上运动神经元损伤后脊髓前角运动神经元中降钙素基因相关肽的变化

目的 观察上运动神经元损伤后大鼠脊髓前角运动神经元中降钙素基因相关肽（ＣＧＲＰ）的变化。方法 选用３６只成年雄性Ｗｉｓｔａｒ大鼠,于下胸段行脊髓横断术,分别于术后０、１、２、４、７、１４ｄ取出腰段脊髓并分为腹侧和背侧,用放免方法测定腹侧脊髓中ＣＧＲＰ的含量。结果 大鼠脊髓前角ＣＧＲＰ的含量自术后第２天开始显著降低,最低值出现在术后第２天,此后维持这一低水平。结论 上运动神经元损伤后大鼠脊髓前角ＣＧ     

降钙素基因相关肽对心肌缺血/再灌注损伤保护作用信号通路研究进展

背景 降钙素基因相关肽(calcitonin gene-related peptide,CGRP)是一种重要的感觉神经肽,能减轻心肌缺血/再灌注损伤(myocardial ischemia/reperfusion injury,MI/RI). 目的 就CGRP发挥心肌保护作用的信号通路进行综述. 内容 概述CGRP的生物学特征、对MI/RI的影响以及所涉及的信号通路. 趋向 研究CGRP对MI/RI的信号转导机制有助于阐明CGRP对心肌保护的重要性,并提供新的治疗靶点.     

烧伤早期营养对大鼠降钙素基因相关肽影响的实验研究

目的观察烧伤早期不同营养途径对肠道的复苏效应,及其与降钙素基因相关肽(cal-citoningene-relatedpeptide,CGRP)的关系方法30%TBSAⅢ度烧伤Wistar大鼠,随机分为灌喂组(EF组,30只)及早期静脉营养组(EPN组,30只).此外,6只大鼠不烧伤,作对照组(C组).伤后6、12、24、48、72h观察大鼠一般情况、肠黏膜血流量、血浆CGRP免疫活性物质浓度、CGRP染色阳性物质在肠道的变化.结果烧伤后大鼠肠黏膜血流量下降,EF组下降程度明显低于EPN组(P＜0.05～0.01);烧伤后血浆CGRP升高,EF组血浆CGRP在伤后72h明显低于EPN组(P＜0.01);肠道CGRP阳性染色物质在烧伤后明显减少(P＜0.05～0.01),EF组在伤后24、48h明显多于EPN组(P＜0.05);肠黏膜血流量下降和肠肌间丛CGRP下降呈正相关(r=0.72,P＜0.05).结论肠道营养在烧伤早期肠道的复苏效应方面较静脉营养优越,伤后肠道CGRP免疫活性物质减少,血浆CGRP免疫活性物质过度增高可能是烧伤后肠道血供减少的重要机制之一,早期肠道营养可能通过调节CGRP而发挥复苏作用.     

血管束、感觉神经束植入组织工程骨降钙素基因相关肽和受体的时空分布

目的 探讨单纯血管束、感觉神经束分别植入组织工程骨修复兔骨缺损对降钙素基因相关肽(CGRP)及受体(CGRPR-1)表达的影响.方法 54只新西兰兔按随机数字表法分为三组(n=18):感觉神经束植入组(A组)、血管束植入组(B组)、单纯组织工程骨对照组(C组),于术后4、8、12周分别处死18只动物,对修复骨段行Masson染色观察骨形成与改建过程,同时行免疫组化染色检测修复骨段内CGRP及CGRPR-1的表达,并提取总RNA行Real-time PCR检测CGRP及CGRPR-1的表达情况.结果 各时间点A组和B组CGRP、CGRPR-1 mRNA的表达均高于C组,且A组表达高于B组,差异均有统计学意义(P<0.05);随时间延长,组织工程骨内CGRP及CGRPR-1 mRNA呈先增高后逐渐降低趋势,8周时mRNA高于4周和12周,4周时mRNA在3个检测时间点中最低,差异均有统计学意义(P<0.05);组织工程骨内新生骨质边缘、骨膜、血管周围均有CGRP阳性表达,分布均匀;CGRPR-1于成骨细胞周围表达较多.结论 植入感觉神经柬和血管束均能促进神经肽分泌,植入血管束分泌更多.     

