内皮源性降钙素基因相关肽合成与释放调节机制及其病理生理意义
|
摘要
研究背景
降钙素基因相关肽(CGRP)是一种强效的舒血管物质,是辣椒素敏感神经的主要递质,广泛分布于神经和心血管系统。在外周神经系统,背根神经节是CGRP合成的主要部位。除神经细胞外,人淋巴细胞、人肺泡Ⅱ型上皮细胞、Langerhans细胞和内皮细胞等也能合成CGRP。有证据显示,局部来源的CGRP具有特殊的生理作用。我们近来的研究表明,内皮源性CGRP涉及热应激诱导的内皮保护功能。研究发现自发性高血压或苯酚诱导高血压大鼠,神经源性CGRP的产生降低,然而,内皮源性的CGRP的变化和机制尚不清楚。
高血压时,大多数情况下交感神经系统的活力是增加的。研究表明,在苯酚诱导高血压大鼠(交感神经兴奋是其主要机制),血浆去甲肾上腺素(NE,一种非选择性α肾上腺素受体激动剂)水平随着血压升高而增加。我们最近发现,激α2肾上腺素受体,能够诱导内皮细胞CGRP合成与释放。我们推测,在苯酚诱导高血压,NE通过激动α2肾上腺素受体可能上调内皮细胞源性CGRP水平,对抗升高的血压。
在本实验中,利用苯酚诱导高血压大鼠模型和培养的内皮细胞,我们探讨了内皮源性CGRP的变化及其信号途径。
方法
实验一：苯酚诱导高血压中内皮源性CGRP的变化
苯酚诱导的高血压模型：雄性SD大鼠,左肾下极注射10%苯酚50μl制备高血压模型,15 d后取主动脉、肠系膜上动脉。4%多聚甲醛固定,30%蔗糖过夜,制成冰冻切片。取冰冻切片原位杂交检测血管内皮细胞CGRP mRNA的表达,原位杂交及其以前的各步处理中,所有液体试剂都经DEPC处理,抑制RNA酶的降解作用。原位杂交化学反应按常规步骤进行,NBTBCIP染色,图像分析。另取冰冻切片免疫组化检测血管内皮细胞CGRP含量,免疫组织化学按常规步骤进行,DAB染色,图像分析。实验分为3组：①对照组；②高血压组；③药物处理组：给予哌唑嗪(3mg/kg/d),每d灌胃1次,连续给药14 d。
实验二：去甲肾上腺素对内皮细胞CGRP表达的影响及机制
培养人脐静脉内皮细胞株HUVEC-12,分别加入不同剂量的NE孵育内皮细胞,并在确定其量效和时效关系的基础上分别加入特异性α肾上腺素受体阻断剂(哌唑嗪,育亨宾)和特异性一氧化氮合酶抑制剂(L-NAME)以确定信号途径。RT-PCR检测内皮细胞中CGRP mRNA水平,硝酸还原酶法测定细胞培养上清中的总NO含量。
结果
(1)苯酚诱导高血压中,大鼠主动脉、肠系膜上动脉血管内皮CGRP mRNA的表达和CGRP的含量增加,其作用可被哌唑嗪部分阻断。
(2)NE能剂量依赖性上调内皮源性α-和β-CGRP mRNA的表达,并在培养细胞6 h达到最高水平,此作用能被预先给予育享宾和L-NAME取消,但不受哌唑嗪影响。
(3)NE能增加培养细胞上清中的NO含量,此作用能被预先给予育享宾和L-NAME阻断,哌唑嗪无此作用。
结论
在苯酚诱导的大鼠高血压中,内皮源性CGRP合成与释放增加可能是一种内源性对抗血压升高的代偿机制。内皮细胞CGRP的表达受NE的调节,其机制涉及α2受体及NO通路。
研究背景
新近研究发现,除神经细胞外,非神经组织细胞如淋巴细胞、内皮细胞也能合成CGRP。局部来源的CGRP具有特殊的生理作用。例如淋巴细胞能合成和分泌CGRP,参与调节淋巴细胞对于免疫刺激的应答功能。我们实验室工作表明,原代内皮细胞和人脐静内皮细胞株能合成和分泌CGRP,内皮源性CGRP涉及热应激诱导的内皮保护功能。
可乐定是传统的中枢抗高血压药物,为α2肾上腺素受体激动剂,对中枢神经系统有明显的抑制作用。除降低中枢交感神经张力外,可乐定的抗高血压机制尚不完全清楚。研究表明,可乐定能激动内皮细胞上的α2肾上腺素受体而产生血管舒张作用,此作用可被一氧化氮合酶抑制剂L-NAME所阻断,提示NO通路参与了此过程。
本实验探讨可乐定是否能够通过激动内皮细胞上的α2肾上腺素受体调节CGRP的合成与释放,并确定是否涉及NO途径。
方法
培养人脐静脉内皮细胞株HUVEC-12,分别加入不同剂量的可乐定孵育内皮细胞,在确定其量效和时效关系的基础上分别加入特异性α2肾上腺素受体阻断剂(育亨宾)和特异性一氧化氮合酶抑制剂(L-NAME)以确定信号途径。RT-PCR和Real time-PCR检测内皮细胞中CGRP mRNA水平；放射免疫法检测内皮细胞及培养上清中CGRP的含量；硝酸还原酶法测定细胞培养上清中的总NO含量。
结果
(1)可乐定(10-8,1 0-7和10-6M)孵育内皮细胞24 h可剂量依赖性地升高α-和β-CGRP mRNA的表达水平。
(2)可乐定(10-6M)孵育内皮细胞12 h时CGRP mRNA表达水平开始上升,24 h时达最高峰,48 h时仍维持高水平。
(3)可乐定上调内皮源性CGRP mRNA表达和增加培养细胞及上清中CGRP含量,此作用能被预先给予的育亨宾和L-NAME取消。
结论
可乐定能够通过激动内皮细胞α2肾上腺素受体促进CGRP的合成与释放,此过程涉及NO途径,这可能也是可乐定降压作用的机制之一。
研究背景
肾素-血管紧张素系统(RAS)活性增高是造成血压升高的重要机制之一。研究发现,在肾性和自发性高血压大鼠动物模型长期给予肾素-血管紧张素转换酶抑制剂(ACEI)卡托普利及血管紧张素Ⅰ型受体(AT1)拮抗剂氯沙坦后,降压的同时均伴有CGRP的合成与释放增加,这些研究提示,RAS参与CGRP合成与释放的调节。已知RAS在血管重构和高血压的发生发展中起非常重要作用。RAS对神经源性CGRP表达的调节作用已有文献报道,但其对内皮源性CGRP的表达是否具有调节作用尚未见报道。
血管紧张素Ⅱ(AngⅡ)作为RAS主要的生物活性物质,是机体重要的调节因子,发挥多种生物功能,在血管内外平衡、内膜的形成及心肌梗死后心肌重塑中有重要的作用,可刺激活性氧的产生,诱导血管内皮细胞发生凋亡,而血管内皮细胞凋亡是动脉粥样硬化、心肌梗死等多种心血管疾病发生的始动环节。有文献报道,CGRP具有抗细胞凋亡作用。AngⅡ诱导的内皮细胞凋亡是否与其抑制内皮源性CGRP的表达有关尚不清楚。
新近发现,辣椒素通过激动内皮细胞上的VR1受体能长时程的上调内皮源性CGRP的表达,VR1受体阻断剂caspazepine可以取消此作用。本研究利用培养的内皮细胞探讨以下几个问题：(1) AngⅡ是否能调节内皮源性CGRP合成与释放；(2) CGRP是否具有抗AngⅡ诱导的内皮细胞凋亡的作用；(3)用辣椒素刺激内皮细胞CGRP的合成与释放是否能对抗AngⅡ诱导的内皮细胞凋亡。
方法
实验一：AngⅡ对内皮细胞CGRP合成与释放的影响
培养人脐静脉内皮细胞株HUVEC-12,分别加入不同剂量的AngⅡ孵育内皮细胞,研究其量效和时效关系,并给予特异性ATl受体阻断剂氯沙坦研究其可能的机制。Real time-PCR检测内皮细胞中CGRP mRNA水平；放射免疫法检测内皮细胞及培养上清中CGRP的含量。
实验二：CGRP抗内皮细胞凋亡作用
在培养的人脐静脉内皮细胞给予AngⅡ诱导细胞凋亡,外源性给予CGRP和辣椒素。Hoechst细胞染色、Annexin V-FITC流式细胞检测细胞凋亡；比色法测定caspase-3活性；RT-PCR检测内皮细胞中CGRP、Bcl-2和Bax mRNA的表达。
结果
(1) AngⅡ孵育内皮细胞可剂量和时间依赖性地降低α-和β-CGRP mRNA的表达水平和CGRP含量,此作用可被预先给予的氯沙坦阻断。
(2) CGRP可剂量依赖性降低AngⅡ诱导的内皮细胞凋亡,减弱AngⅡ增加内皮细胞caspase-3活性,此作用能被预先给予的CGRP受体阻断剂CGRP8-37取消。
(3)辣椒素可剂量依赖性上调内皮源性α-和β-CGRP mRNA的表达水平,此作用能被预先给予的VR1受体阻断剂capsazepine取消。
(4)辣椒素可剂量依赖性降低Angll诱导的内皮细胞凋亡,减弱Angll增加内皮细胞caspase-3活性,此作用能被预先给予的capsazepine和CGRP8-37取消。
(5)辣椒素可以上调抗凋亡分子Bcl-2 mRNA的表达,下调促凋亡分子Bax mRNA的表达,此作用能被预先给予的capsazepine和CGRP8-37取消。
结论
AngⅡ能抑制内皮细胞合成与释放CGRP;用辣椒素促进内皮源性CGRP的表达能对抗AngⅡ诱导的内皮细胞凋亡。
Chapter 1
Upregulation of endothelium-derived CGRP production in phenol-induced hypertension via activation ofα2-adrenergic receptor
BACKGROUND
Calcitonin gene-related peptide (CGRP), a very potent vasodilator, is the predominant neurotransmitter in capsaicin-sensitive sensory nerves and widely distributes in the nerve and cardiovascular systems. In peripheral nerve system, the dorsal root ganglia (DRG) are the major site for CGRP synthesis. Besides nerve cells, other type of cells such as human lymphocytes, human typeⅡalveolar epithelial cells, Langerhans cells and endothelial cells has been also reported to synthesize CGRP. There is evidence that local source of CGRP may have special physiological functions. Our recent work has demonstrated that endothelial cell-derived CGRP was involved in heat stress-induced protection of endothelial function. Although the nerve cell-derived CGRP production is decreased in SHR or in phenol-induced hypertensive rats, little is known about the change of endothelia cell-derived CGRP and the underlying mechanisms.
In most of cases, the activity of sympathetic nervous system is increased in hypertension. It has been shown that the plasma level of norepinephrine (NE) was elevated in phenol-induced hypertensive rats. Recently, we have found that activation of a2-adrenoceptor can induce CGRP production in endothelial cells. As a compensatory vasodilator mechanism to counteract the increased blood pressue, we postulate that the endothelium-derived CGRP production is likely upregulated in phenol-induced hypertension through the activation ofα2-adrenegic receptor.
In the present study, by using the established phenol-induced hypertensive rat model and the cultured endothelial cells, we explored the changes in endothelium-derived CGRP production and the involved signal transduction pathway.
METHODS
Hypertensive rats were induced by injecting 50μl of 10% phenol in the lower pole of the left kidney. Fifteen days after phenol treatment, the thoracic aorta and mesenteric artery were excised to determine CGRP peptide and mRNA by immunohistochemistry and in situ hybridization, respectively. In order to test the efect of prazosin on the expression of CGRP, the rats was treated with prazosin (3 mg/kg/d, i.g) for 14 days.
In the cultured HUVEC-12, cells were treated with NE at concentration of 10-9,10-8,10-7,10-6 or 10-5 M for 24 h to evaluate the dose-effect relationship on CGRP expression or incubated with NE at concentration of 10"6M for 6,12,24,36 or 48 h to evaluate the time-effect relationship. Next, the cells were incubated with NE (10-5M) for 6 h after the pretreatment with yohimbine, prazosin or L-NAME for 30 min to determine the likely involved subtype of adrenergic signaling pathway in CGRP mRNA expression and to determine whether NO pathway was also involved. The level of CGRP mRNA was detected by RT-PCR. The level of nitrite/nitrate in the conditioned medium was measured with the Griess regent.
