Howes Laurence Guy, Brillante Divina Gracila
Griffith University and Bond University Medical Schools, Gold Coast Hospital, Department of Pharmacology and Therapeutics, Nerang St, Southport, Queensland 4215, Australia.
Expert Opin Investig Drugs. 2008 Oct;17(10):1573-80. doi: 10.1517/13543784.17.10.1573.
Tilarginine is L-N-monomethyl arginine (L-NMMA) or N(G)-monomethyl-L-arginine HCL, a non-selective inhibitor of nitric oxide synthase (NOS), which has been studied in the treatment of septic shock and cardiogenic shock complicating myocardial infarction. Despite strong evidence that excessive nitric oxide (NO) production plays a pivotal role in the pathogenesis of septic shock and may contribute to the pathogenesis of cardiogenic shock complicating myocardial infarction, outcome studies in these two disorders have proved disappointing. L-NMMA therapy was associated with an excess mortality, particularly at doses > 5 mg/(kg h), in septic shock whereas the effects of a lower dose (1 mg/(kg h)) in cardiogenic shock complicating myocardial infarction were neutral. The excess mortality in patients with septic shock was almost certainly the result of unfavourable haemodynamic changes induced by L-NMMA (decreased cardiac output, increased pulmonary vascular resistance and reduced tissue oxygen delivery) whereas the lack of benefit in patients with cardiogenic shock complicating myocardial infarction may have been because the dose of L-NMMA was too low. Further studies of L-NMMA at doses < 5 mg/(kg h) in conjunction with inotrope support may produce more beneficial results. Conversely, the use of a selective inducible NOS inhibitor to reduce the pathological effects of excessive NO production although leaving the beneficial effects of vascular NO production by endothelial NOS unaltered may prove to be of value.
替拉吉宁是L-N-单甲基精氨酸（L-NMMA）或盐酸N(G)-单甲基-L-精氨酸，一种一氧化氮合酶（NOS）的非选择性抑制剂，已被用于研究治疗脓毒性休克和心肌梗死并发的心源性休克。尽管有强有力的证据表明，过量一氧化氮（NO）生成在脓毒性休克发病机制中起关键作用，且可能促使心肌梗死并发的心源性休克发病，但针对这两种疾病的结局研究结果却令人失望。在脓毒性休克中，L-NMMA治疗与死亡率增加相关，尤其是剂量>5mg/（kg·h）时，而在心肌梗死并发的心源性休克中，较低剂量（1mg/（kg·h））的效果则不明显。脓毒性休克患者死亡率增加几乎肯定是L-NMMA引起的不良血流动力学变化（心输出量降低、肺血管阻力增加和组织氧输送减少）所致，而心肌梗死并发的心源性休克患者未获益处可能是因为L-NMMA剂量过低。对剂量<5mg/（kg·h）的L-NMMA联合使用血管活性药物进行进一步研究可能会产生更有益的结果。相反，使用选择性诱导型NOS抑制剂来减轻过量NO生成的病理效应，同时保留内皮型NOS产生血管NO的有益作用，可能被证明是有价值的。
