Levy B, Valtier M, de Chillou C, Bollaert P E, Cane D, Mallie J P
Service de Réanimation Médicale, Hôpital Central, Nancy, France.
Shock. 1999 Feb;11(2):98-103. doi: 10.1097/00024382-199902000-00005.
Overproduction of NO by an inducible NO synthase (iNOS) plays a role in the pathophysiology of septic shock. In such situations, NOS inhibition might be of therapeutic value, although detrimental side effects possibly related to inhibition of constitutive NOS have been reported. The use of L-canavanine, a selective inhibitor of iNOS, might be more suitable. The aim of the study was to compare in a rodent endotoxic shock the effects of saline (2 mL/h), N(G)-methyl-L-arginine(L-NMMA) (10 mg/kg/h) and L-canavanine (100 mg/kg/h) on muscle intracellular pH (pHi) and intracellular bioenergetic patterns (ATP, phosphocreatine/inorganic phosphate ratio) using in vivo 31P magnetic resonance spectroscopy (31P MRS). Three groups of anesthetized, mechanically ventilated and paralyzed rats received an intravenous infusion of 15 mg/kg of endotoxin. A fourth time-matched control group (n = 8) received 2 mL/h of saline. Mean arterial pressure, femoral blood flow, arterial blood gases, lactate, nitrate level, and 31P nuclear magnetic resonance (31P MRS) measurements were acquired at onset (T = 0), 90 min (T = 90), and 180 min (T180) after the endotoxin challenge. Femoral oxygen delivery was calculated as the product of femoral blood flow (mL/min) and arterial oxygen content. Endotoxin induced a marked decrease in arterial pressure and femoral oxygen delivery and an increase in lactate level. Intracellular pH and phosphocreatine/inorganic phosphate ratio decreased. ATP level did not change. Both L-NMMA and L-canavanine reversed the endotoxin-induced decrease in arterial pressure. L-NMMA attenuated the decrease in femoral oxygen delivery and the increase in lactate level while these were corrected by L-canavanine. Considering 31P MRS derived bioenergetic indices, the endotoxin-induced decrease in pHi and Pcr/Pi was attenuated by L-NMMA and corrected by L-canavanine. In conclusion, in a rodent model of endotoxinic shock, the continuous infusion of L-canavanine, a selective iNOS inhibitor, improved the systemic hemodynamic parameters and the intracellular bio-energetic patterns estimated by in vivo 31P MRS. To the contrary, the continuous infusion of both constitutive and inducible NOS inhibitor L-NMMA was not followed by the same achievement.
诱导型一氧化氮合酶（iNOS）产生过量的一氧化氮（NO）在脓毒性休克的病理生理学中起作用。在这种情况下，抑制一氧化氮合酶可能具有治疗价值，尽管已有报道称可能存在与抑制组成型一氧化氮合酶相关的有害副作用。使用L-刀豆氨酸，一种iNOS的选择性抑制剂，可能更合适。本研究的目的是在啮齿动物内毒素休克模型中，使用体内31P磁共振波谱（31P MRS）比较生理盐水（2 mL/h）、N（G）-甲基-L-精氨酸（L-NMMA）（10 mg/kg/h）和L-刀豆氨酸（100 mg/kg/h）对肌肉细胞内pH值（pHi）和细胞内生物能量模式（三磷酸腺苷（ATP）、磷酸肌酸/无机磷酸比值）的影响。三组麻醉、机械通气和麻痹的大鼠接受静脉注射15 mg/kg内毒素。第四个时间匹配的对照组（n = 8）接受2 mL/h生理盐水。在内毒素攻击后0分钟（T = 0）、90分钟（T = 90）和180分钟（T180）采集平均动脉压、股血流量、动脉血气、乳酸、硝酸盐水平和31P核磁共振（31P MRS）测量值。股氧输送量计算为股血流量（mL/min）与动脉血氧含量的乘积。内毒素导致动脉压和股氧输送量显著降低，乳酸水平升高。细胞内pH值和磷酸肌酸/无机磷酸比值降低。ATP水平未改变。L-NMMA和L-刀豆氨酸均逆转了内毒素引起的动脉压降低。L-NMMA减轻了股氧输送量的降低和乳酸水平的升高，而L-刀豆氨酸纠正了这些变化。考虑到31P MRS得出的生物能量指标，L-NMMA减轻了内毒素引起的pHi和磷酸肌酸/无机磷酸比值的降低，L-刀豆氨酸纠正了这些变化。总之，在啮齿动物内毒素休克模型中，持续输注选择性iNOS抑制剂L-刀豆氨酸可改善全身血流动力学参数以及通过体内31P MRS评估的细胞内生物能量模式。相反，持续输注组成型和诱导型一氧化氮合酶抑制剂L-NMMA并未取得同样的效果。