RESULTS
The immunostaining signal of CGRP was significantly increased in the intima layer of aorta or mesenteric artery in the hypertension group, which was attenuated by prazosin treatment. Consistent with the immunostaining results of CGRP protein, the results of in situ hybridization showed that CGRP mRNA expression was significantly increased in the intima layer of aorta or mesenteric artery in the hypertension group, which was attenuated by prazosin treatment.
NE significantly induced CGRP mRNA expression in a dose-dependent manner and increased gradually and reached the highest point at 6 h, and then went down after that, the effect of which was inhibited by yohimbine and L-NAME but not by prazosin, indicating that it isα2-but notα1-adrenoreceptor. NE treatment (10-5M) for 6 h significantly increased the NO level in the culture medium. These effects were attenuated in the presence of yohimbine or L-NAME but not prazosin, consistent with the change of CGRP mRNA expression mentioned above.
CONCLUSION
The present results suggest that the endothelium-derived CGRP production was increased in phenol-induced hypertension, which may represent an endogenous compensatory mechanism to counteract the elevated blood pressure. The up-regulation of endothelium-derived CGRP production is through activation ofα2-adrenergic receptor, which was associated with the NO pathway.
Chapter 2
The effect of clonidine on calcitonin gene-related peptide expression in cultured endothelial cells
BACKGROUND
In addition to nerve cells, other type of cells such as lymphocytes and endothelial cells has been also reported to synthesize CGRP. It has been shown that local source of CGRP may have special physiological significance. For example, lymphocyte was able to produce and secret CGRP, which were supposed to participate in the modulating lymphocyte function in response to immune stimulation. Endothelial cell is able to synthesis and secret CGRP, too. Our recent work has demonstrated that endothelial cell-derived CGRP was involved in heat stress-induced protection of endothelial function.
Clonidine is a centrally acting agonist ofα2 adrenergic receptor prescribed historically as an antihypertensive drug. The mechanism of the anti-hypertensive effect of clonidine is not completely understood but probably reduction of central sympathetic tone must play a very important role. There is evidence that clonidine is able to stimulate the peripheralα2 receptors and induce vasodilatation through activation ofα2 receptors in endothelial cells, an effect which was blocked by L-NAME, the inhibitor of NOS, suggesting that NO pathway may involve in this process.
In the present study, we examined whether clonidine could induce CGRP synthesis and secretion in endothelial cell through activating a2-adrenoceptor and whether clonidine-induced CGRP production is mediated by the NO pathway.
METHODS
Endothelial cells were treated with clonidine at concentration of 10-8, 10-7 or 10-6 M for 24 h to evaluate the dose-effect relationship on CGRP expression or incubated with clonidine at concentration of 10-6M for 12, 24,36 or 48 h to evaluate the time-effect relationship. Next, the cells were incubated with clonidine (10-6M) for 24 h after the pretreatment with yohimbine or L-NAME for 30 min to examine whether the effect of clonidine on regulating CGRP mRNA expression in HUVECs is through the activation of a2-adrenergic receptor and whether NO pathway is involved. The level of CGRP mRNA was detected by RT-PCR and Real time-PCR, while protein level was measured by radioimmunoassay (RIA). The level of nitrite/nitrate in the conditioned medium measured with the Griess regent.
RESULTS
Treating the cells with clonidine significantly induced CGRP mRNA expression in a dose-dependent manner. The expression of CGRP mRNA increased gradually and reached the highest point at 24 h, and then went down after that, the effect of which was inhibited by yohimbine or L-NAME. In line with these results, clonidine treatment also significantly increased CGRP content. These effects were abolished by pretreatment with yohimbine or L-NAME. Clonidine treatment (10-5M) for 24 h significantly increased the NO level in the culture medium. These effects were attenuated in the presence of yohimbine or L-NAME consistent with the change of CGRP mRNA expression mentioned above.
CONCLUSION
The present results suggest that clonidine could stimulate CGRP synthesis and secretion in endothelial cells through activation of a2-adrenoceptor, which is involved in the NO pathway.
Chapter 3
The role of endothelial cell-derived calcitonin gene-related peptide in angiotensinⅡ-induced endothelial cell apoptosis
BACKGROUND
The increase in RAS activity is one of the important mechanisms in the development of hypertension. It has been shown that the synthesis and release of CGRP was increased with the reduced blood pressure after taking captopril or losartan in renal hypertension rat and SHR, suggesting that RAS participated in regulating the synthesis and release of CGRP. It is well known that RAS plays a very important role in vascular remodeling and the decelopment of hypertension. There were reports that RAS participated in the regulation of nerve-derived CGRP. However, little is known about the role of RAS in regulating the endothelium-derived CGRP.
As a major member of RAS, AngⅡpossesses multiplebiological functions. It involves in many pathophysiological process such as vascular remodeling, cellular apoptosis, oxidative stress, etc. Endothelial cell apoptosis has been thought closely related to the development of many cardiovascular diseases such as atherosclerosis and myocardial infarction. There is evidence that CGRP has the property of anti-apoptosis. It is not known whether AngⅡ-induced endothelial cell apoptosis is related to the inhibition of endothelium-derived CGRP expression.
Our recent works has demonstrated that vascular endothelial cell can situ synthesis CGRP and express VR1, and capsaicin can stimulate the expression of endothelial cell-derived CGRP, which is abolished by antagonist of VR1 receptor caspazepine. In the present study, therefore, we explored the role of endothelial cell-derived CGRP in the AngⅡ-induced endothelial cell apoptosis.
METHODS
Endothelial cells were treated with AnglⅡat concentration of 10-8, 10-7 or 10-6 M for 24 h to evaluate the dose-effect relationship on CGRP expression or incubated with AngⅡat concentration of 10"6M for 6,12, 24,36 or 48 h to evaluate the time-effect relationship. Next, the cells were incubated with AngⅡ(10-5M) for 24 h after the pretreatment with losartan for 30 min to determine whether AT1 receptor was involved. The level of CGRP mRNA was detected by Real time-PCR and theprotein level was measured by radioimmunoassay.
To explore the effect of CGRP on the AngⅡ-induced apoptosis, endothelial cells were pretreated with CGRP or capsaicin before AngⅡtreatment. Cell apoptosis was examined by hoechst 33258 staining and FITC-AnnexinⅤflow cytometry. Activity of Caspase 3 was measured by colorimetry. The level of CGRP, Bcl-2 and Bax mRNA were detected by RT-PCR.
RESULTS
AngⅡsignificantly decreasedα-andβ-CGRP mRNA expression and the content of CGRP in cultured endothelial cell in a dose-dependent manner, which was inhibited by pretreatment with losartan. Treating the cells with AngⅡat concentration of 10-6M for 6,12,24,36 or 48 h, the expression level of CGRP(α-andβ-) mRNA decreased gradually from the time point of 6 h.
Pretreatment the cells with exogenous CGRP decreased AngⅡ-induced endothelial cell apoptosis accompanied by the decreased caspase-3 activity, which was attenuated in the presence of CGRP8-37, the antagonist of CGRP receptor
Treating the cells with capsaicin at concentration of 10-8,10-7 or 10-6 M for 24 h, the expression level of CGRP(αandβ) mRNA increased in a dose-dependent manner, which was inhibited by capsazepine, the antagonist of VR1 receptor
Pretreatment the cells with capsaicin decreased AngⅡ-induced endothelial cell apoptosis accompanied by the increased Bcl-2 mRNA expression, the decreased Bax mRNA expression and caspase-3activity which was attenuated in the presence of capsazepine or CGRP8-37.
CONCLUSION
AngⅡis able to inhibit the synthesis and release of CGRP in the cultured HUVECs, which may contribute to AngⅡ-induced endothelial cell apoptosis. Exogenous administration of CGRP or stimulating the synthesis of endogenous CGRP may provide a novel approach to prevent the AngⅡ-induced endothelial cell apoptosis.
降钙素基因相关肽(CGRP)是一种强效的舒血管物质,是辣椒素敏感神经的主要递质,广泛分布于神经和心血管系统。在外周神经系统,背根神经节是CGRP合成的主要部位。除神经细胞外,人淋巴细胞、人肺泡Ⅱ型上皮细胞、Langerhans细胞和内皮细胞等也能合成CGRP。有证据显示,局部来源的CGRP具有特殊的生理作用。我们近来的研究表明,内皮源性CGRP涉及热应激诱导的内皮保护功能。研究发现自发性高血压或苯酚诱导高血压大鼠,神经源性CGRP的产生降低,然而,内皮源性的CGRP的变化和机制尚不清楚。
高血压时,大多数情况下交感神经系统的活力是增加的。研究表明,在苯酚诱导高血压大鼠(交感神经兴奋是其主要机制),血浆去甲肾上腺素(NE,一种非选择性α肾上腺素受体激动剂)水平随着血压升高而增加。我们最近发现,激α2肾上腺素受体,能够诱导内皮细胞CGRP合成与释放。我们推测,在苯酚诱导高血压,NE通过激动α2肾上腺素受体可能上调内皮细胞源性CGRP水平,对抗升高的血压。
在本实验中,利用苯酚诱导高血压大鼠模型和培养的内皮细胞,我们探讨了内皮源性CGRP的变化及其信号途径。
方法
实验一：苯酚诱导高血压中内皮源性CGRP的变化
苯酚诱导的高血压模型：雄性SD大鼠,左肾下极注射10%苯酚50μl制备高血压模型,15 d后取主动脉、肠系膜上动脉。4%多聚甲醛固定,30%蔗糖过夜,制成冰冻切片。取冰冻切片原位杂交检测血管内皮细胞CGRP mRNA的表达,原位杂交及其以前的各步处理中,所有液体试剂都经DEPC处理,抑制RNA酶的降解作用。原位杂交化学反应按常规步骤进行,NBTBCIP染色,图像分析。另取冰冻切片免疫组化检测血管内皮细胞CGRP含量,免疫组织化学按常规步骤进行,DAB染色,图像分析。实验分为3组：①对照组；②高血压组；③药物处理组：给予哌唑嗪(3mg/kg/d),每d灌胃1次,连续给药14 d。
实验二：去甲肾上腺素对内皮细胞CGRP表达的影响及机制
培养人脐静脉内皮细胞株HUVEC-12,分别加入不同剂量的NE孵育内皮细胞,并在确定其量效和时效关系的基础上分别加入特异性α肾上腺素受体阻断剂(哌唑嗪,育亨宾)和特异性一氧化氮合酶抑制剂(L-NAME)以确定信号途径。RT-PCR检测内皮细胞中CGRP mRNA水平,硝酸还原酶法测定细胞培养上清中的总NO含量。
结果
(1)苯酚诱导高血压中,大鼠主动脉、肠系膜上动脉血管内皮CGRP mRNA的表达和CGRP的含量增加,其作用可被哌唑嗪部分阻断。
(2)NE能剂量依赖性上调内皮源性α-和β-CGRP mRNA的表达,并在培养细胞6 h达到最高水平,此作用能被预先给予育享宾和L-NAME取消,但不受哌唑嗪影响。
(3)NE能增加培养细胞上清中的NO含量,此作用能被预先给予育享宾和L-NAME阻断,哌唑嗪无此作用。
结论
在苯酚诱导的大鼠高血压中,内皮源性CGRP合成与释放增加可能是一种内源性对抗血压升高的代偿机制。内皮细胞CGRP的表达受NE的调节,其机制涉及α2受体及NO通路。
研究背景
新近研究发现,除神经细胞外,非神经组织细胞如淋巴细胞、内皮细胞也能合成CGRP。局部来源的CGRP具有特殊的生理作用。例如淋巴细胞能合成和分泌CGRP,参与调节淋巴细胞对于免疫刺激的应答功能。我们实验室工作表明,原代内皮细胞和人脐静内皮细胞株能合成和分泌CGRP,内皮源性CGRP涉及热应激诱导的内皮保护功能。
可乐定是传统的中枢抗高血压药物,为α2肾上腺素受体激动剂,对中枢神经系统有明显的抑制作用。除降低中枢交感神经张力外,可乐定的抗高血压机制尚不完全清楚。研究表明,可乐定能激动内皮细胞上的α2肾上腺素受体而产生血管舒张作用,此作用可被一氧化氮合酶抑制剂L-NAME所阻断,提示NO通路参与了此过程。
本实验探讨可乐定是否能够通过激动内皮细胞上的α2肾上腺素受体调节CGRP的合成与释放,并确定是否涉及NO途径。