Posttreatment with adenovirus-mediated gene transfer of calcitonin gene-related peptide to reverse cerebral vasospasm in dogs

OBJECT: Gene transfer to cerebral vessels is a promising new therapeutic approach for cerebral vasospasm after subarachnoid hemorrhage (SAH). This study was undertaken to explore whether a delayed treatment with adenovirus encoding the prepro-calcitonin gene-related peptide (CGRP), 2 days after initial blood injection, reduces cerebral vasospasm in a double-hemorrhage model of severe vasospasm in dogs. METHODS: In 20 dogs, arterial blood was injected into the cisterna magna on Days 0 and 2. Thirty minutes after the second blood injection, the animals received either adenovirus encoding the prepro-CGRP gene (AdCMVCGRP-treated group, eight dogs) or adenovirus encoding the beta-galactosidase gene (AdCMVbeta gal-treated group, six dogs) under the cytomegalovirus (CMV) promoter. One group of dogs did not receive treatment and served as controls (control SAH group, six dogs). Angiography was performed on Days 0 and 7 to assess cerebral vasospasm. On Day 7 following angiography, the animals were killed and their brains were stained with X-gal to detect the distribution of gene expression. Cerebrospinal fluid (CSF) was also tested for CGRP immunoreactivity. Severe vasospasm was observed in control SAH dogs on Day 7, and the mean basilar artery (BA) diameter was 53.4 +/- 5.5% of the value measured on Day 0. Treatment with AdCMVbeta gal did not alter vasospasm (the BA diameter was 55 +/- 3.9% of that measured on Day 0). The leptomeninges and adventitia of the BAs of dogs treated using AdCMVbeta gal demonstrated positive staining with X-gal. High levels of CGRP were measured in CSF from dogs that received AdCMVCGRP. In the group treated with AdCMVCGRP, vasospasm was significantly reduced (the BA diameter was 78.2 +/- 5.3% of that measured on Day 0, p < 0.05 compared with the control SAH group and the AdCMVbeta gal group). CONCLUSIONS: In a model of severe vasospasm in dogs, gene transfer of CGRP after injection of blood attenuated cerebral vasospasm after SAH.     

内皮素-1及降钙基因相关肽在颅脑损伤后脑血管痉挛中的作用

目的：探讨内皮素－1（ET－1）及降钙基因相关肽（CGRP）在颅脑损伤后脑血管痉挛中的作用。方法：以放射免疫法测定43例颅脑损伤成年患者伤后不同时点血浆内皮素－1及CGRP的浓度，同时行经颅多普勒（TCD）检查判定患者脑血管痉挛情况。结果：颅脑损伤后24h内血浆内皮素－1开始升高，3－5d最明显，持续到7d开始下降，14d时接近正常水平；血浆CGRP伤后3d开始下降，5－7d最低，14d时多恢复正常。伤后24h内即出现血管痉挛，3d左右脑血管痉挛明显增多，5－7d达峰值，14d明显减轻。重伤组尤其合并蛛网膜下腔出血者，脑血管痉挛发生频率及程度明显高于轻中伤组，脑血管痉挛与血浆内皮素－1浓度变化呈正相关，与CGRP呈负相关。结论：颅脑损伤后血浆内皮素－1升高及CGRP降低是脑血管痉挛发生的重要因素之一。     

Effects of calcitonin, amylin, and calcitonin gene-related peptide on osteoclast development

Amylin and calcitonin gene-related peptide (CGRP) are homologous 37 amino acid peptides that are found in the circulation. Both peptides belong to the calcitonin family. Similar to calcitonin, amylin and CGRP inhibit osteoclast activity, although they are much less potent than calcitonin. Calcitonin is known to act on the latter stages of osteoclast development, inhibiting the fusion of committed preosteoclasts to form mature multinucleated cells; however, whether or not calcitonin acts earlier in the formation of the precursor osteoclasts is controversial. The question of osteoclast development has never been examined with respect to amylin and CGRP. These issues are addressed in the present study. We studied the effects of calcitonin (salmon and rat), amylin (human and rat), and CGRP (human and rat) in mouse bone marrow cultures stimulated to generate osteoclasts using 1alpha,25-dihydroxyvitamin D3. Calcitonin dose-dependently decreased the numbers of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells as well as TRAP-positive mono-/binucleated cells at concentrations >10(-13) mol/L. Amylin and CGRP showed similar effects at concentrations >10(-9) mol/L. In addition, calcitonin substantially reduced the ratio of TRAP-positive multinucleated to mono-binucleated cells, indicating an effect on fusion of osteoclast precursors. The present data establish that this family of peptides not only acts on mature osteoclasts but also inhibits their development in bone marrow cultures. This activity is shared by amylin and CGRP. The much greater potency of calcitonin than amylin and CGRP is consistent with the action of these peptides being mediated by calcitonin receptors.     

