Neuronal nitric oxide synthase regulates basal microvascular tone in humans in vivo
Neuronal nitric oxide synthase regulates basal microvascular tone in humans in vivo
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DOI：
10.1161/circulationaha.107.744540
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发表时间：
2008-04-15
期刊：
影响因子：
37.8
通讯作者：
Shah, Ajay M.
中科院分区：
文献类型：
--
作者：
Seddon, Michael D.;Chowienczyk, Philip J.;Shah, Ajay M.
背景-一氧化氮（NO）在调节血管张力和血流中起关键作用，其功能失调的释放导致疾病的病理生理学。这些影响已被归因于NO生产的内皮NO合酶（eNOS），然而，最近的证据表明，神经元NO合酶（nNOS）也可能在动脉vessel.Methods和Results表达-我们进行了第一次在人类调查的nNOS的作用，在健康受试者的血管血流的局部调节。肱动脉输注nNOS特异性抑制剂S-甲基- L-硫代瓜氨酸（SMTC，0.025 μ mol/ min至0.2 μ mol/ min）导致基础流量的剂量依赖性减少，最高剂量时减少30.1 ± 3.8%（n = 10;平均值± SE; P < 0.01）. SMTC的作用可被NO合成酶底物L-精氨酸阻断，但不受D-精氨酸的影响。使用非选择性NO合成酶抑制剂N-G-单甲基-L-精氨酸时，（L-NMMA; 37.4 +/-3.1%，n = 10）需要高20倍的剂量4 μ mol/min。在基础流量产生相当减少的剂量下，仅L-NMMA（4 μ mol/ min）而非SMTC（0.2 μ mol/ min）抑制乙酰胆碱诱导的血管舒张;但是，在此情况下，SMTC和L-NMMA均能抑制前臂血管对精神应激的舒张反应。结论-人前臂基础血流量受nNOS调节，衍生的NO，与乙酰胆碱估计的血流增加相反，如前所述，其主要由eNOS介导。这些数据表明，血管nNOS在体内人体微血管张力的生理调节中具有独特的局部作用。
Background - Nitric oxide ( NO) has a pivotal role in the regulation of vascular tone and blood flow, with dysfunctional release contributing to disease pathophysiology. These effects have been attributed to NO production by the endothelial NO synthase ( eNOS); however, recent evidence suggests that a neuronal NO synthase ( nNOS) may also be expressed in arterial vessels.Methods and Results - We undertook a first-in- humans investigation of the role of nNOS in the local regulation of vascular blood flow in healthy subjects. Brachial artery infusion of the nNOS- specific inhibitor S- methyl- L- thiocitrulline ( SMTC, 0.025 mu mol/ min to 0.2 mu mol/ min) caused a dose- dependent reduction in basal flow, with a 30.1 +/- 3.8% decrease at the highest dose ( n = 10; mean +/- SE; P < 0.01). The effect of SMTC was abolished by coinfusion of the NO synthase substrate L- arginine but was unaffected by D- arginine. A similar reduction in basal flow with the nonselective NO synthase inhibitor N-G- monomethyl-L-arginine ( L- NMMA; 37.4 +/- 3.1%, n = 10) required a 20- fold higher dose of 4 mu mol/ min. At doses that produced comparable reductions in basal flow, only L- NMMA ( 4 mu mol/ min) and not SMTC ( 0.2 mu mol/ min) inhibited acetylcholine- induced vasodilation; however, both SMTC and L- NMMA inhibited the forearm vasodilator response to mental stress.Conclusions - Basal forearm blood flow in humans is regulated by nNOS- derived NO, in contrast to the acetylcholinestimulated increase in blood flow, which, as shown previously, is mediated primarily by eNOS. These data indicate that vascular nNOS has a distinct local role in the physiological regulation of human microvascular tone in vivo.