中枢性抗高血压药：兴趣的复兴。作用机制与血流动力学。

Centrally acting antihypertensives: a renaissance of interest. Mechanisms and haemodynamics.

作者信息

van Zwieten P A

机构信息

Department of Pharmacotherapy, University of Amsterdam, The Netherlands.

出版信息

J Hypertens Suppl. 1997 Jan;15(1):S3-8.

PMID:9050980

Abstract

BACKGROUND

Classic centrally acting antihypertensives are known to stimulate alpha2-adrenoceptors located in the pontomedullary region, in the vicinity of the nucleus tractus solitarii, vasomotor centre, vagal nucleus and the various interconnecting neurones. The stimulation of these central alpha2-adrenoceptors induces peripheral sympathoinhibition and hence a reduction in (elevated) blood pressure, predominantly as a result of vasodilation and a consequent decrease in peripheral vascular resistance.

ANTIHYPERTENSIVES

Clonidine, guanfacine, guanabenz and alpha-methyldopa (via its active metabolite alpha-methylnoradrenaline) are well-known examples of classic centrally acting antihypertensives. They are effective antihypertensives with an attractive haemodynamic profile. However, these agents have lost much of their clinical interest because of their subjectively unpleasant side-effects (sedation, dry mouth, impotence). Since these side-effects are also mediated, to a major extent, by alpha2-adrenoceptors it is virtually impossible to separate the desired centrally induced antihypertensive effect and the adverse reactions by designing new compounds.

DRUG TARGETS

I1-Imidazoline receptors have recently been discovered as a new target of centrally acting antihypertensives. When stimulated with agonists the I1-imidazoline receptors, located in the nucleus reticularis lateralis will trigger peripheral sympathoinhibition, following similar pathways as involved in the effects of the classic alpha2-adrenoceptor stimulants. Moxonidine and rilmenidine are I1-imidazoline receptor stimulants with little affinity for alpha2-adrenoceptors. Accordingly, such agents lower elevated blood pressure in a similar manner as the aforementioned older drugs, but it may be hoped that their side-effect profile is more favourable.

CONCLUSION

Accordingly, it would now be possible to separate the attractive haemodynamic properties and the side-effects of centrally acting antihypertensives.

摘要

背景

经典的中枢性抗高血压药物可刺激位于脑桥延髓区域、孤束核、血管运动中枢、迷走神经核及各种相互连接神经元附近的α2-肾上腺素能受体。刺激这些中枢α2-肾上腺素能受体可诱导外周交感神经抑制，从而降低（升高的）血压，主要是由于血管舒张及外周血管阻力随之降低。

抗高血压药物

可乐定、胍法辛、胍那苄和α-甲基多巴（通过其活性代谢产物α-甲基去甲肾上腺素）是经典中枢性抗高血压药物的著名例子。它们是有效的抗高血压药物，具有吸引人的血流动力学特征。然而，由于其主观上令人不适的副作用（镇静、口干、阳痿），这些药物已失去了很多临床应用价值。由于这些副作用在很大程度上也是由α2-肾上腺素能受体介导的，通过设计新化合物几乎不可能将所需的中枢诱导性抗高血压作用与不良反应分开。

药物靶点

I1-咪唑啉受体最近被发现是中枢性抗高血压药物的新靶点。当用激动剂刺激位于外侧网状核的I1-咪唑啉受体时，将触发外周交感神经抑制，其途径与经典α2-肾上腺素能受体激动剂的作用途径相似。莫索尼定和利美尼定是对α2-肾上腺素能受体亲和力很小的I1-咪唑啉受体激动剂。因此，这类药物以与上述较老药物相似的方式降低升高的血压，但人们希望它们的副作用谱更有利。