Strunk V, Hahnenkamp K, Schneuing M, Fischer L G, Rich G F
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Anesth Analg. 2001 Mar;92(3):681-7. doi: 10.1097/00000539-200103000-00025.
Nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) mediates hypotension and metabolic derangements in sepsis. We hypothesized that selective iNOS-inhibition would prevent hypotension in septic rats without inhibiting endothelium-dependent vasodilation caused by the physiologically important endothelial NOS. Rats were exposed to lipopolysaccharide (LPS) for 6 h and the selective iNOS-inhibitor L-N6-(1-iminoethyl)-lysine (L-NIL), the nonselective NOS-inhibitor N:(G)-nitro-L-arginine methyl ester (L-NAME), or control. Mean arterial pressure (MAP) and vasodilation to acetylcholine (ACh, endothelium-dependent), sodium nitroprusside (SNP, endothelium-independent), and isoproterenol (ISO, endothelium-independent beta agonist) were determined. Exhaled NO, nitrate/nitrite-(NOx) levels, metabolic data, and immunohistochemical staining for nitrotyrosine, a tracer of peroxynitrite-formation were also determined. In control rats, L-NAME increased MAP, decreased the response to ACh, and increased the response to SNP, whereas L-NIL did not alter these variables. LPS decreased MAP by 18% +/- 1%, decreased vasodilation (ACh, SNP, and ISO), increased exhaled NO, NOx, nitrotyrosine staining, and caused acidosis and hypoglycemia. L-NIL restored MAP and vasodilation (ACh, SNP, and ISO) to baseline and prevented the changes in exhaled NO, NOx, pH, and glucose levels. In contrast, L-NAME restored MAP and SNP vasodilation, but did not alter the decreased response to ACh and ISO or prevent the changes in exhaled NO and glucose levels. Finally, L-NIL but not L-NAME decreased nitrotyrosine staining in LPS rats. In conclusion, L-NIL prevents hypotension and metabolic derangements in septic rats without affecting endothelium-dependent vasodilation whereas L-NAME does not.
Sepsis causes hypotension and metabolic derangements partly because of increased nitric oxide. Selective inhibition of nitric oxide produced by the inducible nitric oxide synthase enzyme prevents hypotension and attenuates metabolic derangements while preserving the important vascular function associated with endothelium-dependent vasodilation in septic rats.
诱导型一氧化氮合酶（iNOS）产生的一氧化氮（NO）介导脓毒症中的低血压和代谢紊乱。我们假设选择性抑制iNOS可预防脓毒症大鼠的低血压，同时不抑制由生理上重要的内皮型一氧化氮合酶引起的内皮依赖性血管舒张。将大鼠暴露于脂多糖（LPS）6小时，并给予选择性iNOS抑制剂L-N6-（1-亚氨基乙基）-赖氨酸（L-NIL）、非选择性一氧化氮合酶抑制剂N：（G）-硝基-L-精氨酸甲酯（L-NAME）或作为对照。测定平均动脉压（MAP）以及对乙酰胆碱（ACh，内皮依赖性）、硝普钠（SNP，非内皮依赖性）和异丙肾上腺素（ISO，非内皮依赖性β激动剂）的血管舒张反应。还测定呼出的NO、硝酸盐/亚硝酸盐-（NOx）水平、代谢数据以及过氧亚硝酸盐形成的示踪剂硝基酪氨酸的免疫组织化学染色。在对照大鼠中，L-NAME升高MAP，降低对ACh的反应，并增加对SNP的反应，而L-NIL未改变这些变量。LPS使MAP降低18%±1%，降低血管舒张（ACh、SNP和ISO），增加呼出的NO、NOx、硝基酪氨酸染色，并导致酸中毒和低血糖。L-NIL使MAP和血管舒张（ACh、SNP和ISO）恢复至基线，并防止呼出的NO、NOx、pH和葡萄糖水平的变化。相比之下，L-NAME恢复了MAP和SNP血管舒张，但未改变对ACh和ISO降低的反应，也未防止呼出的NO和葡萄糖水平的变化。最后，L-NIL而非L-NAME降低了LPS大鼠中的硝基酪氨酸染色。总之，L-NIL可预防脓毒症大鼠的低血压和代谢紊乱，而不影响内皮依赖性血管舒张，而L-NAME则不能。
脓毒症导致低血压和代谢紊乱部分是因为一氧化氮增加。选择性抑制诱导型一氧化氮合酶产生的一氧化氮可预防低血压并减轻代谢紊乱，同时保留脓毒症大鼠中与内皮依赖性血管舒张相关的重要血管功能。