方法
培养人脐静脉内皮细胞株HUVEC-12,分别加入不同剂量的可乐定孵育内皮细胞,在确定其量效和时效关系的基础上分别加入特异性α2肾上腺素受体阻断剂(育亨宾)和特异性一氧化氮合酶抑制剂(L-NAME)以确定信号途径。RT-PCR和Real time-PCR检测内皮细胞中CGRP mRNA水平；放射免疫法检测内皮细胞及培养上清中CGRP的含量；硝酸还原酶法测定细胞培养上清中的总NO含量。
结果
(1)可乐定(10-8,1 0-7和10-6M)孵育内皮细胞24 h可剂量依赖性地升高α-和β-CGRP mRNA的表达水平。
(2)可乐定(10-6M)孵育内皮细胞12 h时CGRP mRNA表达水平开始上升,24 h时达最高峰,48 h时仍维持高水平。
(3)可乐定上调内皮源性CGRP mRNA表达和增加培养细胞及上清中CGRP含量,此作用能被预先给予的育亨宾和L-NAME取消。
结论
可乐定能够通过激动内皮细胞α2肾上腺素受体促进CGRP的合成与释放,此过程涉及NO途径,这可能也是可乐定降压作用的机制之一。
研究背景
肾素-血管紧张素系统(RAS)活性增高是造成血压升高的重要机制之一。研究发现,在肾性和自发性高血压大鼠动物模型长期给予肾素-血管紧张素转换酶抑制剂(ACEI)卡托普利及血管紧张素Ⅰ型受体(AT1)拮抗剂氯沙坦后,降压的同时均伴有CGRP的合成与释放增加,这些研究提示,RAS参与CGRP合成与释放的调节。已知RAS在血管重构和高血压的发生发展中起非常重要作用。RAS对神经源性CGRP表达的调节作用已有文献报道,但其对内皮源性CGRP的表达是否具有调节作用尚未见报道。
血管紧张素Ⅱ(AngⅡ)作为RAS主要的生物活性物质,是机体重要的调节因子,发挥多种生物功能,在血管内外平衡、内膜的形成及心肌梗死后心肌重塑中有重要的作用,可刺激活性氧的产生,诱导血管内皮细胞发生凋亡,而血管内皮细胞凋亡是动脉粥样硬化、心肌梗死等多种心血管疾病发生的始动环节。有文献报道,CGRP具有抗细胞凋亡作用。AngⅡ诱导的内皮细胞凋亡是否与其抑制内皮源性CGRP的表达有关尚不清楚。
新近发现,辣椒素通过激动内皮细胞上的VR1受体能长时程的上调内皮源性CGRP的表达,VR1受体阻断剂caspazepine可以取消此作用。本研究利用培养的内皮细胞探讨以下几个问题：(1) AngⅡ是否能调节内皮源性CGRP合成与释放；(2) CGRP是否具有抗AngⅡ诱导的内皮细胞凋亡的作用；(3)用辣椒素刺激内皮细胞CGRP的合成与释放是否能对抗AngⅡ诱导的内皮细胞凋亡。
方法
实验一：AngⅡ对内皮细胞CGRP合成与释放的影响
培养人脐静脉内皮细胞株HUVEC-12,分别加入不同剂量的AngⅡ孵育内皮细胞,研究其量效和时效关系,并给予特异性ATl受体阻断剂氯沙坦研究其可能的机制。Real time-PCR检测内皮细胞中CGRP mRNA水平；放射免疫法检测内皮细胞及培养上清中CGRP的含量。
实验二：CGRP抗内皮细胞凋亡作用
在培养的人脐静脉内皮细胞给予AngⅡ诱导细胞凋亡,外源性给予CGRP和辣椒素。Hoechst细胞染色、Annexin V-FITC流式细胞检测细胞凋亡；比色法测定caspase-3活性；RT-PCR检测内皮细胞中CGRP、Bcl-2和Bax mRNA的表达。
结果
(1) AngⅡ孵育内皮细胞可剂量和时间依赖性地降低α-和β-CGRP mRNA的表达水平和CGRP含量,此作用可被预先给予的氯沙坦阻断。
(2) CGRP可剂量依赖性降低AngⅡ诱导的内皮细胞凋亡,减弱AngⅡ增加内皮细胞caspase-3活性,此作用能被预先给予的CGRP受体阻断剂CGRP8-37取消。
(3)辣椒素可剂量依赖性上调内皮源性α-和β-CGRP mRNA的表达水平,此作用能被预先给予的VR1受体阻断剂capsazepine取消。
(4)辣椒素可剂量依赖性降低Angll诱导的内皮细胞凋亡,减弱Angll增加内皮细胞caspase-3活性,此作用能被预先给予的capsazepine和CGRP8-37取消。
(5)辣椒素可以上调抗凋亡分子Bcl-2 mRNA的表达,下调促凋亡分子Bax mRNA的表达,此作用能被预先给予的capsazepine和CGRP8-37取消。
结论
AngⅡ能抑制内皮细胞合成与释放CGRP;用辣椒素促进内皮源性CGRP的表达能对抗AngⅡ诱导的内皮细胞凋亡。
Chapter 1
Upregulation of endothelium-derived CGRP production in phenol-induced hypertension via activation ofα2-adrenergic receptor
BACKGROUND
Calcitonin gene-related peptide (CGRP), a very potent vasodilator, is the predominant neurotransmitter in capsaicin-sensitive sensory nerves and widely distributes in the nerve and cardiovascular systems. In peripheral nerve system, the dorsal root ganglia (DRG) are the major site for CGRP synthesis. Besides nerve cells, other type of cells such as human lymphocytes, human typeⅡalveolar epithelial cells, Langerhans cells and endothelial cells has been also reported to synthesize CGRP. There is evidence that local source of CGRP may have special physiological functions. Our recent work has demonstrated that endothelial cell-derived CGRP was involved in heat stress-induced protection of endothelial function. Although the nerve cell-derived CGRP production is decreased in SHR or in phenol-induced hypertensive rats, little is known about the change of endothelia cell-derived CGRP and the underlying mechanisms.
In most of cases, the activity of sympathetic nervous system is increased in hypertension. It has been shown that the plasma level of norepinephrine (NE) was elevated in phenol-induced hypertensive rats. Recently, we have found that activation of a2-adrenoceptor can induce CGRP production in endothelial cells. As a compensatory vasodilator mechanism to counteract the increased blood pressue, we postulate that the endothelium-derived CGRP production is likely upregulated in phenol-induced hypertension through the activation ofα2-adrenegic receptor.
In the present study, by using the established phenol-induced hypertensive rat model and the cultured endothelial cells, we explored the changes in endothelium-derived CGRP production and the involved signal transduction pathway.
METHODS
Hypertensive rats were induced by injecting 50μl of 10% phenol in the lower pole of the left kidney. Fifteen days after phenol treatment, the thoracic aorta and mesenteric artery were excised to determine CGRP peptide and mRNA by immunohistochemistry and in situ hybridization, respectively. In order to test the efect of prazosin on the expression of CGRP, the rats was treated with prazosin (3 mg/kg/d, i.g) for 14 days.
In the cultured HUVEC-12, cells were treated with NE at concentration of 10-9,10-8,10-7,10-6 or 10-5 M for 24 h to evaluate the dose-effect relationship on CGRP expression or incubated with NE at concentration of 10"6M for 6,12,24,36 or 48 h to evaluate the time-effect relationship. Next, the cells were incubated with NE (10-5M) for 6 h after the pretreatment with yohimbine, prazosin or L-NAME for 30 min to determine the likely involved subtype of adrenergic signaling pathway in CGRP mRNA expression and to determine whether NO pathway was also involved. The level of CGRP mRNA was detected by RT-PCR. The level of nitrite/nitrate in the conditioned medium was measured with the Griess regent.
RESULTS
The immunostaining signal of CGRP was significantly increased in the intima layer of aorta or mesenteric artery in the hypertension group, which was attenuated by prazosin treatment. Consistent with the immunostaining results of CGRP protein, the results of in situ hybridization showed that CGRP mRNA expression was significantly increased in the intima layer of aorta or mesenteric artery in the hypertension group, which was attenuated by prazosin treatment.
NE significantly induced CGRP mRNA expression in a dose-dependent manner and increased gradually and reached the highest point at 6 h, and then went down after that, the effect of which was inhibited by yohimbine and L-NAME but not by prazosin, indicating that it isα2-but notα1-adrenoreceptor. NE treatment (10-5M) for 6 h significantly increased the NO level in the culture medium. These effects were attenuated in the presence of yohimbine or L-NAME but not prazosin, consistent with the change of CGRP mRNA expression mentioned above.
CONCLUSION
The present results suggest that the endothelium-derived CGRP production was increased in phenol-induced hypertension, which may represent an endogenous compensatory mechanism to counteract the elevated blood pressure. The up-regulation of endothelium-derived CGRP production is through activation ofα2-adrenergic receptor, which was associated with the NO pathway.
Chapter 2
The effect of clonidine on calcitonin gene-related peptide expression in cultured endothelial cells
BACKGROUND
In addition to nerve cells, other type of cells such as lymphocytes and endothelial cells has been also reported to synthesize CGRP. It has been shown that local source of CGRP may have special physiological significance. For example, lymphocyte was able to produce and secret CGRP, which were supposed to participate in the modulating lymphocyte function in response to immune stimulation. Endothelial cell is able to synthesis and secret CGRP, too. Our recent work has demonstrated that endothelial cell-derived CGRP was involved in heat stress-induced protection of endothelial function.
Clonidine is a centrally acting agonist ofα2 adrenergic receptor prescribed historically as an antihypertensive drug. The mechanism of the anti-hypertensive effect of clonidine is not completely understood but probably reduction of central sympathetic tone must play a very important role. There is evidence that clonidine is able to stimulate the peripheralα2 receptors and induce vasodilatation through activation ofα2 receptors in endothelial cells, an effect which was blocked by L-NAME, the inhibitor of NOS, suggesting that NO pathway may involve in this process.
In the present study, we examined whether clonidine could induce CGRP synthesis and secretion in endothelial cell through activating a2-adrenoceptor and whether clonidine-induced CGRP production is mediated by the NO pathway.
METHODS
Endothelial cells were treated with clonidine at concentration of 10-8, 10-7 or 10-6 M for 24 h to evaluate the dose-effect relationship on CGRP expression or incubated with clonidine at concentration of 10-6M for 12, 24,36 or 48 h to evaluate the time-effect relationship. Next, the cells were incubated with clonidine (10-6M) for 24 h after the pretreatment with yohimbine or L-NAME for 30 min to examine whether the effect of clonidine on regulating CGRP mRNA expression in HUVECs is through the activation of a2-adrenergic receptor and whether NO pathway is involved. The level of CGRP mRNA was detected by RT-PCR and Real time-PCR, while protein level was measured by radioimmunoassay (RIA). The level of nitrite/nitrate in the conditioned medium measured with the Griess regent.
RESULTS
Treating the cells with clonidine significantly induced CGRP mRNA expression in a dose-dependent manner. The expression of CGRP mRNA increased gradually and reached the highest point at 24 h, and then went down after that, the effect of which was inhibited by yohimbine or L-NAME. In line with these results, clonidine treatment also significantly increased CGRP content. These effects were abolished by pretreatment with yohimbine or L-NAME. Clonidine treatment (10-5M) for 24 h significantly increased the NO level in the culture medium. These effects were attenuated in the presence of yohimbine or L-NAME consistent with the change of CGRP mRNA expression mentioned above.
CONCLUSION
The present results suggest that clonidine could stimulate CGRP synthesis and secretion in endothelial cells through activation of a2-adrenoceptor, which is involved in the NO pathway.
Chapter 3
The role of endothelial cell-derived calcitonin gene-related peptide in angiotensinⅡ-induced endothelial cell apoptosis
BACKGROUND
The increase in RAS activity is one of the important mechanisms in the development of hypertension. It has been shown that the synthesis and release of CGRP was increased with the reduced blood pressure after taking captopril or losartan in renal hypertension rat and SHR, suggesting that RAS participated in regulating the synthesis and release of CGRP. It is well known that RAS plays a very important role in vascular remodeling and the decelopment of hypertension. There were reports that RAS participated in the regulation of nerve-derived CGRP. However, little is known about the role of RAS in regulating the endothelium-derived CGRP.
