Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans
Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans
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DOI：
10.1161/01.cir.0000105764.22626.b1
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发表时间：
2004-01-20
期刊：
影响因子：
37.8
通讯作者：
Fliser, D
中科院分区：
文献类型：
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作者：
Kielstein, JT;Impraim, B;Fliser, D
内源性一氧化氮合酶（NOS）抑制剂不对称二甲基精氨酸（ADMA）的血药浓度升高与心血管疾病的发病率和死亡率以及肾脏疾病的进展有关。我们使用侵入性技术，即右心导管和菊粉/对氨基马尿酸清除率，评估了ADMA输注对健康受试者的全身心血管效应。血浆NO主要第二信使cGMP浓度降低（P < 0.05），心输出量显著降低（P < 0.05）（5.3 ± 0.4 vs 5.8 ± 0.6 L/min; P < 0.05 vs基线），全身血管阻力显著较高（1403+/-123 vs 1221+/-100 dyn . S . cm（-5）;相对于基线P < 0.05）。ADMA 0.25 mg· kg（-1）· min（-1）或N-G-硝基-L-精氨酸甲酯3 μg· kg（-1）· min（-1）（一种有效的合成NOS抑制剂，作用时间长）均导致有效肾血浆流量的减少（从670±40到596± 29 mL · min（-1）; P < 0.05）和肾血管阻力增加（从79+/-5到90+/-7 mm Hg。mL（-1）。min（-1）; P < 0.05）。ADMA可引起钠潴留和血压升高（P均< 0.05）。所观察到的ADMA在体循环中的作用持续，对应于23.5+/-6.8分钟的平均血浆半衰期，其由健康受试者的血浆ADMA衰减曲线计算。心输出量适度降低，有效肾血浆流量降低相当，同时全身血管阻力和血压增加，相关的方式。
Background - Increased blood concentrations of the endogenous nitric oxide synthase ( NOS) inhibitor asymmetrical dimethylarginine ( ADMA) have been linked to excess cardiovascular morbidity and mortality and to progression of renal disease. We evaluated systemic cardiovascular effects of ADMA infusion in healthy subjects using invasive techniques, ie, right heart catheter and inulin/para-aminohippurate clearance.Methods and Results - Plasma ADMA concentrations encountered in patients with cardiovascular diseases, ie, between 2 and 10 mumol/L, caused a significant (P < 0.05) decrease in concentrations of plasma cGMP, the main second messenger of NO. In addition, cardiac output was significantly lower (5.3 ± 0.4 versus 5.8 ± 0.6 L/min; P < 0.05 versus baseline), and systemic vascular resistance was significantly higher (1403+/-123 versus 1221+/- 100 dyn . s . cm(-5); P < 0.05 versus baseline). The infusion of 0.25 mg ADMA • kg(-1) • min(-1) or 3 μg N-G-nitro-L-arginine methyl ester • kg(-1) • min(-1), a potent synthetic NOS inhibitor with long action, resulted in a comparable decrease in effective renal plasma flow ( from 670±40 to 596± 29 mL • min(-1); P < 0.05) and an increase in renovascular resistance (from 79+/-5 to 90+/-7 mm Hg . mL(-1) . min(-1); P < 0.05). Moreover, administration of ADMA caused significant sodium retention and blood pressure increase (both P < 0.05). The observed effects of ADMA in the systemic circulation were sustained corresponding to a mean plasma half-life of 23.5+/-6.8 minutes, calculated from plasma ADMA decay curves in healthy subjects.Conclusions - Systemic ADMA infusion is responsible for a short-term, modest decrease in cardiac output with comparable decrease in effective renal plasma flow while increasing systemic vascular resistance and blood pressure in a dose-related manner.