糖尿病患者肾血流与内皮素及降钙素基因相关肽关系

目的为了解内皮素（ＥＴ）及降钙素基因相关肽（ＣＧＲＰ）与糖尿患者不同阶段时肾血流的关系。方法肾彩色多普勒超声检查确定为糖尿病肾血流正常组（Ａ组）１５例、糖尿病肾血流减少组（Ｂ组）１５例，正常对照组１８例。分别采血测定血浆ＥＴ－１和ＣＧＲＰ浓度。结果Ａ组ＥＴ－１水平低于正常对照组（Ｐ＜０．０１），Ｂ组ＥＴ－１水平高于正常对照组（Ｐ＜０．０１）。二组ＥＴ－１水平与肾动脉收缩期峰值血流速度（Ｖｍａｘ）、肾动脉血流量（Ｑ）呈负相关（Ｐ＜０．０１），与尿白蛋白排泄率（ＵＡＥＲ）呈正相关（Ｐ＜０．０５）。二组的ＣＧＲＰ水平均低于正常组（Ｐ均＜０．０１），但Ａ与Ｂ组的ＣＧＲＰ水平差异无显著性（Ｐ＞０．０５）。未发现ＣＧＲＰ水平与Ｖｍａｘ、Ｑ和ＵＡＥＲ呈相关关系。结论ＥＴ－１在糖尿病不同阶段时对肾血流量的病理生理作用可能不同；糖尿病患者呈现低ＣＧＲＰ血症，但它对不同阶段的糖尿病肾血流的影响尚有待探讨。     

降钙素基因多肽对骨代谢的影响

根据骨质疏松的发病机制不同,可分为原发性骨质疏松和继发性骨质疏松,原发性骨质疏松又可分为绝经性骨质疏松和老年性骨质疏松。骨质疏松是由多种发病因素共同作用的结果,在各型骨质疏松中,降钙素均发挥重要的调节作用。近年研究发现某些神经、血管活性肽,如降钙素基因多肽(Calcitonin gene-related peptide,CGRP）,在结构和功能上与降钙素具有一定的相似性。本文将降钙素基因多肽对骨代谢影响的相关研究进展作以下综述。     

Cardiovascular action of calcitonin gene-related peptide in humans

Summary Calcitonin gene-related peptide (CGRP) has been localized in cardiac nerve fibers and blood vessels from which it may be released as neurotransmitter or neuromodulator. Acute cardiovascular effects of i.v. administered CGRP have been studied in human subjects. CGRP (25.3 nmol) caused a mean maximal increase of the heart rate of 41 beats per min (P<0.01) and lowered arterial systolic and diastolic pressures by 26 mm Hg and 20 mm Hg, respectively (P<0.01) (n=6 subjects). These effects were associated with facial flushing, and a rise of plasma levels of norepinephrine and epinephrine of 257 pg/ml and 9 pg/ml, respectively (P<0.01). Administration of equimolar amounts of human calcitonin caused no cardiovascular effects except for minor facial flushing. Serum calcium was marginally lowered with both CGRP (0.2 mg/100 ml) and calcitonin (0.4 mg/100 ml) (P<0.05). Further-more, CGRP (12.7 nmol) reduced the preejection period and duration of the electromechanical systole by 26 msec and 66 msec, respectively (P<0.001 andP<0.01), presumably acting as positive inotropic agent. Labetalol, blocking adrenergic receptors, obliterated these inotropic effects, whereas the positve chronotropic and hypotensive actions of CGRP remained unchanged.     

Binding of calcitonin and calcitonin gene-related peptide to calvarial cells and renal cortical membranes

Binding of calcitonin (CT) and calcitonin gene-related peptide (CGRP) to rat hemicalvariae and renal membranes was examined in an effort to determine whether CT and CGRP interact with the same bone cell binding site, and to see whether the binding pattern was similar for bone and renal cortex. Specific binding of 125I-salmon CT to rat calvariae was inhibited by unlabeled salmon, porcine, or human CT, but not by rat CGRP. Binding of 125I-rat CGRP to calvariae was inhibited by CGRP and high doses of salmon CT, but not by human or porcine CT. Binding of 125I-salmon CT to renal membranes was inhibited by unlabeled salmon CT or rat CGRP, but no specific binding of 125I-rat CGRP could be detected. The results suggest that separate bone cell receptors for CT and CGRP exist and that CGRP can interact with renal receptors for CT.     

