血性休克血管反应性的影响，并探讨其机制。方法 40只SD大鼠，雌雄不限，按照随机数字表法分为正常组、休克组、复方氯化钠（即林格液，SC）组、HES130／0．4组和HES200／0．5组，每组8只。股动脉放血至大鼠平均动脉压（MAP）为40mmHg（1mmHg=0．133kPa），维持30min后分别输注溶液，使MAP升至70mmHg，并维持60min；观察各用药组在60min内维持MAP70mmHg所需补液量。分别在休克前及休克30、60和90min静脉注射去甲肾上腺素（NE）2μg／kg，观察液体对NE升压反应的影响；取动脉血测定血浆一氧化氮（NO）和一氧化氮合酶（NOS）含量。结果各用药组之间维持MAP70mmHg所需补液量比较差异均有显著性（P均〈0．01），其中HES200／0．5组所需补液量最少，HES130／0．4组次之，SC组最多。休克90min时，HES130／0．4组、HES200／0．5组MAP升高幅度均明显高于SC组（P均〈0．05），血浆NO和NOS含量均明显低于SC组（P〈0．05或P〈0．01）。结论 HES130／0．4和HES200／0．5可通过降低血浆NO和NOS含量，从而改善休克大鼠的血管反应性。     

Mechanisms of Rho kinase regulation of vascular reactivity following hemorrhagic shock in rats

Our previous research showed that Rho kinase took part in the regulation of vascular hyporeactivity after shock. The objective of the present study was to investigate its mechanism. With isolated superior mesenteric artery (SMA) from hemorrhagic shock rats, we studied the relationship of Rho kinase regulating vascular reactivity to calcium sensitivity and myosin light chain phosphatase (MLCP) and myosin light chain kinase (MLCK). The vascular reactivity and calcium sensitivity of SMA were observed by measuring the contraction initiated by accumulative norepinephrine (NE) and calcium under depolarizing condition (120 mM K(+)) with an isolated organ perfusion system. Hypoxia-treated vascular smooth muscle cells (VSMCs) were used to study the effects of Rho kinase on the activity of MLCP and MLCK and the phosphorylation of 20-kDa myosin light chain (MLC(20)). Myosin light chain (20 kDa) phosphorylation of VSMC in mesenteric artery was detected by immunoprecipitation and Western blotting. The activity of MLCP and MLCK was assayed by enzymatic catalysis. The contractile response of VSMC was measured by the ratio of accumulative infiltration of fluorescent isothiocyanate-conjugated bovine serum albumin through transwell. The results indicated that the vascular reactivity and calcium sensitivity of SMA to NE and calcium following hemorrhagic shock and the contractile response of VSMC to NE following hypoxia were significantly decreased. Angiotensin II (Ang-II), the Rho kinase stimulator, significantly improved hypoxia or hemorrhagic shock-induced decrease of vascular reactivity and calcium sensitivity. These effects of Ang-II on vascular reactivity were abolished by Y-27632, the specific Rho kinase inhibitor. Calyculin A, the MLCP inhibitor, further enhanced Ang-II-induced increase of calcium sensitivity, but ML-9, the MLCK inhibitor, had no effect. Further studies showed Ang-II reversed the hypoxia-induced increase of MLCP activity and increased the hypoxia-induced decrease of MLC(20) phosphorylation in VSMC. It was suggested that Rho kinase played an important role in the regulation of vascular reactivity after hemorrhagic shock. The mechanisms may be related to its calcium sensitivity regulation. Rho kinase up-regulates calcium sensitivity of VSMC possibly through inhibiting the activity of MLCP and increasing the phosphorylation of MLC(20).     

Mesenteric lymph return is an important contributor to vascular hyporeactivity and calcium desensitization after hemorrhagic shock

Vascular hyporeactivity is an important factor in irreversible shock, whereas calcium desensitization is one of the mechanisms of vascular hyporeactivity, and the intestinal lymphatic pathway plays an important role in multiple organ injury after severe hemorrhagic shock (HS). In this study, our aims were to determine the effects of mesenteric lymph on vascular reactivity during HS and the mechanisms involved. First, the in vivo pressor response was observed by intravenous injection of norepinephrine (3 μg/kg) at different time points after HS. We found that mesenteric lymph duct ligation (MLDL) and mesenteric lymph drainage (MLD) enhanced the pressor response at multiple time points after shock. Next, vascular reactivity and calcium sensitivity in superior mesenteric artery (SMA) vascular rings were examined using an isolated organ perfusion system. Vascular reactivity and calcium sensitivity were higher for SMA rings from rats that had undergone HS plus MLDL or MLD that those from rats that had undergone only HS. The effects of MLDL and MLD on vascular reactivity and calcium sensitivity were significantly increased following incubation with the calcium sensitizer angiotensin II and were reduced after incubation with the calcium sensitivity inhibitor insulin. When SMA rings from normal rats were incubated with mesenteric lymph from rats subjected to HS, lymph obtained 0 to 0.5 h after shock enhanced vascular reactivity and calcium sensitivity, whereas lymph obtained 1 to 3 h after shock blunted these effects. We finally examined vascular reactivity and calcium sensitivity in HS rats subjected to MLD at 0 to 3 h or 1 to 3 h after shock. We found that contractile activity of SMAs in response to norepinephrine or Ca was higher in HS rats subjected to MLD at 1 to 3 h after shock compared with rats subjected to MLD at 0 to 3 h after shock. These results indicate that mesenteric lymph return plays an important role in biphasic changes in vascular reactivity during HS. Even more importantly, mesenteric lymph 1 h after shock was an important contributor to vascular hyporeactivity, and its mechanism of action was related to calcium desensitization. Targeting lymph may therefore have therapeutic potential in the treatment of severe shock-induced hypotension.