Myers T P, Myers P R, Adams H R, Parker J L
Dalton Cardiovascular Research Center and Department of Medicine, University of Missouri, Columbia 65211, USA.
Shock. 1999 Jun;11(6):436-42.
Endotoxemia secondary to gram-negative sepsis has been shown to inhibit endothelium-dependent vasomotion in numerous vascular beds, including guinea pig aortae and coronary arteries. We tested the hypothesis that in vivo endotoxin impairs endothelium-dependent nitric oxide-mediated relaxation responses of pulmonary arteries isolated from guinea pigs given intraperitoneal injections of Escherichia coli endotoxin lipopolysaccharide (LPS) or saline (control) 16 h before sacrifice. Pulmonary rings from the main artery and primary branches were isolated and studied in vitro using conventional isometric techniques. Interestingly, endotoxemia resulted in enhanced pulmonary artery relaxation in response to the endothelium-dependent receptor agonists acetylcholine (10(-10) -10(-5) M) and adenosine diphosphate (ADP; 10(-9) -10(-5) M), as compared with control responses (p < .05). Nitric oxide synthase inhibitors N-monomethyl-L-arginine (300 microM) and N-nitro-L-arginine methyl ester (100 microm) reduced acetylcholine- and adenosine diphosphate-mediated relaxation in both groups (p < .05); however, vasodilation responses in arteries from LPS animals remained enhanced relative to those of control arteries. In contrast to nitric oxide synthase inhibitors, the cyclooxygenase inhibitor indomethacin markedly inhibited acetylcholine- and adenosine diphosphate-mediated relaxation responses of pulmonary arteries isolated from LPS-treated animals (p < .05) but not control arteries; indomethacin effectively reversed LPS-induced enhanced vasodilation of pulmonary arteries. Relaxation responses to the receptor-independent calcium ionophore (A23187) and to the direct smooth muscle vasodilator sodium nitroprusside (+ N-nitro-L-arginine methyl ester) were not significantly altered by LPS treatment (p > .05). These data suggest that in pulmonary arteries, unlike aortae and coronary arteries isolated from the same model, in vivo LPS enhances agonist-mediated endothelium-dependent vasodilation responses to acetylcholine and adenosine diphosphate. Underlying mechanisms appear to involve increased dependency upon vasodilator prostanoids and decreased dependency on nitric oxide synthesis/release for LPS-induced alterations in pulmonary relaxation responses.
革兰氏阴性菌败血症继发的内毒素血症已被证明会抑制包括豚鼠主动脉和冠状动脉在内的众多血管床中内皮依赖性血管运动。我们检验了这样一个假设：在体内，内毒素会损害从腹腔注射大肠杆菌内毒素脂多糖（LPS）或生理盐水（对照）16小时后处死的豚鼠分离出的肺动脉的内皮依赖性一氧化氮介导的舒张反应。从主肺动脉和一级分支分离出肺血管环，并使用传统的等长技术进行体外研究。有趣的是，与对照反应相比，内毒素血症导致肺动脉对内皮依赖性受体激动剂乙酰胆碱（10^(-10) - 10^(-5) M）和二磷酸腺苷（ADP；10^(-9) - 10^(-5) M）的舒张增强（p < 0.05）。一氧化氮合酶抑制剂N-单甲基-L-精氨酸（300 microM）和N-硝基-L-精氨酸甲酯（100 microM）降低了两组中乙酰胆碱和二磷酸腺苷介导的舒张（p < 0.05）；然而，LPS处理动物的动脉中的血管舒张反应相对于对照动脉仍增强。与一氧化氮合酶抑制剂相反，环氧化酶抑制剂吲哚美辛显著抑制了从LPS处理动物分离出的肺动脉的乙酰胆碱和二磷酸腺苷介导的舒张反应（p < 0.05），但对对照动脉无此作用；吲哚美辛有效逆转了LPS诱导的肺动脉血管舒张增强。LPS处理对受体非依赖性钙离子载体（A23187）和直接平滑肌血管舒张剂硝普钠（+ N-硝基-L-精氨酸甲酯）的舒张反应无显著改变（p > 0.05）。这些数据表明，在肺动脉中，与从同一模型分离出的主动脉和冠状动脉不同，体内LPS增强了激动剂介导的对乙酰胆碱和二磷酸腺苷的内皮依赖性血管舒张反应。潜在机制似乎涉及对血管舒张性前列腺素的依赖性增加以及对LPS诱导的肺舒张反应改变中一氧化氮合成/释放的依赖性降低。