As a major member of RAS, AngⅡpossesses multiplebiological functions. It involves in many pathophysiological process such as vascular remodeling, cellular apoptosis, oxidative stress, etc. Endothelial cell apoptosis has been thought closely related to the development of many cardiovascular diseases such as atherosclerosis and myocardial infarction. There is evidence that CGRP has the property of anti-apoptosis. It is not known whether AngⅡ-induced endothelial cell apoptosis is related to the inhibition of endothelium-derived CGRP expression.
Our recent works has demonstrated that vascular endothelial cell can situ synthesis CGRP and express VR1, and capsaicin can stimulate the expression of endothelial cell-derived CGRP, which is abolished by antagonist of VR1 receptor caspazepine. In the present study, therefore, we explored the role of endothelial cell-derived CGRP in the AngⅡ-induced endothelial cell apoptosis.
METHODS
Endothelial cells were treated with AnglⅡat concentration of 10-8, 10-7 or 10-6 M for 24 h to evaluate the dose-effect relationship on CGRP expression or incubated with AngⅡat concentration of 10"6M for 6,12, 24,36 or 48 h to evaluate the time-effect relationship. Next, the cells were incubated with AngⅡ(10-5M) for 24 h after the pretreatment with losartan for 30 min to determine whether AT1 receptor was involved. The level of CGRP mRNA was detected by Real time-PCR and theprotein level was measured by radioimmunoassay.
To explore the effect of CGRP on the AngⅡ-induced apoptosis, endothelial cells were pretreated with CGRP or capsaicin before AngⅡtreatment. Cell apoptosis was examined by hoechst 33258 staining and FITC-AnnexinⅤflow cytometry. Activity of Caspase 3 was measured by colorimetry. The level of CGRP, Bcl-2 and Bax mRNA were detected by RT-PCR.
RESULTS
AngⅡsignificantly decreasedα-andβ-CGRP mRNA expression and the content of CGRP in cultured endothelial cell in a dose-dependent manner, which was inhibited by pretreatment with losartan. Treating the cells with AngⅡat concentration of 10-6M for 6,12,24,36 or 48 h, the expression level of CGRP(α-andβ-) mRNA decreased gradually from the time point of 6 h.
Pretreatment the cells with exogenous CGRP decreased AngⅡ-induced endothelial cell apoptosis accompanied by the decreased caspase-3 activity, which was attenuated in the presence of CGRP8-37, the antagonist of CGRP receptor
Treating the cells with capsaicin at concentration of 10-8,10-7 or 10-6 M for 24 h, the expression level of CGRP(αandβ) mRNA increased in a dose-dependent manner, which was inhibited by capsazepine, the antagonist of VR1 receptor
Pretreatment the cells with capsaicin decreased AngⅡ-induced endothelial cell apoptosis accompanied by the increased Bcl-2 mRNA expression, the decreased Bax mRNA expression and caspase-3activity which was attenuated in the presence of capsazepine or CGRP8-37.
CONCLUSION
AngⅡis able to inhibit the synthesis and release of CGRP in the cultured HUVECs, which may contribute to AngⅡ-induced endothelial cell apoptosis. Exogenous administration of CGRP or stimulating the synthesis of endogenous CGRP may provide a novel approach to prevent the AngⅡ-induced endothelial cell apoptosis.
引文
[1]Deng PY, Li YJ:Calcitonin gene-related peptide and hypertension. Peptides 2005,26(9):1676-1685.
[2]Westlund KN, DiPette DJ, Carson J, Holland OB:Decreased spinal cord content of calcitonin gene-related peptide in the spontaneously hypertensive rat. Neurosci Lett 1991,131(2):183-186.
[3]Gangula PR, Zhao H, Supowit SC, Wimalawansa SJ, Dipette DJ, Westlund KN, Gagel RF, Yallampalli C:Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice. Hypertension 2000,35(1 Pt 2):470-475.
[4]Katki KA, Supowit SC, DiPette DJ:Role of calcitonin gene-related peptide and substance P in Dahl-salt hypertension. Hypertension 2001,38(3 Pt 2):679-682.
[5]Chattergoon NN, D'Souza FM, Deng W, Chen H, Hyman AL, Kadowitz PJ, Jeter JR, Jr.:Antiproliferative effects of calcitonin gene-related peptide in aortic and pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2005,288(1):L202-211.
[6]Gangula PR, Supowit SC, Wimalawansa SJ, Zhao H, Hallman DM, DiPette DJ, Yallampalli C:Calcitonin gene-related peptide is a depressor in NG-nitro-L-arginine methyl ester-induced hypertension during pregnancy. Hypertension 1997,29(1 Pt 2):248-253.
[7]Deng PY, Ye F, Zhu HQ, Cai WJ, Deng HW, Li YJ:An increase in the synthesis and release of calcitonin gene-related peptide in two-kidney, one-clip hypertensive rats. Regul Pept 2003,114(2-3):175-182.
[8]Wang H, Xing L, Li W, Hou L, Guo J, Wang X:Production and secretion of calcitonin gene-related peptide from human lymphocytes. J Neuroimmunol 2002,130(1-2):155-162.
[9]Li W, Hou L, Hua Z, Wang X:Interleukin-lbeta induces beta-calcitonin gene-related peptide secretion in human type II alveolar epithelial cells. Faseb J 2004,18(13):1603-1605.
[10]He Y, Ding G, Wang X, Zhu T, Fan S:Calcitonin gene-related peptide in Langerhans cells in psoriatic plaque lesions. Chin Med J (Engl) 2000, 113(8):747-751.
[11]Doi Y, Kudo H, Nishino T, Kayashima K, Kiyonaga H, Nagata T, Nara S, Morita M, Fujimoto S:Synthesis of calcitonin gene-related peptide (CGRP) by rat arterial endothelial cells. Histol Histopathol 2001,16(4):1073-1079.
[12]Luo D, Zhang YW, Peng WJ, Peng J, Chen QQ, Li D, Deng HW, Li YJ: Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide. Regul Pept 2008, 150(1-3):66-72.
[13]Zhang YM, Peng J, Hu CP, Jiang QT, Jiang GL, Li YJ:Clonidine induces calcitonin gene-related peptide expression via nitric oxide pathway in endothelial cells. Peptides 2009,30(9):1746-1752.
[14]Cai WQ, Dikranian K, Bodin P, Turmaine M, Burnstock G:Colocalization of vasoactive substances in the endothelial cells of human umbilical vessels. Cell Tissue Res 1993,274(3):533-538.
[15]Ye F, Deng PY, Li D, Luo D, Li NS, Deng S, Deng HW, Li YJ:Involvement of endothelial cell-derived CGRP in heat stress-induced protection of endothelial function. Vascul Pharmacol 2007,46(4):238-246.
[16]Ye S, Zhong H, Duong VN, Campese VM:Losartan reduces central and peripheral sympathetic nerve activity in a rat model of neurogenic hypertension. Hypertension 2002,39(6):1101-1106.
[17]Ye S, Zhong H, Yanamadala V, Campese VM:Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity. Am J Hypertens 2002,15(8):717-724.
[18]Deng PY, Ye F, Cai WJ, Deng HW, Li YJ:Role of calcitonin gene-related peptide in the phenol-induced neurogenic hypertension in rats. Regul Pept 2004, 119(3):155-161.
[19]Deng PY, Yu J, Ye F, Li D, Luo D, Cai WJ, Zhang JW, Luo XG, Deng HW, Li YJ:Interactions of sympathetic nerves with capsaicin-sensitive sensory nerves: neurogenic mechanisms for phenol-induced hypertension in the rat. J Hypertens 2005,23(3):603-609.
[20]Bell D, McDermott BJ:Calcitonin gene-related peptide in the cardiovascular system:characterization of receptor populations and their (patho) physiological significance. Pharmacol Rev 1996,48(2):253-288.
[21]Peng J, Li YJ:New insights into nitroglycerin effects and tolerance:role of calcitonin gene-related peptide. Eur J Pharmacol 2008,586(1-3):9-13.
[22]Marquez-Rodas I, Longo F, Rothlin RP, Balfagon G:Pathophysiology and therapeutic possibilities of calcitonin gene-related peptide in hypertension. J Physiol Biochem 2006,62(1):45-56.
[23]Li J, Vause CV, Durham PL:Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Res 2008,1196:22-32.
[24]Li D, Chen BM, Peng J, Zhang YS, Li XH, Yuan Q, Hu CP, Deng HW, Li YJ: Role of anandamide transporter in regulating calcitonin gene-related peptide production and blood pressure in hypertension. J Hypertens 2009,27(6): 1224-1232.
[25]Wang ZG, Liu JL, Liu Y, Wen SJ, Wen J, Liu YP, Chen XJ, Wu ZS:[Increased plasma vasoactive substances and antioxidant enzymes levels in prehypertensive patients]. Zhonghua Xin Xue Guan Bing Za Zhi 2007,35(8): 719-722.
[26]Kuwasako K, Kitamura K:Bone and bone related biochemical examinations. Hormone and hormone related substances. Calcitonin gene-related peptide (CGRP). Clin Calcium 2006,16(6):905-912.
[27]Jin WY, Sun W, Zhang YZ, Li HY, Chen MZ, Guo JX:[Effect of benidipine on plasma level of calcitonin gene-related peptide in essential hypertension]. Zhonghua Nei Ke Za Zhi 2004,43(10):747-749.
[28]Harada N, Shimozawa N, Okajima K:AT (1) receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats. Transl Res 2009,154(3):142-152.
[29]Supowit SC, Hallman DM, Zhao H, Dipette DJ:Alpha 2-adrenergic receptor activation inhibits calcitonin gene-related peptide expression in cultured dorsal root ganglia neurons. Brain Res 1998,782(1-2):184-193.
[30]Strecker T, Koulchitsky S, Dieterle A, Neuhuber WL, Weyand M, Messlinger K: Release of calcitonin gene-related peptide from the jugular-nodose ganglion complex in rats--a new model to examine the role of cardiac peptidergic and nitrergic innervation. Neuropeptides 2008,42(5-6):543-550.
[31]Eberhardt M, Neeb L, Vogel EM, Tiegs G, Reuter U, Messlinger K, Fischer MJ: Glyceroltrinitrate facilitates stimulated CGRP release but not gene expression of CGRP or its receptor components in rat trigeminal ganglia. Neuropeptides 2009, 43(6):483-489.
[32]Brzozowski T, Konturek PC, Sliwowski Z, Drozdowicz D, Burnat G, Pajdo R, Pawlik M, Bielanski W, Kato I, Kuwahara A et al:Gastroprotective action of orexin-A against stress-induced gastric damage is mediated by endogenous prostaglandins, sensory afferent neuropeptides and nitric oxide. Regul Pept 2008,148(1-3):6-20.
[33]Chen QQ, Li D, Guo R, Luo D, Yang J, Hu CP, Li YJ:Decrease in the synthesis and release of calcitonin gene-related peptide in dorsal root ganglia of spontaneously hypertensive rat:role of nitric oxide synthase inhibitors. Eur J Pharmacol 2008,596(1-3):132-137.
[34]Strecker T, Dux M, Messlinger K:Nitric oxide releases calcitonin-gene-related peptide from rat dura mater encephali promoting increases in meningeal blood flow. J Vase Res 2002,39(6):489-496.
[1]Bell D, McDermott BJ:Calcitonin gene-related peptide in the cardiovascular system:characterization of receptor populations and their (patho) physiological significance. Pharmacol Rev 1996,48(2):253-288.
[2]Deng PY, Li YJ:Calcitonin gene-related peptide and hypertension. Peptides 2005,26(9):1676-1685.
[3]Luo D, Zhang YW, Peng WJ, Peng J, Chen QQ, Li D, Deng HW, Li YJ:
Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide. Regul Pept 2008,150 (1-3):66-72.
[4]Wang H, Xing L, Li W, Hou L, Guo J, Wang X:Production and secretion of calcitonin gene-related peptide from human lymphocytes. J Neuroimmunol 2002,130(1-2):155-162.
[5]Cai WQ, Dikranian K, Bodin P, Turmaine M, Burnstock G:Colocalization of vasoactive substances in the endothelial cells of human umbilical vessels. Cell Tissue Res 1993,274(3):533-538.