Cosecretion of calcitonin and calcitonin gene-related peptide from cultured rat medullary thyroid C cells

Whether C cells cosecrete calcitonin (CT) and CGRP was examined by exposing cultured rat medullary thyroid carcinoma 6-23 cells for 2 h to high medium Ca and to agents with a potential for affecting Ca-dependent secretion. In every experiment exposure of cells to high medium Ca (2.0-2.5 mM) provoked an increased release of both peptides that was highly correlated (r = 0.73). With other test substances, also, changes in both hormones occurred in parallel. The Ca-channel activator, BAY-K-8644 (10 microM) increased secretion, and this was inhibited by the Ca channel blocker, nitrendipine (10 microM). The Ca2+ ionophore, ionomycin (5 microM), increased release, and the calmodulin-Ca channel inhibitor, phenytoin (100 microM), inhibited Ca-induced release. The active 4 beta isomer of phorbol-12,13-didecanoate (0.1 microM), but not the inactive 4 alpha isomer, increased secretion. The findings suggest that pathways mediating C cell secretion include plasma membrane Ca channels, intracellular [Ca2+], calmodulin, and protein kinase C. The results show that the secretory process in rat C cells involves the release of CGRP as well as CT.     

A role for calcitonin gene-related peptide in protection against gastric ulceration.

OBJECTIVE: The goal of this investigation was to determine the role of calcitonin gene-related peptide (CGRP) in gastric mucosal resistance to ulceration. SUMMARY BACKGROUND DATA: CGRP is a 37-amino acid peptide found in the peripheral ends of afferent gastric neurons. CGRP is known to inhibit acid secretion, stimulate mucosal blood flow, and stimulate release of somatostatin. METHODS: The release of CGRP in response to intragastric and intra-arterial administration of capsaicin in the isolated, vascularly perfused rat stomach was measured by radioimmunoassay. The molecular forms of CGRP released were analyzed by gel filtration chromatography. The effect of intravenous CGRP or intragastric capsaicin on gastric ulceration induced by 100 mmol/L HCl and indomethacin was studied in intact and endogenous CGRP-depleted rats. RESULTS: Intra-arterial capsaicin (concentration range, 10(-7) to 10(-5) mol/L) stimulated a prompt and sustained release of immunoreactive CGRP, of which 84% coeluted with rat 1-37 CGRP I by gel filtration. Intragastric capsaicin (range, 10(-5) to 10(-4) mol/L) failed to release CGRP into the vascular perfusate. In intact rats, intragastric capsaicin (10(-6) mol/L) or intravenous CGRP I (10 micrograms/kg/hr) reduced the number and area of mucosal lesions caused by HCl and indomethacin compared with the findings in control rats. Rats depleted of endogenous CGRP were more susceptible to gastric ulceration than were normal rats. Intragastric capsaicin failed to protect the mucosa of CGRP-depleted rats, whereas exogenous intravenous CGRP was effective. CONCLUSIONS: These data support the hypothesis that CGRP released from gastric enteric neurons mediates gastric mucosal resistance to ulceration by noxious agents.     

Inhibition of secretion of rat calcitonin by calmodulin inhibitors

Summary Studies were designed to investigate the potential importance of calmodulin in release of calcitonin (CT) in response to an increase in the concentration of extracellular Ca.In vitro release of CT from baby rat thyroparathyroids incubated up to 8 h was examined at normal (1 mM) and high (2.5 mM) Ca in serum-free medium in the presence and absence of the potent calmodulin inhibitors, trifluoperazine (TFP) and N-(6-aminohexyl)-5-Cl-1-naphthalene sulfonamide (W-7). The drugs chloropromazine (CLP) and haloperiodol (HAL) which, like TFP, are anti-psychotic agents also were tested. In some studies release of parathyroid hormone (PTH) into medium also was studied. At 2.5 mM Ca, CT release was increased five- tenfold compared with 1 mM Ca while PTH was suppressed by ≈ 80%. The increased release of CT induced by 2.5 mM Ca was inhibited 60–90% by 10⁻⁴ M TFP and 10⁻⁴ M W-7, but was unaffected by 10⁻⁴M CLP or HAL. In the presence of 1 mM Ca, the increased release of PTH also was inhibited significantly by 10⁻⁴ M TFP and 10⁻⁴ M W-7. In relatedin vivo studies, administration of TFP i.v. to rats just before induction of hypercalcemia with i.v. CaCl₂ suppressed the increase in plasma CT normally observed 3 min later in a dose-related manner. The results show that calmodulin inhibitors can inhibitin vitro secretion of CT, and release of PTH as well. Additionally, inhibition of thein vivo CT response to a Ca challenge was observed within minutes of drug administration. The findings support the notion that calmodulin plays an important role in Ca-mediated release of CT from the C-cell.     

