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Effects of N^G-nitro-L-arginine on hemodynamic changes in endotoxin shock

N^G-硝基-L-精氨酸对内毒素休克血流动力学变化的影响

基本信息

批准号：
05671252
负责人：
MITAKA Chieko
金额：
$ 1.47万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1995
项目状态：
已结题

项目摘要

1.Effects of TNF-alpha on hemodynamic changes and circulating endothelium-derived vasoactive factors in dogsAfter administration of TNF-alpha, mean arterial pressure and cardiac index significantly decreased, whereas systemic (SVRI) and pulmonary (PVRI) vascular resistance index increased. Plasma levels of ET-1, ET-3, NOx, and 6-keto-PGF_<1alpha> significantly (P<0.0) increased at 1 h. L-NNA or indomethacin blocked TNF-alpha induced hypotension and remarkably increased SVRI but did not affect decreased cardiac index. Our data suggest that endogenous ET-1 may partly contribute to TNF-alpha -induced increases in SVRI and PVRI,against which ET-3, NO,and prostacyclin may function as compensatory vasodilators.2.Effects of nitric oxide synthase inhibitor on hemodynamic change and O_2 delivery in septic dogsInfusion of LPS (250ng/kg/min) for 2 h decreased mean arterial pressure over 1-4 h. Although L-NNA (10mg/kg) blocked LPS-induced hypotension, it decreased cardiac index oxygen delivery index, arterial pH,and arterial PO_2 and increased systemic vascular resistance index in the presence or absence of LPS.Administration of D-NNA (10mg/kg) alone caused fewer hemodynamic effects (increased systemic vascular resistance index and decreased cardiac index) than L-NNA alone. Our study provides evidence that L-NNA prevents endotoxin-induced hypotension but decreases cardiac output and oxygen delivery, effects that may, in part, be due a nonspecific NO synthase-independent event. Thus clinical use of NO synthase inhibitors for the treatment of septic shock should be cautiously considered. Infusion of aminoguanidine (AG,5mg/kg/h, for 2 h), a putative inhibitor for iNOS,prevented LPS-induced hypotension and did not decrease cardiac index. Thus, AG may have some possibility for the treatment of septic shock.

1. TNF-α对犬血流动力学和循环内皮源性血管活性因子的影响TNF-α给药后，犬平均动脉压和心脏指数显著降低，而体循环（SVRI）和肺循环（PVRI）血管阻力指数升高。血浆ET-1、ET-3、NOx和6-keto-PGF_2水平<1alpha>在1h时显著升高（P<0.0）。L-NNA或吲哚美辛阻断TNF-α诱导的低血压，并显著增加SVRI，但对降低的心脏指数无影响。结果提示，内源性ET-1可能参与TNF-α引起的SVRI和PVRI的升高，ET-3、NO和前列环素可能起代偿性扩血管作用。2.一氧化氮合酶抑制剂对脓毒症犬血流动力学和氧供的影响L-NNA（10 mg/kg）虽能阻断LPS引起的低血压，但能降低心指数氧输送指数、动脉血pH值和动脉血PO_2，增加体循环血管阻力指数，而D-NNA（10 mg/kg）单独给药的血流动力学效应（增加体循环血管阻力指数和降低心指数）较L-NNA单独给药的小。我们的研究提供了证据表明，L-NNA预防内毒素诱导的低血压，但减少心输出量和氧输送，这种影响可能部分是由于非特异性NO酶非依赖性事件。因此，临床应用NO合酶抑制剂治疗感染性休克应慎重考虑。氨基胍（AG，5 mg/kg/h，持续2小时），一种假定的iNOS抑制剂，可预防LPS诱导的低血压，且不降低心脏指数。因此，AG有可能用于治疗感染性休克。