[6]Ozaka T, Doi Y, Kayashima K, Fujimoto S:Weibel-Palade bodies as a storage site of calcitonin gene-related peptide and endothelin-1 in blood vessels of the rat carotid body. Anat Rec 1997,247(3):388-394.
[7]Doi Y, Kudo H, Nishino T, Kayashima K, Kiyonaga H, Nagata T, Nara S, Morita M, Fujimoto S:Synthesis of calcitonin gene-related peptide (CGRP) by rat arterial endothelial cells. Histol Histopathol 2001,16(4):1073-1079.
[8]Ye F, Deng PY, Li D, Luo D, Li NS, Deng S, Deng HW, Li YJ:Involvement of endothelial cell-derived CGRP in heat stress-induced protection of endothelial function. Vascul Pharmacol 2007,46(4):238-246.
[9]Zhu QM, Lesnick JD, Jasper JR, MacLennan SJ, Dillon MP, Eglen RM, Blue DR, Jr.:Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice. Br J Pharmacol 1999,126(6):1522-1530.
[10]Pimentel AM, Costa CA, Carvalho LC, Brandao RM, Rangel BM, Tano T, Soares de Moura R, Resende AC:The role of NO-cGMP pathway and potassium channels on the relaxation induced by clonidine in the rat mesenteric arterial bed. Vascul Pharmacol 2007,46(5):353-359.
[11]Booth BP, Tabrizi-Fard MA, Fung H:Calcitonin gene-related peptide-dependent vascular relaxation of rat aorta. An additional mechanism for nitroglycerin. Biochem Pharmacol 2000,59(12):1603-1609.
[12]Peng J, Li YJ:New insights into nitroglycerin effects and tolerance:role of calcitonin gene-related peptide. Eur J Pharmacol 2008,586(1-3):9-13.
[13]Wang X, Xing L, Xing Y, Tang Y, Han C:Identification and characterization of immunoreactive calcitonin gene-related peptide from lymphocytes of the rat. J Neuroimmunol 1999,94(1-2):95-102.
[14]Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre Ⅰ:Calcitonin gene-related peptide is a potent vasodilator. Nature 1985,313(5997):54-56.
[15]Lu LF, Fiscus RR:Nitric oxide donors enhance calcitonin gene-related peptide-induced elevations of cyclic AMP in vascular smooth muscle cells. Eur J Pharmacol 1999,376(3):307-314.
[16]de Hoon JN, Pickkers P, Smits P, Struijker-Boudier HA, Van Bortel LM: Calcitonin gene-related peptide:exploring its vasodilating mechanism of action in humans. Clin Pharmacol Ther 2003,73(4):312-321.
[17]Brain SD, Grant AD:Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 2004,84(3):903-934.
[18]Li D, Peng J, Xin HY, Luo D, Zhang YS, Zhou Z, Jiang DJ, Deng HW, Li YJ: Calcitonin gene-related peptide-mediated antihypertensive and anti-platelet effects by rutaecarpine in spontaneously hypertensive rats. Peptides 2008, 29(10):1781-1788.
[19]Marquez-Rodas I, Longo F, Rothlin RP, Balfagon G:Pathophysiology and therapeutic possibilities of calcitonin gene-related peptide in hypertension. J Physiol Biochem 2006,62(1):45-56.
[20]Portaluppi F, Trasforini G, Margutti A, Vergnani L, Ambrosio MR, Rossi R, Bagni B, Pansini R, degli Uberti EC:Circadian rhythm of calcitonin gene-related peptide in uncomplicated essential hypertension. J Hypertens 1992, 10(10):1227-1234.
[21]Shi XY, Yang Y, Zhao YT:[Plasma calcitonin gene-related peptide (CGRP) level in patients with essential hypertension]. Zhonghua Nei Ke Za Zhi 1990, 29(10):616-618,639.
[22]Deng PY, Ye F, Zhu HQ, Cai WJ, Deng HW, Li YJ:An increase in the synthesis and release of calcitonin gene-related peptide in two-kidney, one-clip hypertensive rats. Regul Pept 2003,114(2-3):175-182.
[23]Booth BP, Nolan TD, Fung HL:Nitroglycerin-inhibited whole blood
aggregation is partially mediated by calcitonin gene-related peptide--a neurogenic mechanism. Br J Pharmacol 1997,'122(3):577-583.
[24]Wei EP, Moskowitz MA, Boccalini P, Kontos HA:Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arterioles. Circ Res 1992,70(6):1313-1319.
[25]Wang X, Wu ZX, Tang YM, Han QD:Endotoxin causes release of calcitonin gene-related peptide (CGRP) from the isolated mesenteric arterial bed in rat. Sheng Li Xue Bao 1996,48(1):37-42.
[26]Zhou ZH, Deng HW, Li YJ:Involvement of calcitonin gene-related peptide in the development of tolerance to nitroglycerin in the rat. Eur J Pharmacol 2001, 427(2):137-141.
[27]Zhou ZH, Jiang JL, Peng J, Deng HW, Li YJ:Reversal of tolerance to nitroglycerin with N-acetylcysteine or captopril:a role of calcitonin gene-related peptide. Eur J Pharmacol 2002,439(1-3):129-134.
[28]Villalon CM, Albarran-Juarez JA, Lozano-Cuenca J, Pertz HH, Gornemann T, Centurion D:Pharmacological profile of the clonidine-induced inhibition of vasodepressor sensory outflow in pithed rats:correlation with alpha(2A/2C)-adrenoceptors. Br J Pharmacol 2008,154(1):51-59.
[29]Frisk-Holmberg M, Paalzow L, Wibell L:Relationship between the cardiovascular effects and steady-state kinetics of clonidine in hypertension. Demonstration of a therapeutic window in man. Eur J Clin Pharmacol 1984, 26(3):309-313.
[30]Wing LM, Reid JL, Davies DS, Neill EA, Tippett P, Dollery CT: Pharmacokinetic and concentration-effect relationships of clonidine in essential hypertension. Eur J Clin Pharmacol 1977,12(6):463-469.
[31]Hastings RH, Hua XY:Expression of calcitonin gene-related peptide by cultured rat alveolar type Ⅱ cells. Am J Respir Cell Mol Biol 1995, 13(5):563-569.
[32]Li W, Hou L, Hua Z, Wang X:Interleukin-lbeta induces beta-calcitonin gene-related peptide secretion in human type II alveolar epithelial cells. Faseb J 2004,18(13):1603-1605.
[33]Xing L, Guo J, Wang X:Induction and expression of beta-calcitonin gene-related peptide in rat T lymphocytes and its significance. J Immunol 2000, 165(8):4359-4366.
[1]Hobara N, Gessei-Tsutsumi N, Goda M, Takayama F, Akiyama S, Kurosaki Y, Kawasaki H:Long-term inhibition of angiotensin prevents reduction of periarterial innervation of calcitonin gene-related peptide (CGRP)-containing nerves in spontaneously hypertensive rats. Hypertens Res 2005,28(5):465-474.
[2]Kramer HH, Schmidt K, Leis S, Schmelz M, Sommer C, Birklein F: Angiotensin converting enzyme has an inhibitory role in CGRP metabolism in human skin. Peptides 2006,27(4):917-920.
[3]Thota C, Yallampalli C:Progesterone upregulates calcitonin gene-related peptide and adrenomedullin receptor components and cyclic adenosine 3'5'-monophosphate generation in Eker rat uterine smooth muscle cell line. Biol Reprod 2005,72(2):416-422.
[4]Ferrario CM, Strawn WB:Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 2006, 98(1):121-128.
[5]Dimmeler S, Zeiher AM:Reactive oxygen species and vascular cell apoptosis in response to angiotensin Ⅱ and pro-atherosclerotic factors. Regul Pept 2000, 90(1-3):19-25.
[6]Bonavita F, Stefanelli C, Giordano E, Columbaro M, Facchini A, Bonafe F, Caldarera CM, Guarnieri C:H9c2 cardiac myoblasts undergo apoptosis in a model of ischemia consisting of serum deprivation and hypoxia:inhibition by PMA. FEBS Lett 2003,536(1-3):85-91.
[7]Shichiri M, Kato H, Doi M, Marumo F, Hirata Y:Induction of max by adrenomedullin and calcitonin gene-related peptide antagonizes endothelial apoptosis. Mol Endocrinol 1999,13(8):1353-1363.
[8]Song S, Liu N, Liu W, Shi R, Guo KJ, Liu YF:The effect of pretreatment with calcitonin gene-related peptide on attenuation of liver ischemia and reperfusion injury due to oxygen free radicals and apoptosis. Hepatogastroenterology 2009, 56(96):1724-1729.
[9]Song SW, Guo KJ, Shi R, Cheng Y, Liu YF:Pretreatment with calcitonin gene-related peptide attenuates hepatic ischemia/reperfusion injury in rats. Transplant Proc 2009,41(5):1493-1498.
[10]Chan JJ, Farmer PJ, Southwell BR, Sourial M, Hutson JM:Calcitonin gene-related peptide is a survival factor, inhibiting apoptosis in neonatal rat gubernaculum in vitro. J Pediatr Surg 2009,44(8):1497-1501.
[11]Fu HM, Xu F, Liu CJ, Kuang FW, Huang B, Fang F, Fu YQ:Influence of 60% oxygen inhalation on type Ⅱ alveolar epithelial cells and protective role of calcitonin gene-related peptide from their damage induced in premature rat. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2008,20(10):578-581.
[12]Li W, Hou L, Hua Z, Wang X:Interleukin-lbeta induces beta-calcitonin gene-related peptide secretion in human type Ⅱ alveolar epithelial cells. Faseb J 2004,18(13):1603-1605.
[13]Wang H, Xing L, Li W, Hou L, Guo J, Wang X:Production and secretion of calcitonin gene-related peptide from human lymphocytes. J Neuroimmunol 2002,130(1-2):155-162.
[14]Zhou FW, Li YJ, Deng HW:Early and delayed protection by capsaicin against reperfusion injury in rat hearts. Zhongguo Yao Li Xue Bao 1999,20 (10): 912-916.
[15]Tang YH, Lu R, Li YJ, Peng CF, Deng HW:Effect of calcitonin gene-related peptide-induced preconditioning on attenuated endothelium-dependent vasorelaxation induced by lysophosphatidylcholine. Zhongguo Yao Li Xue Bao 1997,18(5):405-407.
[16]Luo D, Zhang YW, Peng WJ, Peng J, Chen QQ, Li D, Deng HW, Li YJ: Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide. Regul Pept 2008, 150(1-3):66-72.
[17]Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM:Angiotensin Ⅱ induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circ Res 1997,81(6):970-976.
[18]Shan HY, Bai XJ, Chen XM:Apoptosis is involved in the senescence of endothelial cells induced by angiotensin Ⅱ. Cell Biol Int 2008,32(2):264-270.
[19]Qin XP, Ye F, Hu CP, Liao DF, Deng HW, Li YJ:Effect of calcitonin gene-related peptide on angiotensin II-induced proliferation of rat vascular smooth muscle cells. Eur J Pharmacol 2004,488(1-3):45-49.
[20]Sueur S, Pesant M, Rochette L, Connat JL:Antiapoptotic effect of calcitonin gene-related peptide on oxidative stress-induced injury in H9c2 cardiomyocytes via the RAMP1/CRLR complex. J Mol Cell Cardiol 2005,39(6):955-963.
[1]Luo D, Deng PY, Ye F, Peng WJ, Deng HW, Li YJ:Delayed preconditioning by cardiac ischemia involves endogenous calcitonin gene-related peptide via the nitric oxide pathway. Eur J Pharmacol 2004,502(1-2):135-141.
[2]Li D, Li NS, Chen QQ, Guo R, Xu PS, Deng HW, Li YJ:Calcitonin gene-related peptide-mediated cardioprotection of postconditioning in isolated rat hearts. Regul Pept 2008,147(1-3):4-8.
[3]Ye F, Deng PY, Li D, Luo D, Li NS, Deng S, Deng HW, Li YJ:Involvement of endothelial cell-derived CGRP in heat stress-induced protection of endothelial function. Vascul Pharmacol 2007,46(4):238-246.
[4]Luo D, Zhang YW, Peng WJ, Peng J, Chen QQ, Li D, Deng HW, Li YJ:
Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide. Regul Pept 2008, 150(1-3):66-72.
