Bigendothelin-1 (1-21) fragment during early sepsis modulates tau, p38-MAPK phosphorylation and nitric oxide synthase activation
Bigendothelin-1 (1-21) fragment during early sepsis modulates tau, p38-MAPK phosphorylation and nitric oxide synthase activation
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DOI：
10.1007/s11010-005-6416-3
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发表时间：
2005-03-01
影响因子：
4.3
通讯作者：
Sharma, A
中科院分区：
文献类型：
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作者：
Brahmbhatt, S;Gupta, A;Sharma, A
早期我们已经证明，内皮素生物合成的抑制改善内毒素血症诱导的诱导型一氧化氮合酶（iNOS）的激活和p38-丝裂原活化蛋白激酶（pp 38-MAPK）的磷酸化。因此，在本研究中，我们测试的假设，激活内皮素（ET）-1的生物合成，在早期脓毒症使用bigET-1将上调诱导型一氧化氮合酶和影响心肌功能的大鼠。将雄性Sprague-Dawley大鼠（350-400 g）用Nembutal（R）（50 mg/kg，i. p.）和颈静脉、尾动脉（平均动脉压，MAP）和右颈动脉（前进到左心室，LV）插管。将大鼠随机分为生理盐水组、bigET-1组和bigET-1（22-38）C末端片段组。使用腹膜内注射从供体大鼠获得的盲肠接种物（200 mg/kg，在5 ml 5%无菌葡萄糖水中，D5 W）诱导脓毒症。假手术动物接受腹膜内注射D5 W（5 ml/kg）。于假手术或脓毒症诱导后0、2、6、12和24 h记录MAP和LVP并计算心脏动力学参数。在24 h时，在溶剂处理的脓毒症组中观察到LV等容舒张速率常数（tau）、LV舒张末期压（LVEDP）和速率压力乘积（RPP）显著升高。BigET-1显著增加假手术组和脓毒症组左室ET-1浓度。BigET-1在假手术和脓毒症动物中早在12 h就升高tau和LVEDP，并持续至24 h。而bigET-1（22-38）在脓毒症组24 h时升高了LVEDP，而在假手术组则没有。BigET-1在6、12和24 h均加重假手术和脓毒症动物的血浆一氧化氮副产物（NOx）水平。脓毒症24 h心肌iNOS水平升高。BigET-1显著上调心肌iNOS和pp 38-MAPK的表达。这些数据表明，在脓毒症诱导时ET-1底物可用性增加有助于舒张功能障碍、iNOS激活和p38-MAPK磷酸化。
Earlier we have demonstrated that inhibition of endothelin biosynthesis ameliorates endotoxemia-induced inducible nitric oxide synthase (iNOS) activation and phosphorylation of p38-mitogen activated protein kinase (pp38-MAPK). Therefore, in the present study, we tested the hypothesis that activation of endothelin (ET)-1 biosynthesis using bigET-1 during early sepsis would upregulate iNOS and affect myocardial function in the rat. Male Sprague-Dawley rats (350-400 g) were anesthetised using Nembutal (R) (50 mg/kg, i.p.) and jugular vein, tail artery (Mean arterial pressure, MAP) and right carotid arteries (advanced to left ventricle, LV) were cannulated. The rats were randomly divided into saline-, bigET-1- and C-terminal fragment of bigET-1(bigET-1(22-38))-treated groups. Sepsis was induced using i.p. injection of cecal inoculum obtained from a donor rat (200 mg/kg in 5 ml 5% sterile dextrose water, D5W). Sham animals received an i.p. injection of D5W (5 ml/kg). MAP and LVP were recorded and cardiodynamic parameters were calculated at 0, 2, 6, 12 and 24 h post sham or sepsis-induction. A significant elevation in LV isovolumic relaxation rate constant (tau), LV end diastolic pressure (LVEDP) and rate pressure product (RPP) was observed in vehicle-treated septic group at 24 h. BigET-1 significantly increased concentration of LV ET-1 both in sham and septic groups. BigET-1 elevated tau and LVEDP both in sham and septic animals as early as 12 h which persisted through 24 h. However, bigET-1(22-38) elevated LVEDP in septic group at 24 h but not in sham group. BigET-1 accentuated the levels of plasma nitric oxide byproduct (NOx) levels in both sham and septic animals at 6, 12 and 24 h. Sepsis increased myocardial iNOS at 24 h. BigET-1 significantly upregulated expression of myocardial iNOS and pp38-MAPK. The data suggest that increased substrate availability for ET-1 at the time of sepsis-induction contributes in diastolic dysfunction, iNOS activation and p38-MAPK phosphorylation.