Increased blood pressure in α-calcitonin gene-related peptide/calcitonin gene knockout mice
Increased blood pressure in α-calcitonin gene-related peptide/calcitonin gene knockout mice
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DOI：
10.1161/01.hyp.35.1.470
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发表时间：
2000-01-01
期刊：
影响因子：
8.3
通讯作者：
Yallampalli, C
中科院分区：
文献类型：
--
作者：
Gangula, PRR;Zhao, HW;Yallampalli, C
含有降钙素基因相关肽（CGRP）的神经是感觉神经系统的组成部分。虽然传统上认为这些传入神经在外围感知刺激并集中传递信息，但它们也具有传出血管舒张功能。急性给予CCRP受体拮抗剂可使几种高血压模型的血压升高，这表明这种有效的血管扩张剂在这些情况下起反调节作用，以减轻血压升高。为了确定这种肽在包括高血压在内的心血管功能的长期调节中的作用，我们获得了铜降钙素基因相关肽（α - cgrp）基因缺失的小鼠。尽管β -降钙素基因相关肽（β - cgrp）基因在这些小鼠中是完整的，但α - cgrp是迄今为止在背根神经节（DRG）感觉神经元中产生的CCRP的主要种类。最初，我们检测了α - cgrp缺失对基线血压、β - cgrp和P物质mRNA表达的影响。与野生型相比，基因敲除小鼠（n=7）的雄性小鼠（160+/-6.1 vs 125+/-4.8 mm Hg）和雌性小鼠（163+/-4.8 vs 135+/-33 mm Hg）的收缩压均显著升高。接下来，基因敲除和野生型小鼠组（n=7）通过手术将导管置入右颈动脉，记录平均动脉压。在动物完全清醒和不受约束的情况下，与野生型小鼠相比，敲除小鼠的雄性（139+/-4.9 vs 118+/-4.9 mm Hg）和雌性（121+/-3.4 vs 107+/-3.1 mm Hg）小鼠的平均动脉压均升高。DRG RNA样品的Northern blot分析证实敲除小鼠中不存在α - cgrp mRNA。两组间DRG中物质P mRNA含量没有变化，但敲除小鼠的β - cgrp mRNA水平降低了2倍。这些结果首次表明α - cgrp可能参与静息血压的长期调节，并表明由于代偿性血管舒张机制的丧失，这些小鼠对血压稳态的挑战特别敏感。
Nerves that contain calcitonin gene-related peptide (CGRP) are components of the sensory nervous system. Although these afferent nerves have traditionally been thought to sense stimuli in the periphery and transmit the information centrally, they also have an efferent vasodilator function. Acute administration of a CCRP receptor antagonist increases the blood pressure (BP) in several models of hypertension, which indicates that this potent vasodilator plays a counterregulatory role to attenuate the BP increase in these settings. To determine the role of this peptide in the long-term regulation of cardiovascular function, including hypertension, we obtained mice that have a deletion of the cu-calcitonin gene-related peptide (alpha-CGRP) gene. Although the beta-calcitonin gene-related peptide (beta-CGRP) gene is intact in these mice, alpha-CGRP is by far the predominant species of CCRP produced in dorsal root ganglia (DRG) sensory neurons. Initially, we examined the effect of deletion of the alpha-CGRP on baseline BP and beta-CGRP and substance P mRNA expression. Systolic BP was significantly higher in the knockout mice (n=7) compared with wild-type in both male (160+/-6.1 vs 125+/-4.8 mm Hg) and female (163+/-4.8 vs 135+/-33 mm Hg) mice. Next, groups (n=7) of knockout and wild-type mice had catheters surgically placed in the right carotid artery for mean arterial pressure recording. With the animals fully awake and unrestrained, The knockout mice displayed an elevated mean arterial pressure compared with wild-type in both male (139+/-4.9 vs 118+/-4.9 mm Hg) and female (121+/-3.4 vs 107+/-3.1 mm Hg) mice. Northern blot analysis of DRG RNA samples confirmed the absence of alpha-CGRP mRNA in the knockout mice. Substance P mRNA content in DRG was unchanged between the 2 groups: however, beta-CGRP mRNA levels were reduced 2-fold in the knockout mice. These results indicate for the first time that alpha-CGRP may be involved in the long-term regulation of resting BP and suggest that these mice are particularly sensitive to challenges to BP homeostasis because of the loss of a compensatory vasodilator mechanism.