[5]Chattergoon NN, D'Souza FM, Deng W, Chen H, Hyman AL, Kadowitz PJ, Jeter JR, Jr.:Antiproliferative effects of calcitonin gene-related peptide in aortic and pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2005,288(1):L202-211.
[6]Qin XP, Ye F, Hu CP, Liao DF, Deng HW, Li YJ:Effect of calcitonin gene-related peptide on angiotensin II-induced proliferation of rat vascular smooth muscle cells. Eur J Pharmacol 2004,488(1-3):45-49.
[7]Peng J, Li YJ:The vanilloid receptor TRPV1:Role in cardiovascular and gastrointestinal protection. Eur J Pharmacol 2009,627(1-3):1-7.
[8]Feng G, Xu X, Wang Q, Liu Z, Li Z, Liu G:The protective effects of calcitonin gene-related peptide on gastric mucosa injury after cerebral ischemia reperfusion in rats. Regul Pept 2009,160(1-3):121-128..
[9]Evangelista S:Role of calcitonin gene-related Peptide in gastric mucosal defence and healing. Curr Pharm Des 2009,15(30):3571-3576.
[10]Ohno T, Hattori Y, Komine R, Ae T, Mizuguchi S, Arai K, Saeki T, Suzuki T, Hosono K, Hayashi I et al:Roles of calcitonin gene-related peptide in maintenance of gastric mucosal integrity and in enhancement of ulcer healing and angiogenesis. Gastroenterology 2008,134(1):215-225.
[11]Huang W, Wang H, Galligan JJ, Wang DH:Transient receptor potential vanilloid subtype 1 channel mediated neuropeptide secretion and depressor effects:role of endoplasmic reticulum associated Ca2+release receptors in rat dorsal root ganglion neurons. J Hypertens 2008,26(10):1966-1975.
[12]Wang DH:The vanilloid receptor and hypertension. Acta Pharmacol Sin 2005, 26(3):286-294.
[13]Demirbilek S, Ersoy MO, Demirbilek S, Karaman A, Gurbuz N, Bayraktar N, Bayraktar M:Small-dose capsaicin reduces systemic inflammatory responses in septic rats. Anesth Analg 2004,99(5):1501-1507; table of contents.
[14]Hu CP, Li NS, Xiao L, Deng HW, Li YJ:Involvement of capsaicin-sensitive
sensory nerves in cardioprotection of rutaecarpine in rats. Regul Pept 2003, 114(1):45-49.
[15]Hu CP, Xiao L, Deng HW, Li YJ:The cardioprotection of rutaecarpine is mediated by endogenous calcitonin related-gene peptide through activation of vanilloid receptors in guinea-pig hearts. Planta Med 2002,68(8):705-709.
[16]Xing Y, Liu Z, Wang LH, Huang F, Wang HJ, Li ZZ:Butyrate sensitizes the release of substance P and calcitonin gene-related peptide evoked by capsaicin from primary cultured rat dorsal root ganglion neurons. Neuro Endocrinol Lett 2006,27(6):695-701.
[17]Yang X, Han JQ, Liu R:Effects of experimental colitis on the expressions of calcitonin gene-related peptide and vanilloid receptor 1 in rat spinal cord sensory neurons. Sheng Li Xue Bao 2008,60(1):143-148.
[18]Sugiyama T, Hatanaka Y, Iwatani Y, Jin X, Kawasaki H:Lafutidine facilitates calcitonin gene-related peptide (CGRP) nerve-mediated vasodilation via vanilloid-1 receptors in rat mesenteric resistance arteries. J Pharmacol Sci 2008, 106(3):505-511.
[19]Price TJ, Patwardhan AM, Flores CM, Hargreaves KM:A role for the anandamide membrane transporter in TRPV1-mediated neurosecretion from trigeminal sensory neurons. Neuropharmacology 2005,49(1):25-39.
[20]Li D, Chen BM, Peng J, Zhang YS, Li XH, Yuan Q, Hu CP, Deng HW, Li YJ: Role of anandamide transporter in regulating calcitonin gene-related peptide production and blood pressure in hypertension. J Hypertens 2009, 27(6):1224-1232.
[21]Deng PY, Ye F, Cai WJ, Deng HW, Li YJ:Role of calcitonin gene-related peptide in the phenol-induced neurogenic hypertension in rats. Regul Pept 2004, 119(3):155-161.
[22]Zhang YM, Peng J, Hu CP, Jiang QT, Jiang GL, Li YJ:Clonidine induces calcitonin gene-related peptide expression via nitric oxide pathway in endothelial cells. Peptides 2009,30(9):1746-1752.
[23]Hobara N, Gessei-Tsutsumi N, Goda M, Takayama F, Akiyama S, Kurosaki Y, Kawasaki H:Long-term inhibition of angiotensin prevents reduction of
periarterial innervation of calcitonin gene-related peptide (CGRP)-containing nerves in spontaneously hypertensive rats. Hypertens Res 2005,28(5):465-474.
[24]Kramer HH, Schmidt K, Leis S, Schmelz M, Sommer C, Birklein F: Angiotensin converting enzyme has an inhibitory role in CGRP metabolism in human skin. Peptides 2006,27(4):917-920.
[25]Thota C, Yallampalli C:Progesterone upregulates calcitonin gene-related peptide and adrenomedullin receptor components and cyclic adenosine 3'5'-monophosphate generation in Eker rat uterine smooth muscle cell line. Biol Reprod 2005,72(2):416-422.
[26]Harada N, Shimozawa N, Okajima K:AT(1) receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats. Transl Res 2009,154(3):142-152.
[27]Schnegelsberg B, Sun TT, Cain G, Bhattacharya A, Nunn PA, Ford AP, Vizzard MA, Cockayne DA:Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity and changes in urinary bladder function. Am J Physiol Regul Integr Comp Physiol 2009,298(3):534-547.
[28]Strecker T, Koulchitsky S, Dieterle A, Neuhuber WL, Weyand M, Messlinger K: Release of calcitonin gene-related peptide from the jugular-nodose ganglion complex in rats--a new model to examine the role of cardiac peptidergic and nitrergic innervation. Neuropeptides 2008,42(5-6):543-550.
[29]Chen QQ, Li D, Guo R, Luo D, Yang J, Hu CP, Li YJ:Decrease in the synthesis and release of calcitonin gene-related peptide in dorsal root ganglia of spontaneously hypertensive rat:role of nitric oxide synthase inhibitors. Eur J Pharmacol 2008,596(1-3):132-137.
[30]Zhang W, Zhao Y, Wang L:[The changes of plasma calcitonin gene-related peptide level in women with normal pregnancy and pregnancy induced hypertension]. Zhonghua Fu Chan Ke Za Zhi 1998,33(12):715-716.
[31]Supowit SC, Zhao H, Hallman DM, DiPette DJ:Calcitonin gene-related peptide is a depressor of deoxycorticosterone-salt hypertension in the rat. Hypertension 1997,29(4):945-950.
[32]Deng PY, Ye F, Zhu HQ, Cai WJ, Deng HW, Li YJ:An increase in the synthesis
and release of calcitonin gene-related peptide in two-kidney, one-clip hypertensive rats. Regul Pept 2003,114(2-3):175-182.
[33]Deng PY, Li YJ:Calcitonin gene-related peptide and hypertension. Peptides 2005,26(9):1676-1685.
[34]Li D, Peng J, Xin HY, Luo D, Zhang YS, Zhou Z, Jiang DJ, Deng HW, Li YJ: Calcitonin gene-related peptide-mediated antihypertensive and anti-platelet effects by rutaecarpine in spontaneously hypertensive rats. Peptides 2008, 29(10):1781-1788.
[35]Qin XP, Ye F, Liao DF, Li YJ:Involvement of calcitonin gene-related peptide in the depressor effects of losartan and perindopril in rats. Eur J Pharmacol 2003, 464(1):63-67.
[2]Westlund KN, DiPette DJ, Carson J, Holland OB:Decreased spinal cord content of calcitonin gene-related peptide in the spontaneously hypertensive rat. Neurosci Lett 1991,131(2):183-186.
[3]Gangula PR, Zhao H, Supowit SC, Wimalawansa SJ, Dipette DJ, Westlund KN, Gagel RF, Yallampalli C:Increased blood pressure in alpha-calcitonin gene-related peptide/calcitonin gene knockout mice. Hypertension 2000,35(1 Pt 2):470-475.
[4]Katki KA, Supowit SC, DiPette DJ:Role of calcitonin gene-related peptide and substance P in Dahl-salt hypertension. Hypertension 2001,38(3 Pt 2):679-682.
[5]Chattergoon NN, D'Souza FM, Deng W, Chen H, Hyman AL, Kadowitz PJ, Jeter JR, Jr.:Antiproliferative effects of calcitonin gene-related peptide in aortic and pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2005,288(1):L202-211.
[6]Gangula PR, Supowit SC, Wimalawansa SJ, Zhao H, Hallman DM, DiPette DJ, Yallampalli C:Calcitonin gene-related peptide is a depressor in NG-nitro-L-arginine methyl ester-induced hypertension during pregnancy. Hypertension 1997,29(1 Pt 2):248-253.
[7]Deng PY, Ye F, Zhu HQ, Cai WJ, Deng HW, Li YJ:An increase in the synthesis and release of calcitonin gene-related peptide in two-kidney, one-clip hypertensive rats. Regul Pept 2003,114(2-3):175-182.
[8]Wang H, Xing L, Li W, Hou L, Guo J, Wang X:Production and secretion of calcitonin gene-related peptide from human lymphocytes. J Neuroimmunol 2002,130(1-2):155-162.
[9]Li W, Hou L, Hua Z, Wang X:Interleukin-lbeta induces beta-calcitonin gene-related peptide secretion in human type II alveolar epithelial cells. Faseb J 2004,18(13):1603-1605.
[10]He Y, Ding G, Wang X, Zhu T, Fan S:Calcitonin gene-related peptide in Langerhans cells in psoriatic plaque lesions. Chin Med J (Engl) 2000, 113(8):747-751.
[11]Doi Y, Kudo H, Nishino T, Kayashima K, Kiyonaga H, Nagata T, Nara S, Morita M, Fujimoto S:Synthesis of calcitonin gene-related peptide (CGRP) by rat arterial endothelial cells. Histol Histopathol 2001,16(4):1073-1079.
[12]Luo D, Zhang YW, Peng WJ, Peng J, Chen QQ, Li D, Deng HW, Li YJ: Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide. Regul Pept 2008, 150(1-3):66-72.
[13]Zhang YM, Peng J, Hu CP, Jiang QT, Jiang GL, Li YJ:Clonidine induces calcitonin gene-related peptide expression via nitric oxide pathway in endothelial cells. Peptides 2009,30(9):1746-1752.
[14]Cai WQ, Dikranian K, Bodin P, Turmaine M, Burnstock G:Colocalization of vasoactive substances in the endothelial cells of human umbilical vessels. Cell Tissue Res 1993,274(3):533-538.
[15]Ye F, Deng PY, Li D, Luo D, Li NS, Deng S, Deng HW, Li YJ:Involvement of endothelial cell-derived CGRP in heat stress-induced protection of endothelial function. Vascul Pharmacol 2007,46(4):238-246.
[16]Ye S, Zhong H, Duong VN, Campese VM:Losartan reduces central and peripheral sympathetic nerve activity in a rat model of neurogenic hypertension. Hypertension 2002,39(6):1101-1106.
[17]Ye S, Zhong H, Yanamadala V, Campese VM:Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity. Am J Hypertens 2002,15(8):717-724.
[18]Deng PY, Ye F, Cai WJ, Deng HW, Li YJ:Role of calcitonin gene-related peptide in the phenol-induced neurogenic hypertension in rats. Regul Pept 2004, 119(3):155-161.
[19]Deng PY, Yu J, Ye F, Li D, Luo D, Cai WJ, Zhang JW, Luo XG, Deng HW, Li YJ:Interactions of sympathetic nerves with capsaicin-sensitive sensory nerves: neurogenic mechanisms for phenol-induced hypertension in the rat. J Hypertens 2005,23(3):603-609.
[20]Bell D, McDermott BJ:Calcitonin gene-related peptide in the cardiovascular system:characterization of receptor populations and their (patho) physiological significance. Pharmacol Rev 1996,48(2):253-288.
