Khan Sitara G, Geer Amber, Fok Henry W, Shabeeh Husain, Brett Sally E, Shah Ajay M, Chowienczyk Philip J
From the Departments of Cardiology (S.G.K., H.S., A.M.S.) and Clinical Pharmacology (A.G., H.W.F., S.E.B., P.J.C.), British Heart Foundation Centre, King's College London, King's Health Partners, London United Kingdom.
Hypertension. 2015 Apr;65(4):903-9. doi: 10.1161/HYPERTENSIONAHA.114.04538. Epub 2015 Mar 2.
Neuronal NO synthase (nNOS) regulates blood flow in resistance vasculature at rest and during mental stress. To investigate whether nNOS signaling is dysfunctional in essential hypertension, forearm blood flow responses to mental stress were examined in 88 subjects: 48 with essential hypertension (42±14 years; blood pressure, 141±17/85±15 mm Hg; mean±SD) and 40 normotensive controls (38±14 years; 117±13/74±9 mm Hg). A subsample of 34 subjects (17 hypertensive) participated in a single blind 2-phase crossover study, in which placebo or sildenafil 50 mg PO was administered before an intrabrachial artery infusion of the selective nNOS inhibitor S-methyl-l-thiocitrulline (SMTC, 0.05, 0.1, and 0.2 μmol/min) at rest and during mental stress. In a further subsample (n=21) with an impaired blood flow response to mental stress, responses were measured in the presence and absence of the α-adrenergic antagonist phentolamine. The blood flow response to mental stress was impaired in hypertensive compared with normotensive subjects (37±7% versus 70±8% increase over baseline; P<0.001). SMTC blunted responses to mental stress in normotensive but not in hypertensive subjects (reduction of 40±11% versus 3.0±14%, respectively, P=0.01, between groups). Sildenafil reduced the blood flow response to stress in normotensive subjects from 89±14% to 43±14% (P<0.03) but had no significant effect in hypertensive subjects. Phentolamine augmented impaired blood flow responses to mental stress from 39±8% to 67±13% (P<0.02). Essential hypertension is associated with impaired mental stress-induced nNOS-mediated vasodilator responses; this may relate to increased sympathetic outflow in hypertension. nNOS dysfunction may impair vascular homeostasis in essential hypertension and contribute to stress-induced cardiovascular events.
神经元型一氧化氮合酶（nNOS）在静息状态和精神应激期间调节阻力血管的血流。为了研究nNOS信号在原发性高血压中是否功能失调，对88名受试者的前臂血流对精神应激的反应进行了检查：48名原发性高血压患者（42±14岁；血压，141±17/85±15 mmHg；均值±标准差）和40名血压正常的对照者（38±14岁；117±13/74±9 mmHg）。34名受试者（17名高血压患者）的一个子样本参与了一项单盲2期交叉研究，在静息状态和精神应激期间，在肱动脉内输注选择性nNOS抑制剂S-甲基-L-硫代瓜氨酸（SMTC，0.05、0.1和0.2 μmol/min）之前，给予安慰剂或50 mg口服西地那非。在另一个对精神应激的血流反应受损的子样本（n = 21）中，在有和没有α-肾上腺素能拮抗剂酚妥拉明的情况下测量反应。与血压正常的受试者相比，高血压患者对精神应激的血流反应受损（较基线增加37±7% 对70±8%；P<0.001）。SMTC使血压正常的受试者对精神应激的反应减弱，但对高血压患者没有影响（分别降低40±11% 对3.0±14%，组间P = 0.01）。西地那非使血压正常的受试者对应激的血流反应从89±14% 降至43±14%（P<0.03），但对高血压患者没有显著影响。酚妥拉明使受损的对精神应激的血流反应从39±8% 增加到67±13%（P<0.02）。原发性高血压与精神应激诱导的nNOS介导的血管舒张反应受损有关；这可能与高血压中交感神经输出增加有关。nNOS功能障碍可能损害原发性高血压中的血管稳态，并导致应激诱导的心血管事件。
