原发性高血压患者内皮依赖性血管舒张功能受损。一氧化氮异常并非局限于单一信号转导途径的证据。

Impaired endothelium-dependent vasodilation in patients with essential hypertension. Evidence that nitric oxide abnormality is not localized to a single signal transduction pathway.

作者信息

Panza J A, García C E, Kilcoyne C M, Quyyumi A A, Cannon R O

机构信息

Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. 20892.

出版信息

Circulation. 1995 Mar 15;91(6):1732-8. doi: 10.1161/01.cir.91.6.1732.

DOI:10.1161/01.cir.91.6.1732

PMID:7882481

Abstract

BACKGROUND

Patients with essential hypertension have abnormal endothelium-dependent vascular relaxation, largely related to reduced bioactivity of nitric oxide (NO). The purpose of the present investigation was to determine whether this defect is due to a deficit at the specific intracellular signal-transduction pathway level or is a consequence of a more generalized endothelial abnormality.

METHODS AND RESULTS

The responses of the forearm vasculature to acetylcholine and bradykinin (endothelium-dependent agents that act through different signal transduction pathways) and to sodium nitroprusside (a direct dilator of vascular smooth muscle) were studied in 10 hypertensive patients (5 men, 5 women; aged 48 +/- 9 years old [mean +/- SD]) and 12 control subjects (6 men, 6 women; aged 48 +/- 7 years old). To determine the contribution of NO to bradykinin-induced vasodilation, the vascular responses to bradykinin were also measured after administration of NG-monomethyl-L-arginine, an arginine analogue that inhibits the synthesis of NO. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. The response to acetylcholine was significantly blunted in hypertensive patients (maximal blood flow, 7.5 +/- 2 versus 16.6 +/- 8 mL.min-1.100 mL-1 in control subjects [mean +/- SD]; P < .005). Similarly, the vasodilator effect of bradykinin was significantly reduced in hypertensive patients compared with control subjects (maximal blood flow, 8.7 +/- 2 versus 15.8 +/- 6 mL.min-1.100 mL-1 in control subjects; P < .005). A significant correlation was found between the maximal blood flow with acetylcholine and that with bradykinin (r = .89). No significant differences were found between the two groups for vascular response to sodium nitroprusside. NG-monomethyl-L-arginine significantly blunted the response to bradykinin in control subjects (maximal blood flow decreased from 15.8 +/- 6 to 10.1 +/- 2 mL.min-1.100 mL-1, P < .003). In contrast, inhibition of NO synthesis did not modify the response to bradykinin in hypertensive patients (maximal blood flow, 8.7 +/- 2 and 8.5 +/- 3 before and during infusion of NG-monomethyl-L-arginine, respectively; P = NS). As a consequence, the response to bradykinin after inhibition of NO synthesis was not significantly different between the two groups.

CONCLUSIONS

Patients with essential hypertension have impaired endothelium-dependent vasodilator responses to both acetylcholine and bradykinin. These findings indicate that the endothelial dysfunction in this condition is not related to a specific defect of a single intracellular signal-transduction pathway and suggest a more generalized abnormality of endothelial vasodilator function.

摘要

背景

原发性高血压患者存在内皮依赖性血管舒张异常，这在很大程度上与一氧化氮（NO）生物活性降低有关。本研究的目的是确定这种缺陷是由于特定细胞内信号转导途径水平的缺陷，还是更广泛的内皮异常的结果。

方法与结果

在10例高血压患者（5例男性，5例女性；年龄48±9岁[平均值±标准差]）和12例对照受试者（6例男性，6例女性；年龄48±7岁）中，研究了前臂血管对乙酰胆碱和缓激肽（通过不同信号转导途径起作用的内皮依赖性药物）以及对硝普钠（血管平滑肌的直接扩张剂）的反应。为了确定NO对缓激肽诱导的血管舒张的作用，在给予NG-单甲基-L-精氨酸（一种抑制NO合成的精氨酸类似物）后，也测量了对缓激肽的血管反应。将药物注入肱动脉，通过应变片体积描记法测量前臂血流量。高血压患者对乙酰胆碱的反应明显减弱（最大血流量，对照组为16.6±8 mL·min⁻¹·100 mL⁻¹，高血压患者为7.5±2 mL·min⁻¹·100 mL⁻¹[平均值±标准差]；P<.005）。同样，与对照受试者相比，高血压患者缓激肽的血管舒张作用明显降低（最大血流量，对照组为15.8±6 mL·min⁻¹·100 mL⁻¹，高血压患者为8.7±2 mL·min⁻¹·100 mL⁻¹；P<.005）。发现乙酰胆碱诱导的最大血流量与缓激肽诱导的最大血流量之间存在显著相关性（r=.89）。两组对硝普钠的血管反应无显著差异。NG-单甲基-L-精氨酸使对照受试者对缓激肽的反应明显减弱（最大血流量从15.8±6降至10.1±2 mL·min⁻¹·100 mL⁻¹，P<.003）。相比之下，抑制NO合成并未改变高血压患者对缓激肽的反应（分别在输注NG-单甲基-L-精氨酸之前和期间，最大血流量为8.7±2和8.5±3 mL·min⁻¹·100 mL⁻¹；P=无显著性差异）。因此，抑制NO合成后两组对缓激肽的反应无显著差异。