[21]Peng J, Li YJ:New insights into nitroglycerin effects and tolerance:role of calcitonin gene-related peptide. Eur J Pharmacol 2008,586(1-3):9-13.
[22]Marquez-Rodas I, Longo F, Rothlin RP, Balfagon G:Pathophysiology and therapeutic possibilities of calcitonin gene-related peptide in hypertension. J Physiol Biochem 2006,62(1):45-56.
[23]Li J, Vause CV, Durham PL:Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells. Brain Res 2008,1196:22-32.
[24]Li D, Chen BM, Peng J, Zhang YS, Li XH, Yuan Q, Hu CP, Deng HW, Li YJ: Role of anandamide transporter in regulating calcitonin gene-related peptide production and blood pressure in hypertension. J Hypertens 2009,27(6): 1224-1232.
[25]Wang ZG, Liu JL, Liu Y, Wen SJ, Wen J, Liu YP, Chen XJ, Wu ZS:[Increased plasma vasoactive substances and antioxidant enzymes levels in prehypertensive patients]. Zhonghua Xin Xue Guan Bing Za Zhi 2007,35(8): 719-722.
[26]Kuwasako K, Kitamura K:Bone and bone related biochemical examinations. Hormone and hormone related substances. Calcitonin gene-related peptide (CGRP). Clin Calcium 2006,16(6):905-912.
[27]Jin WY, Sun W, Zhang YZ, Li HY, Chen MZ, Guo JX:[Effect of benidipine on plasma level of calcitonin gene-related peptide in essential hypertension]. Zhonghua Nei Ke Za Zhi 2004,43(10):747-749.
[28]Harada N, Shimozawa N, Okajima K:AT (1) receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats. Transl Res 2009,154(3):142-152.
[29]Supowit SC, Hallman DM, Zhao H, Dipette DJ:Alpha 2-adrenergic receptor activation inhibits calcitonin gene-related peptide expression in cultured dorsal root ganglia neurons. Brain Res 1998,782(1-2):184-193.
[30]Strecker T, Koulchitsky S, Dieterle A, Neuhuber WL, Weyand M, Messlinger K: Release of calcitonin gene-related peptide from the jugular-nodose ganglion complex in rats--a new model to examine the role of cardiac peptidergic and nitrergic innervation. Neuropeptides 2008,42(5-6):543-550.
[31]Eberhardt M, Neeb L, Vogel EM, Tiegs G, Reuter U, Messlinger K, Fischer MJ: Glyceroltrinitrate facilitates stimulated CGRP release but not gene expression of CGRP or its receptor components in rat trigeminal ganglia. Neuropeptides 2009, 43(6):483-489.
[32]Brzozowski T, Konturek PC, Sliwowski Z, Drozdowicz D, Burnat G, Pajdo R, Pawlik M, Bielanski W, Kato I, Kuwahara A et al:Gastroprotective action of orexin-A against stress-induced gastric damage is mediated by endogenous prostaglandins, sensory afferent neuropeptides and nitric oxide. Regul Pept 2008,148(1-3):6-20.
[33]Chen QQ, Li D, Guo R, Luo D, Yang J, Hu CP, Li YJ:Decrease in the synthesis and release of calcitonin gene-related peptide in dorsal root ganglia of spontaneously hypertensive rat:role of nitric oxide synthase inhibitors. Eur J Pharmacol 2008,596(1-3):132-137.
[34]Strecker T, Dux M, Messlinger K:Nitric oxide releases calcitonin-gene-related peptide from rat dura mater encephali promoting increases in meningeal blood flow. J Vase Res 2002,39(6):489-496.
[1]Bell D, McDermott BJ:Calcitonin gene-related peptide in the cardiovascular system:characterization of receptor populations and their (patho) physiological significance. Pharmacol Rev 1996,48(2):253-288.
[2]Deng PY, Li YJ:Calcitonin gene-related peptide and hypertension. Peptides 2005,26(9):1676-1685.
[3]Luo D, Zhang YW, Peng WJ, Peng J, Chen QQ, Li D, Deng HW, Li YJ:
Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide. Regul Pept 2008,150 (1-3):66-72.
[4]Wang H, Xing L, Li W, Hou L, Guo J, Wang X:Production and secretion of calcitonin gene-related peptide from human lymphocytes. J Neuroimmunol 2002,130(1-2):155-162.
[5]Cai WQ, Dikranian K, Bodin P, Turmaine M, Burnstock G:Colocalization of vasoactive substances in the endothelial cells of human umbilical vessels. Cell Tissue Res 1993,274(3):533-538.
[6]Ozaka T, Doi Y, Kayashima K, Fujimoto S:Weibel-Palade bodies as a storage site of calcitonin gene-related peptide and endothelin-1 in blood vessels of the rat carotid body. Anat Rec 1997,247(3):388-394.
[7]Doi Y, Kudo H, Nishino T, Kayashima K, Kiyonaga H, Nagata T, Nara S, Morita M, Fujimoto S:Synthesis of calcitonin gene-related peptide (CGRP) by rat arterial endothelial cells. Histol Histopathol 2001,16(4):1073-1079.
[8]Ye F, Deng PY, Li D, Luo D, Li NS, Deng S, Deng HW, Li YJ:Involvement of endothelial cell-derived CGRP in heat stress-induced protection of endothelial function. Vascul Pharmacol 2007,46(4):238-246.
[9]Zhu QM, Lesnick JD, Jasper JR, MacLennan SJ, Dillon MP, Eglen RM, Blue DR, Jr.:Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice. Br J Pharmacol 1999,126(6):1522-1530.
[10]Pimentel AM, Costa CA, Carvalho LC, Brandao RM, Rangel BM, Tano T, Soares de Moura R, Resende AC:The role of NO-cGMP pathway and potassium channels on the relaxation induced by clonidine in the rat mesenteric arterial bed. Vascul Pharmacol 2007,46(5):353-359.
[11]Booth BP, Tabrizi-Fard MA, Fung H:Calcitonin gene-related peptide-dependent vascular relaxation of rat aorta. An additional mechanism for nitroglycerin. Biochem Pharmacol 2000,59(12):1603-1609.
[12]Peng J, Li YJ:New insights into nitroglycerin effects and tolerance:role of calcitonin gene-related peptide. Eur J Pharmacol 2008,586(1-3):9-13.
[13]Wang X, Xing L, Xing Y, Tang Y, Han C:Identification and characterization of immunoreactive calcitonin gene-related peptide from lymphocytes of the rat. J Neuroimmunol 1999,94(1-2):95-102.
[14]Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre Ⅰ:Calcitonin gene-related peptide is a potent vasodilator. Nature 1985,313(5997):54-56.
[15]Lu LF, Fiscus RR:Nitric oxide donors enhance calcitonin gene-related peptide-induced elevations of cyclic AMP in vascular smooth muscle cells. Eur J Pharmacol 1999,376(3):307-314.
[16]de Hoon JN, Pickkers P, Smits P, Struijker-Boudier HA, Van Bortel LM: Calcitonin gene-related peptide:exploring its vasodilating mechanism of action in humans. Clin Pharmacol Ther 2003,73(4):312-321.
[17]Brain SD, Grant AD:Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 2004,84(3):903-934.
[18]Li D, Peng J, Xin HY, Luo D, Zhang YS, Zhou Z, Jiang DJ, Deng HW, Li YJ: Calcitonin gene-related peptide-mediated antihypertensive and anti-platelet effects by rutaecarpine in spontaneously hypertensive rats. Peptides 2008, 29(10):1781-1788.
[19]Marquez-Rodas I, Longo F, Rothlin RP, Balfagon G:Pathophysiology and therapeutic possibilities of calcitonin gene-related peptide in hypertension. J Physiol Biochem 2006,62(1):45-56.
[20]Portaluppi F, Trasforini G, Margutti A, Vergnani L, Ambrosio MR, Rossi R, Bagni B, Pansini R, degli Uberti EC:Circadian rhythm of calcitonin gene-related peptide in uncomplicated essential hypertension. J Hypertens 1992, 10(10):1227-1234.
[21]Shi XY, Yang Y, Zhao YT:[Plasma calcitonin gene-related peptide (CGRP) level in patients with essential hypertension]. Zhonghua Nei Ke Za Zhi 1990, 29(10):616-618,639.
[22]Deng PY, Ye F, Zhu HQ, Cai WJ, Deng HW, Li YJ:An increase in the synthesis and release of calcitonin gene-related peptide in two-kidney, one-clip hypertensive rats. Regul Pept 2003,114(2-3):175-182.
[23]Booth BP, Nolan TD, Fung HL:Nitroglycerin-inhibited whole blood
aggregation is partially mediated by calcitonin gene-related peptide--a neurogenic mechanism. Br J Pharmacol 1997,'122(3):577-583.
[24]Wei EP, Moskowitz MA, Boccalini P, Kontos HA:Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arterioles. Circ Res 1992,70(6):1313-1319.
[25]Wang X, Wu ZX, Tang YM, Han QD:Endotoxin causes release of calcitonin gene-related peptide (CGRP) from the isolated mesenteric arterial bed in rat. Sheng Li Xue Bao 1996,48(1):37-42.
[26]Zhou ZH, Deng HW, Li YJ:Involvement of calcitonin gene-related peptide in the development of tolerance to nitroglycerin in the rat. Eur J Pharmacol 2001, 427(2):137-141.
[27]Zhou ZH, Jiang JL, Peng J, Deng HW, Li YJ:Reversal of tolerance to nitroglycerin with N-acetylcysteine or captopril:a role of calcitonin gene-related peptide. Eur J Pharmacol 2002,439(1-3):129-134.
[28]Villalon CM, Albarran-Juarez JA, Lozano-Cuenca J, Pertz HH, Gornemann T, Centurion D:Pharmacological profile of the clonidine-induced inhibition of vasodepressor sensory outflow in pithed rats:correlation with alpha(2A/2C)-adrenoceptors. Br J Pharmacol 2008,154(1):51-59.
[29]Frisk-Holmberg M, Paalzow L, Wibell L:Relationship between the cardiovascular effects and steady-state kinetics of clonidine in hypertension. Demonstration of a therapeutic window in man. Eur J Clin Pharmacol 1984, 26(3):309-313.
[30]Wing LM, Reid JL, Davies DS, Neill EA, Tippett P, Dollery CT: Pharmacokinetic and concentration-effect relationships of clonidine in essential hypertension. Eur J Clin Pharmacol 1977,12(6):463-469.
[31]Hastings RH, Hua XY:Expression of calcitonin gene-related peptide by cultured rat alveolar type Ⅱ cells. Am J Respir Cell Mol Biol 1995, 13(5):563-569.
[32]Li W, Hou L, Hua Z, Wang X:Interleukin-lbeta induces beta-calcitonin gene-related peptide secretion in human type II alveolar epithelial cells. Faseb J 2004,18(13):1603-1605.
[33]Xing L, Guo J, Wang X:Induction and expression of beta-calcitonin gene-related peptide in rat T lymphocytes and its significance. J Immunol 2000, 165(8):4359-4366.
[1]Hobara N, Gessei-Tsutsumi N, Goda M, Takayama F, Akiyama S, Kurosaki Y, Kawasaki H:Long-term inhibition of angiotensin prevents reduction of periarterial innervation of calcitonin gene-related peptide (CGRP)-containing nerves in spontaneously hypertensive rats. Hypertens Res 2005,28(5):465-474.
[2]Kramer HH, Schmidt K, Leis S, Schmelz M, Sommer C, Birklein F: Angiotensin converting enzyme has an inhibitory role in CGRP metabolism in human skin. Peptides 2006,27(4):917-920.
[3]Thota C, Yallampalli C:Progesterone upregulates calcitonin gene-related peptide and adrenomedullin receptor components and cyclic adenosine 3'5'-monophosphate generation in Eker rat uterine smooth muscle cell line. Biol Reprod 2005,72(2):416-422.
[4]Ferrario CM, Strawn WB:Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. Am J Cardiol 2006, 98(1):121-128.
[5]Dimmeler S, Zeiher AM:Reactive oxygen species and vascular cell apoptosis in response to angiotensin Ⅱ and pro-atherosclerotic factors. Regul Pept 2000, 90(1-3):19-25.
[6]Bonavita F, Stefanelli C, Giordano E, Columbaro M, Facchini A, Bonafe F, Caldarera CM, Guarnieri C:H9c2 cardiac myoblasts undergo apoptosis in a model of ischemia consisting of serum deprivation and hypoxia:inhibition by PMA. FEBS Lett 2003,536(1-3):85-91.
