Krum Henry, Lambert Elisabeth, Windebank Emma, Campbell Duncan J, Esler Murray
National Health and Medical Research Council of Australia, Centre of Clinical Research Excellence in Therapeutics, Monash University, Melbourne, Vic 3004, Australia.
Am J Physiol Heart Circ Physiol. 2006 Apr;290(4):H1706-12. doi: 10.1152/ajpheart.00885.2005. Epub 2005 Nov 11.
It has long been proposed that the renin-angiotensin system exerts a stimulatory influence on the sympathetic nervous system, including augmentation of central sympathetic outflow and presynaptic facilitation of norepinephrine release from sympathetic nerves. We tested this proposition in 19 patients with essential hypertension, evaluating whether the angiotensin receptor blockers (ARBs) eprosartan and losartan had identifiable antiadrenergic properties. This was done in a prospective, randomized, three-way placebo-controlled study of crossover design. Patients were randomized to 600 mg of eprosartan daily, 50 mg of losartan daily, or placebo. The treatment period was 4 wk, with 2-wk washout periods. Multiunit firing rates in efferent sympathetic nerves distributed to skeletal muscle vasculature (muscle sympathetic nerve activity, MSNA) were measured with microneurography, testing whether ARBs inhibit central sympathetic outflow. In parallel, isotope dilution methodology was used to measure whole body norepinephrine spillover to plasma. Mean blood pressure on placebo was 151/98 mmHg, with both ARBs causing reductions of approximately 11 mmHg systolic and 6 mmHg diastolic pressure, placebo corrected. Both MSNA [35 +/- 12 bursts/min (mean +/- SD) on placebo] and whole body norepinephrine spillover [366 +/- 247 ng/min] were unchanged by ARB administration, indicating that the ARBs did not materially inhibit central sympathetic outflow or act presynaptically to reduce norepinephrine release at existing rates of nerve firing. These findings contrast with the easily demonstrable reduction in sympathetic nervous activity produced by antihypertensive drugs of the imidazoline-binding class, which are known to act within the brain to inhibit sympathetic nervous outflow. We conclude that sympathetic nervous inhibition is not a major component of the blood pressure-lowering action of ARBs in essential hypertension.
长期以来，人们一直认为肾素 - 血管紧张素系统对交感神经系统有刺激作用，包括增强中枢交感神经输出以及促进去甲肾上腺素从交感神经的突触前释放。我们在19例原发性高血压患者中对这一观点进行了测试，评估血管紧张素受体阻滞剂（ARB）依普罗沙坦和氯沙坦是否具有可识别的抗肾上腺素能特性。这是一项前瞻性、随机、三向安慰剂对照的交叉设计研究。患者被随机分为每日服用600 mg依普罗沙坦、每日服用50 mg氯沙坦或安慰剂三组。治疗期为4周，洗脱期为2周。通过微神经ography测量分布到骨骼肌血管系统的传出交感神经中的多单位放电率（肌肉交感神经活动，MSNA），以测试ARB是否抑制中枢交感神经输出。同时，采用同位素稀释法测量全身去甲肾上腺素向血浆中的溢出量。安慰剂组的平均血压为151/98 mmHg，两种ARB均使收缩压降低约11 mmHg，舒张压降低约6 mmHg（校正安慰剂效应）。服用ARB后，MSNA[安慰剂组为35±12次/分钟（平均值±标准差）]和全身去甲肾上腺素溢出量[366±247 ng/分钟]均未改变，这表明ARB并未实质性抑制中枢交感神经输出，也未在突触前发挥作用以降低在现有神经放电速率下去甲肾上腺素的释放。这些发现与咪唑啉结合类降压药物所产生的易于证明的交感神经活动降低形成对比，已知这类药物在脑内起作用以抑制交感神经输出。我们得出结论，交感神经抑制不是ARB在原发性高血压中降低血压作用的主要组成部分。
