Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia.
Crit Care Med. 2012 Aug;40(8):2368-75. doi: 10.1097/CCM.0b013e3182514be9.
Nitric oxide plays an important role in the control of renal blood flow and renal function. In sepsis, increased levels of inducible nitric oxide synthase produce excessive nitric oxide, which may contribute to the development of acute kidney injury. We, therefore, examined the effects of intrarenal infusion of selective inducible nitric oxide synthase inhibitors in a large animal model of hyperdynamic sepsis in which acute kidney injury occurs in the presence of increased renal blood flow.
Prospective crossover randomized controlled interventional studies.
University-affiliated research institute.
Twelve unilaterally nephrectomized Merino ewes.
Infusion of a selective (1400W) and a partially selective inducible nitric oxide synthase inhibitor (aminoguanidine) into the renal artery for 2 hrs after the induction of sepsis, and comparison with a nonselective inhibitor (Nω-nitro-L-arginine methyl ester).
In sheep with nonhypotensive hyperdynamic sepsis, creatinine clearance halved (32 to 16 mL/min, ratio [95% confidence interval] 0.51 [0.28-0.92]) despite increased renal blood flow (241 to 343 mL/min, difference [95% confidence interval] 102 [78-126]). Infusion of 1400W did not change renal blood flow, urine output, or creatinine clearance, whereas infusion of Nω-nitro-L-arginine methyl ester and a high dose of aminoguanidine normalized renal blood flow, but did not alter creatinine clearance.
In hyperdynamic sepsis, intrarenal infusion of a highly selective inducible nitric oxide synthase inhibitor did not reduce the elevated renal blood flow or improve renal function. In contrast, renal blood flow was reduced by infusion of a nonselective NOS inhibitor or a high dose of a partially selective inducible nitric oxide synthase inhibitor. The renal vasodilatation in septic acute kidney injury may be due to nitric oxide derived from the endothelial and neural isoforms of nitric oxide synthase, but their blockade did not restore renal function.
一氧化氮在控制肾血流和肾功能方面发挥着重要作用。在脓毒症中，诱导型一氧化氮合酶水平升高会产生过多的一氧化氮，这可能导致急性肾损伤的发生。因此，我们在存在肾血流增加的高动力性脓毒症大型动物模型中，研究了肾内输注选择性诱导型一氧化氮合酶抑制剂的作用。
前瞻性交叉随机对照干预研究。
大学附属研究所。
12 只单侧肾切除的美利奴羊。
在脓毒症诱导后 2 小时内将选择性（1400W）和部分选择性诱导型一氧化氮合酶抑制剂（氨基胍）输注到肾动脉中，并与非选择性抑制剂（Nω-硝基-L-精氨酸甲酯）进行比较。
在非低血压性高动力性脓毒症的绵羊中，尽管肾血流增加（241 至 343 毫升/分钟，差异[95%置信区间]102[78-126]），但肌酐清除率减半（32 至 16 毫升/分钟，比值[95%置信区间]0.51[0.28-0.92]）。1400W 输注并未改变肾血流、尿量或肌酐清除率，而 Nω-硝基-L-精氨酸甲酯和高剂量氨基胍的输注则使肾血流正常化，但并未改变肌酐清除率。
在高动力性脓毒症中，肾内输注高度选择性诱导型一氧化氮合酶抑制剂并未降低升高的肾血流或改善肾功能。相反，输注非选择性 NOS 抑制剂或高剂量部分选择性诱导型一氧化氮合酶抑制剂可降低肾血流。脓毒症急性肾损伤中的肾血管舒张可能是由于来源于内皮型和神经型一氧化氮合酶的一氧化氮所致，但阻断它们并不能恢复肾功能。