[7]Shichiri M, Kato H, Doi M, Marumo F, Hirata Y:Induction of max by adrenomedullin and calcitonin gene-related peptide antagonizes endothelial apoptosis. Mol Endocrinol 1999,13(8):1353-1363.
[8]Song S, Liu N, Liu W, Shi R, Guo KJ, Liu YF:The effect of pretreatment with calcitonin gene-related peptide on attenuation of liver ischemia and reperfusion injury due to oxygen free radicals and apoptosis. Hepatogastroenterology 2009, 56(96):1724-1729.
[9]Song SW, Guo KJ, Shi R, Cheng Y, Liu YF:Pretreatment with calcitonin gene-related peptide attenuates hepatic ischemia/reperfusion injury in rats. Transplant Proc 2009,41(5):1493-1498.
[10]Chan JJ, Farmer PJ, Southwell BR, Sourial M, Hutson JM:Calcitonin gene-related peptide is a survival factor, inhibiting apoptosis in neonatal rat gubernaculum in vitro. J Pediatr Surg 2009,44(8):1497-1501.
[11]Fu HM, Xu F, Liu CJ, Kuang FW, Huang B, Fang F, Fu YQ:Influence of 60% oxygen inhalation on type Ⅱ alveolar epithelial cells and protective role of calcitonin gene-related peptide from their damage induced in premature rat. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2008,20(10):578-581.
[12]Li W, Hou L, Hua Z, Wang X:Interleukin-lbeta induces beta-calcitonin gene-related peptide secretion in human type Ⅱ alveolar epithelial cells. Faseb J 2004,18(13):1603-1605.
[13]Wang H, Xing L, Li W, Hou L, Guo J, Wang X:Production and secretion of calcitonin gene-related peptide from human lymphocytes. J Neuroimmunol 2002,130(1-2):155-162.
[14]Zhou FW, Li YJ, Deng HW:Early and delayed protection by capsaicin against reperfusion injury in rat hearts. Zhongguo Yao Li Xue Bao 1999,20 (10): 912-916.
[15]Tang YH, Lu R, Li YJ, Peng CF, Deng HW:Effect of calcitonin gene-related peptide-induced preconditioning on attenuated endothelium-dependent vasorelaxation induced by lysophosphatidylcholine. Zhongguo Yao Li Xue Bao 1997,18(5):405-407.
[16]Luo D, Zhang YW, Peng WJ, Peng J, Chen QQ, Li D, Deng HW, Li YJ: Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide. Regul Pept 2008, 150(1-3):66-72.
[17]Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM:Angiotensin Ⅱ induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circ Res 1997,81(6):970-976.
[18]Shan HY, Bai XJ, Chen XM:Apoptosis is involved in the senescence of endothelial cells induced by angiotensin Ⅱ. Cell Biol Int 2008,32(2):264-270.
[19]Qin XP, Ye F, Hu CP, Liao DF, Deng HW, Li YJ:Effect of calcitonin gene-related peptide on angiotensin II-induced proliferation of rat vascular smooth muscle cells. Eur J Pharmacol 2004,488(1-3):45-49.
[20]Sueur S, Pesant M, Rochette L, Connat JL:Antiapoptotic effect of calcitonin gene-related peptide on oxidative stress-induced injury in H9c2 cardiomyocytes via the RAMP1/CRLR complex. J Mol Cell Cardiol 2005,39(6):955-963.
[1]Luo D, Deng PY, Ye F, Peng WJ, Deng HW, Li YJ:Delayed preconditioning by cardiac ischemia involves endogenous calcitonin gene-related peptide via the nitric oxide pathway. Eur J Pharmacol 2004,502(1-2):135-141.
[2]Li D, Li NS, Chen QQ, Guo R, Xu PS, Deng HW, Li YJ:Calcitonin gene-related peptide-mediated cardioprotection of postconditioning in isolated rat hearts. Regul Pept 2008,147(1-3):4-8.
[3]Ye F, Deng PY, Li D, Luo D, Li NS, Deng S, Deng HW, Li YJ:Involvement of endothelial cell-derived CGRP in heat stress-induced protection of endothelial function. Vascul Pharmacol 2007,46(4):238-246.
[4]Luo D, Zhang YW, Peng WJ, Peng J, Chen QQ, Li D, Deng HW, Li YJ:
Transient receptor potential vanilloid 1-mediated expression and secretion of endothelial cell-derived calcitonin gene-related peptide. Regul Pept 2008, 150(1-3):66-72.
[5]Chattergoon NN, D'Souza FM, Deng W, Chen H, Hyman AL, Kadowitz PJ, Jeter JR, Jr.:Antiproliferative effects of calcitonin gene-related peptide in aortic and pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2005,288(1):L202-211.
[6]Qin XP, Ye F, Hu CP, Liao DF, Deng HW, Li YJ:Effect of calcitonin gene-related peptide on angiotensin II-induced proliferation of rat vascular smooth muscle cells. Eur J Pharmacol 2004,488(1-3):45-49.
[7]Peng J, Li YJ:The vanilloid receptor TRPV1:Role in cardiovascular and gastrointestinal protection. Eur J Pharmacol 2009,627(1-3):1-7.
[8]Feng G, Xu X, Wang Q, Liu Z, Li Z, Liu G:The protective effects of calcitonin gene-related peptide on gastric mucosa injury after cerebral ischemia reperfusion in rats. Regul Pept 2009,160(1-3):121-128..
[9]Evangelista S:Role of calcitonin gene-related Peptide in gastric mucosal defence and healing. Curr Pharm Des 2009,15(30):3571-3576.
[10]Ohno T, Hattori Y, Komine R, Ae T, Mizuguchi S, Arai K, Saeki T, Suzuki T, Hosono K, Hayashi I et al:Roles of calcitonin gene-related peptide in maintenance of gastric mucosal integrity and in enhancement of ulcer healing and angiogenesis. Gastroenterology 2008,134(1):215-225.
[11]Huang W, Wang H, Galligan JJ, Wang DH:Transient receptor potential vanilloid subtype 1 channel mediated neuropeptide secretion and depressor effects:role of endoplasmic reticulum associated Ca2+release receptors in rat dorsal root ganglion neurons. J Hypertens 2008,26(10):1966-1975.
[12]Wang DH:The vanilloid receptor and hypertension. Acta Pharmacol Sin 2005, 26(3):286-294.
[13]Demirbilek S, Ersoy MO, Demirbilek S, Karaman A, Gurbuz N, Bayraktar N, Bayraktar M:Small-dose capsaicin reduces systemic inflammatory responses in septic rats. Anesth Analg 2004,99(5):1501-1507; table of contents.
[14]Hu CP, Li NS, Xiao L, Deng HW, Li YJ:Involvement of capsaicin-sensitive
sensory nerves in cardioprotection of rutaecarpine in rats. Regul Pept 2003, 114(1):45-49.
[15]Hu CP, Xiao L, Deng HW, Li YJ:The cardioprotection of rutaecarpine is mediated by endogenous calcitonin related-gene peptide through activation of vanilloid receptors in guinea-pig hearts. Planta Med 2002,68(8):705-709.
[16]Xing Y, Liu Z, Wang LH, Huang F, Wang HJ, Li ZZ:Butyrate sensitizes the release of substance P and calcitonin gene-related peptide evoked by capsaicin from primary cultured rat dorsal root ganglion neurons. Neuro Endocrinol Lett 2006,27(6):695-701.
[17]Yang X, Han JQ, Liu R:Effects of experimental colitis on the expressions of calcitonin gene-related peptide and vanilloid receptor 1 in rat spinal cord sensory neurons. Sheng Li Xue Bao 2008,60(1):143-148.
[18]Sugiyama T, Hatanaka Y, Iwatani Y, Jin X, Kawasaki H:Lafutidine facilitates calcitonin gene-related peptide (CGRP) nerve-mediated vasodilation via vanilloid-1 receptors in rat mesenteric resistance arteries. J Pharmacol Sci 2008, 106(3):505-511.
[19]Price TJ, Patwardhan AM, Flores CM, Hargreaves KM:A role for the anandamide membrane transporter in TRPV1-mediated neurosecretion from trigeminal sensory neurons. Neuropharmacology 2005,49(1):25-39.
[20]Li D, Chen BM, Peng J, Zhang YS, Li XH, Yuan Q, Hu CP, Deng HW, Li YJ: Role of anandamide transporter in regulating calcitonin gene-related peptide production and blood pressure in hypertension. J Hypertens 2009, 27(6):1224-1232.
[21]Deng PY, Ye F, Cai WJ, Deng HW, Li YJ:Role of calcitonin gene-related peptide in the phenol-induced neurogenic hypertension in rats. Regul Pept 2004, 119(3):155-161.
[22]Zhang YM, Peng J, Hu CP, Jiang QT, Jiang GL, Li YJ:Clonidine induces calcitonin gene-related peptide expression via nitric oxide pathway in endothelial cells. Peptides 2009,30(9):1746-1752.
[23]Hobara N, Gessei-Tsutsumi N, Goda M, Takayama F, Akiyama S, Kurosaki Y, Kawasaki H:Long-term inhibition of angiotensin prevents reduction of
periarterial innervation of calcitonin gene-related peptide (CGRP)-containing nerves in spontaneously hypertensive rats. Hypertens Res 2005,28(5):465-474.
[24]Kramer HH, Schmidt K, Leis S, Schmelz M, Sommer C, Birklein F: Angiotensin converting enzyme has an inhibitory role in CGRP metabolism in human skin. Peptides 2006,27(4):917-920.
[25]Thota C, Yallampalli C:Progesterone upregulates calcitonin gene-related peptide and adrenomedullin receptor components and cyclic adenosine 3'5'-monophosphate generation in Eker rat uterine smooth muscle cell line. Biol Reprod 2005,72(2):416-422.
[26]Harada N, Shimozawa N, Okajima K:AT(1) receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats. Transl Res 2009,154(3):142-152.
[27]Schnegelsberg B, Sun TT, Cain G, Bhattacharya A, Nunn PA, Ford AP, Vizzard MA, Cockayne DA:Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity and changes in urinary bladder function. Am J Physiol Regul Integr Comp Physiol 2009,298(3):534-547.
[28]Strecker T, Koulchitsky S, Dieterle A, Neuhuber WL, Weyand M, Messlinger K: Release of calcitonin gene-related peptide from the jugular-nodose ganglion complex in rats--a new model to examine the role of cardiac peptidergic and nitrergic innervation. Neuropeptides 2008,42(5-6):543-550.
[29]Chen QQ, Li D, Guo R, Luo D, Yang J, Hu CP, Li YJ:Decrease in the synthesis and release of calcitonin gene-related peptide in dorsal root ganglia of spontaneously hypertensive rat:role of nitric oxide synthase inhibitors. Eur J Pharmacol 2008,596(1-3):132-137.
[30]Zhang W, Zhao Y, Wang L:[The changes of plasma calcitonin gene-related peptide level in women with normal pregnancy and pregnancy induced hypertension]. Zhonghua Fu Chan Ke Za Zhi 1998,33(12):715-716.
[31]Supowit SC, Zhao H, Hallman DM, DiPette DJ:Calcitonin gene-related peptide is a depressor of deoxycorticosterone-salt hypertension in the rat. Hypertension 1997,29(4):945-950.
[32]Deng PY, Ye F, Zhu HQ, Cai WJ, Deng HW, Li YJ:An increase in the synthesis
and release of calcitonin gene-related peptide in two-kidney, one-clip hypertensive rats. Regul Pept 2003,114(2-3):175-182.
[33]Deng PY, Li YJ:Calcitonin gene-related peptide and hypertension. Peptides 2005,26(9):1676-1685.
[34]Li D, Peng J, Xin HY, Luo D, Zhang YS, Zhou Z, Jiang DJ, Deng HW, Li YJ: Calcitonin gene-related peptide-mediated antihypertensive and anti-platelet effects by rutaecarpine in spontaneously hypertensive rats. Peptides 2008, 29(10):1781-1788.
[35]Qin XP, Ye F, Liao DF, Li YJ:Involvement of calcitonin gene-related peptide in the depressor effects of losartan and perindopril in rats. Eur J Pharmacol 2003, 464(1):63-67.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |