Deng Pan-Yue, Ye Feng, Cai Wei-Jun, Tan Gui-Shan, Hu Chang-Ping, Deng Han-Wu, Li Yuan-Jian
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, PR China.
J Hypertens. 2004 Sep;22(9):1819-29. doi: 10.1097/00004872-200409000-00028.
Previous investigations have demonstrated that capsaicin-sensitive primary sensory nerves play an important role in modulation of the peripheral resistance of the circulation system. The vanilloid receptor subtype 1 (VR1) is expressed almost exclusively in the primary sensory nerves and cell bodies of these sensory neurons. Rutaecarpine (Rut) can relax vascular smooth muscle via stimulation of calcitonin gene-related peptide (CGRP) release by activation of VR1.
In the present study, we examined the depressor effect of Rut and the possible mechanisms in the phenol-induced hypertensive rats, in which hypertension was induced by injecting 50 microl of 10% phenol in the lower pole of the left kidney.
Acute administration of Rut (30, 100 or 300 microg/kg, i.v.) caused a depressor effect concomitantly with an increase in the plasma concentration of CGRP in a dose-dependent manner, which was blocked by capsaicin (used to deplete the CGRP from sensory nerves) or capsazepine (a competitive VR1 antagonist), causing an approximately 85% and approximately 80% change in mean arterial pressure, respectively, and by either of them, causing an approximately 90% elevation of plasma CGRP. In the chronic study, Rut at a dose of 3 or 6 mg/kg per day significantly lowered tail-cuff systolic blood pressure to 159 +/- 8 and 136 +/- 10 mmHg, respectively, compared with hypertensive rats (179 +/- 8 mmHg), and caused a sustained hypotensive effect from day 6 on. Pretreatment with capsaicin blocked the depressor effect of Rut by approximately 65%. Treatment with Rut significantly increased the synthesis and release of CGRP, as shown by the increase in the levels of CGRP mRNA and peptide in the dorsal root ganglia, the density of CGRP immunoreactive nerve fibers in the mesenteric artery, the CGRP content in the spinal cord and the plasma concentration of CGRP, which was markedly attenuated by pretreatment with capsaicin.
These results suggest, for the first time, that the hypotensive effect of Rut is mediated by stimulation of CGRP synthesis and release via activation of VR1 in the phenol-induced hypertensive rat.
先前的研究表明，对辣椒素敏感的初级感觉神经在调节循环系统的外周阻力中起重要作用。香草酸受体亚型1（VR1）几乎只在这些感觉神经元的初级感觉神经和细胞体中表达。吴茱萸次碱（Rut）可通过激活VR1刺激降钙素基因相关肽（CGRP）释放，从而舒张血管平滑肌。
在本研究中，我们检测了吴茱萸次碱对苯酚诱导的高血压大鼠的降压作用及其可能机制，该高血压大鼠模型是通过在左肾下极注射50微升10%苯酚诱导而成。
急性给予吴茱萸次碱（30、100或300微克/千克，静脉注射）可产生降压作用，同时血浆CGRP浓度呈剂量依赖性增加，辣椒素（用于耗尽感觉神经中的CGRP）或capsazepine（一种竞争性VR1拮抗剂）可阻断该作用，辣椒素和capsazepine分别使平均动脉压变化约85%和约80%且二者均可使血浆CGRP升高约90%。在慢性研究中，与高血压大鼠（179±8毫米汞柱）相比，每天给予3或6毫克/千克剂量的吴茱萸次碱可使尾袖收缩压分别显著降至159±8和136±10毫米汞柱，并从第6天起产生持续的降压作用。辣椒素预处理可使吴茱萸次碱的降压作用阻断约65%。吴茱萸次碱治疗显著增加了CGRP的合成和释放，表现为背根神经节中CGRP mRNA和肽水平升高、肠系膜动脉中CGRP免疫反应性神经纤维密度增加、脊髓中CGRP含量增加以及血浆CGRP浓度升高，而辣椒素预处理可显著减弱这些作用。
这些结果首次表明，在苯酚诱导的高血压大鼠中，吴茱萸次碱的降压作用是通过激活VR1刺激CGRP合成和释放介导的。
