Simper D, Strobel W M, Linder L, Haefeli W E
Department of Internal Medicine, University Hospital, Basel, Switzerland.
Cardiovasc Res. 1995 Dec;30(6):960-4.
The detrimental haemodynamic changes observed in septicaemia are generalised vasodilation, arterial hypotension, and hyporesponsiveness to vasopressor compound, all of which could be explained by the release of an endogenous vasodilator. Experimental and clinical evidence suggests that tumour necrosis factor-alpha (TNF) induces the expression of vascular nitric oxide (NO) synthase within hours and that NO released from smooth muscle cells could be involved in the pathogenesis of septic shock. The aim of this study was to investigate the role of NO in the vascular effects of TNF.
Using the dorsal hand vein compliance technique, the effect of the NO synthase inhibitor L-NG-monomethyl-arginine (L-NMMA) on alpha 1-adrenergic responsiveness (phenylephrine 1.25-8000 ng/min) was studied after prolonged local venous infusion of TNF (8.7 micrograms in 5 h) in 9 volunteers and in 6 volunteers without previous cytokine exposure.
Mean (+/- s.e.) maximum phenylephrine constriction (Emax) was 73 +/- 6% and log dose-rates exerting 50% of Emax (log ED50) were 3.2 +/- 0.09 (geometric mean: 1535 ng/min). Local co-administration of L-NMMA at a dose sufficiently high to block NO formation (3.4 mumol/min) increased venous sensitivity to phenylephrine threefold (log ED50 2.8 +/- 0.1, P < 0.015; geometric mean: 574 ng/min) whereas Emax was similar (73 +/- 5%). In the controls the phenylephrine dose-response relationship remained unaffected by simultaneous administration of L-NMMA.
As no basal release of NO occurs in hand veins without previous exposure to TNF these results provide direct evidence for induction of NO formation in the human vasculature and consecutive resistance to alpha-adrenergic venoconstriction. NO might, therefore, be a key mediator of haemodynamic impairment in humans under conditions with known elevations of circulating TNF, such as a septic shock.
败血症中观察到的有害血流动力学变化包括全身血管舒张、动脉低血压以及对血管加压化合物反应性降低，所有这些都可以用内源性血管舒张剂的释放来解释。实验和临床证据表明，肿瘤坏死因子-α（TNF）在数小时内诱导血管一氧化氮（NO）合酶的表达，并且平滑肌细胞释放的NO可能参与脓毒性休克的发病机制。本研究的目的是探讨NO在TNF血管效应中的作用。
采用手背静脉顺应性技术，在9名志愿者和6名未接触过细胞因子的志愿者中，长时间局部静脉输注TNF（5小时内8.7微克）后，研究NO合酶抑制剂L-NG-单甲基精氨酸（L-NMMA）对α1-肾上腺素能反应性（去氧肾上腺素1.25 - 8000纳克/分钟）的影响。
平均（±标准误）最大去氧肾上腺素收缩（Emax）为73±6%，产生50% Emax的对数剂量率（对数ED50）为3.2±0.09（几何平均数：1535纳克/分钟）。以足以阻断NO形成的高剂量（3.4微摩尔/分钟）局部联合给予L-NMMA，可使静脉对去氧肾上腺素的敏感性增加三倍（对数ED50 2.8±0.1，P < 0.015；几何平均数：574纳克/分钟），而Emax相似（73±5%）。在对照组中，去氧肾上腺素剂量-反应关系不受同时给予L-NMMA的影响。
由于在未接触过TNF的手部静脉中未发生NO的基础释放，这些结果为人类血管系统中NO形成的诱导以及随后对α-肾上腺素能静脉收缩的抵抗提供了直接证据。因此，在已知循环TNF升高的情况下，如脓毒性休克，NO可能是人类血流动力学损害的关键介质。