Calcitonin and calcitonin gene-related peptide in the human prostate gland

BACKGROUND: Calcitonin-related peptides have been found in the human prostate, and calcitonin (CT) and calcitonin gene-related peptide (CGRP) have been demonstrated in subpopulations of neuroendocrine (NE) cells. The purpose of this study was to determine the concentrations of CT and CGRP as well as the densities of NE cells in normal prostates, benign prostatic hyperplasia (BPH), and carcinoma of the prostate (CAP). METHODS: In 42 specimens of radical prostatectomy, the number of CT- and CGRP-immunoreactive NE cells in areas of normal and BPH tissue was determined, and compared with CAP tissue using immunocytochemistry. In addition, by radioimmunoassay (RIA), tissue levels of CT and CGRP were analyzed in extracts from areas of normal, BPH, and CAP tissue, as verified by adjacent histologic sections. RESULTS: A significant decrease in CT-immunoreactive NE cells was observed in hyperplastic nodules of BPH in comparison to normal tissue. These findings were in parallel with a significant reduction in tissue CT level in BPH compared to normal tissue. There was also a marked, but statistically nonsignificant, reduction in CT levels in CAP tissue. In contrast, levels of CGRP in BPH and CAP tissue did not show any significant differences compared to normal tissue. CONCLUSIONS: CT and CGRP are present in NE cells of the human prostate. Calcitonin levels are significantly reduced in BPH, in parallel with a decreased number of CT-immunoreactive NE cells, whereas no significant changes in tissue levels of CGRP were observed. The functional significance of these findings is discussed.     

Additive interactions of calcitonin gene-related peptide and calcitonin on pancreatic exocrine function in conscious dogs

By convention, establishing a physiologic role for a gut peptide requires demonstration of biologic activity that can be reproduced by exogenous administration of the peptide in amounts that yield plasma concentrations that are not higher than those found after a meal. We have tested the hypothesis that the combined action of two inhibitory peptides may lower the effective doses of each. We further hypothesize that combined peptide responses may be responsible for the action of peptide hormones that have been difficult to demonstrate as physiologically relevant mediators, when examined as independently acting substances. In conscious dogs prepared with chronic pancreatic cannulas, stimulated pancreatic exocrine secretions were depressed in a dose-related manner by intravenous infusions of calcitonin (CT) and calcitonin gene-related peptide (CGRP). Doses of 2.0 nmol/kg/hr of both CT and CGRP yielded maximal inhibition of stimulated secretions of both bicarbonate (greater than 85% inhibition) and protein (greater than 55% inhibition). The lowest effective dose for either CT or CGRP, given alone, was 0.75 nmol/kg/hr, but when infused simultaneously, each at the subthreshold dose of 0.50 nmol/kg/hr, significant inhibition of protein and bicarbonate secretion was achieved. Combined infusions of the submaximal dose of 0.75 nmol/kg/hr resulted in an enhanced inhibitory response. To prove that this effect is not simply combined activation of a common receptor, we tested peptide YY (0.1 to 0.5 nmol/kg/hr) combined with CGRP and obtained similar results. Because a meal simultaneously releases a large number of active peptides, we speculate that such potentiated responses do occur physiologically. Cooperative interaction with other agents may be the primary mode of action for certain gut peptides.     

Calcitonin and the peptides from the calcitonin gene

The alpha-calcitonin gene encodes a small family of peptides: calcitonin, katacalcin, and calcitonin gene-related peptide (CGRP). Calcitonin and katacalcin are produced from one precursor and CGRP from another. Calcitonin and katacalcin come mainly from the thyroid, while CGRP is present in both the thyroid and the central nervous system. Calcitonin is concerned with skeletal integrity, while the function of katacalcin, if any, is unknown. The secretion of calcitonin is, in part, estrogen dependent, and it appears likely that a postmenopausal decline in calcitonin secretion is a factor in the development of postmenopausal osteoporosis. It is possible that calcitonin may prove useful in the prevention and perhaps the treatment of this condition. CGRP, conversely, is one of the most potent vasodilators known and probably plays an important physiologic role in the control of vessel tone and blood flow. CGRP may also have a role as neurotransmitter or neuromodulator.