Département de Physiologie, Faculté de Médecine, Université de Montréal, C.P. 6128 Succursale Centre-ville, Montréal, QC, Canada H3C 3J7.
Neuropeptides. 2010 Apr;44(2):191-8. doi: 10.1016/j.npep.2009.12.011. Epub 2010 Jan 13.
Kinins are neuroactive peptides that could play a role in central autonomic control of blood pressure. Whereas kinin B1R binding sites were increased in specific brain areas of spontaneously hypertensive rats (SHR) and Angiotensin II (AngII)-hypertensive rats, the contribution of kinin B1R in hypertension remains controversial. The aims of the study were to determine: (a) the effects on mean arterial blood pressure (MAP) of centrally and peripherally administered B1R antagonists in SHR (16weeks) and AngII-hypertensive rats (200ng/kg/minx2weeks, s.c.); (b) the contribution of central dopamine in the effects of SSR240612. The rationale is based on the overactivity of the dopaminergic system in hypertension. In both models, SSR240612 (1, 5 and 10mg/kg, gavage) reduced dose-dependently MAP (-75mm Hg at least up to 6-8h) and this therapeutic effect was resolved after 24h. At the dose of 5mg/kg, SSR240612-induced anti-hypertension was prevented by two dopamine receptor blockers, namely raclopride (0.16mg/kg, i.v.) and haloperidol (10mg/kg, s.c.). I.c.v. SSR240612 (1mug) decreased rapidly MAP in both models (1-6h) via a raclopride sensitive mechanism. In comparison, peripherally acting B1R antagonists (R-715 and R-954, 2mg/kg, s.c.) caused shorter and very modest decreases of MAP (from -20 to -30mm Hg). Centrally or peripherally administered B1R antagonists had no effect on MAP in control Wistar-Kyoto rats. Data provide the first pharmacological evidence that the up-regulated brain kinin B1R contributes through a central dopaminergic mechanism (DA-D2R) to the maintenance of arterial hypertension in genetic and experimental animal models of hypertension.
激肽是一种神经活性肽，可能在血压的中枢自主控制中发挥作用。虽然在自发性高血压大鼠（SHR）和血管紧张素 II（AngII）-高血压大鼠的特定脑区中增加了激肽 B1R 结合位点，但激肽 B1R 在高血压中的作用仍存在争议。本研究的目的是确定：（a）在 SHR（16 周）和 AngII-高血压大鼠（200ng/kg/minx2 周，皮下注射）中，中枢和外周给予 B1R 拮抗剂对平均动脉血压（MAP）的影响；（b）SSR240612 作用中中枢多巴胺的贡献。该方案基于高血压中多巴胺能系统的过度活跃。在这两种模型中，SSR240612（1、5 和 10mg/kg，灌胃）剂量依赖性地降低 MAP（至少降低 75mmHg，持续 6-8 小时），并且这种治疗效果在 24 小时后得到解决。在 5mg/kg 剂量下，SSR240612 诱导的抗高血压作用被两种多巴胺受体阻滞剂，即氯丙嗪（0.16mg/kg，静脉注射）和氟哌啶醇（10mg/kg，皮下注射）所阻止。SSR240612（1mug）通过氯丙嗪敏感机制迅速降低两种模型中的 MAP（1-6 小时）。相比之下，外周作用的 B1R 拮抗剂（R-715 和 R-954，2mg/kg，皮下注射）引起的 MAP 下降更短且非常轻微（从-20 至-30mmHg）。中枢或外周给予 B1R 拮抗剂对 Wistar-Kyoto 大鼠的 MAP 没有影响。数据提供了第一个药理学证据，表明上调的脑激肽 B1R 通过中枢多巴胺机制（DA-D2R）对遗传和实验性高血压动物模型中的动脉高血压的维持有贡献。
