Calcitonin gene-related peptide as inflammatory mediator

Sensory neuropeptides have been proposed to play a key role in the pathogenesis of a number of respiratory diseases such as asthma, chronic obstructive pulmonary disease or chronic cough. Next to prominent neuropeptides such as tachykinins or vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) has long been suggested to participate in airway physiology and pathophysiology. CGRP is a 37 amino-acid peptide which is expressed by nerve fibers projecting to the airways and by pulmonary neuroendocrine cells. The most prominent effects of CGRP in the airways are vasodilatation and in a few instances bronchoconstriction. A further pulmonary effect of CGRP is the induction of eosinophil migration and the stimulation of beta-integrin-mediated T cell adhesion to fibronectin at the site of inflammation. By contrast, CGRP inhibits macrophage secretion and the capacity of macrophages to activate T-cells, indicating a potential anti-inflammatory effect. Due to the complex pulmonary effects of CGRP with bronchoconstriction and vasodilatation and diverse immunomodulatory actions, potential anti-asthma drugs based on this peptide have not been established so far. However, targeting the effects of CGRP may be of value for future strategies in nerve modulation.     

降钙素基因相关肽与糖尿病微血管病变

降钙素基因相关肽(CGRP)是目前已知体内最强的舒血管多肽,参与许多重要功能的调节.糖尿病微血管病变是糖尿病常见的慢性并发症,主要累及肾脏和眼,CGRP强大的扩张血管、抑制血管平滑肌细胞增殖、保护内皮细胞、抑制内皮素收缩血管的作用参与了糖尿病肾病的发展过程及糖尿病视网膜病变新生血管的发生并在两者的发生、发展中起了重要作用.通过研究CGRP在微血管病变中的变化趋势,可以为糖尿病微血管病变的早期诊治提供依据.     

降钙素基因相关肽与基因治疗

降钙素基因相关肽(calcitoningene-related peptide,CGRP)是Rosenfeld等于1983年发现的一种生物活性肽,它与降钙素(calcitonin,CT)均来源于位于11号染色体的CT/CGRP基因,由于CT/CGRP基因不同的RNA编码而翻译成CGRP和CT。CGRP是应用DNA基因重组和分子生物技术研究发现的一种由37个氨基酸组成的生物活性多肽,相对分     

Calcitonin gene-related peptide: functional role in cerebrovascular regulation.

Distribution studies disclosed that all major cerebral arteries and cortical arterioles of the cat were invested with fine varicose nerve fibers that contained calcitonin gene-related peptide (CGRP)-like immunoreactivity; the trigeminal ganglia likewise contained CGRP immunoreactivity. Sequential immunostaining with antibodies to CGRP and to substance P (SP) revealed identical distributions of these two peptides in trigeminal ganglia and cerebrovascular nerve fibers, suggesting that CGRP and SP are colocalized in these nerves. CGRP completely disappeared from ipsilateral blood vessels after unilateral section of the trigeminal nerve. Exogenous CGRP was a potent relaxant of feline middle cerebral arteries in vitro (maximum relaxation, 10.5 +/- 1.5 mN; concentration eliciting half-maximal response, 9.6 +/- 1.3 nM). Perivascular microapplication of CGRP to individual cortical arterioles of chloralose-anesthetized cats provoked dose-dependent dilatations (maximum increase in diameter, 38 +/- 5%; concentration eliciting half-maximal response, approximately equal to 3 nM). CGRP was significantly more potent than SP as a cerebrovascular dilator, both in vitro and in situ. Chronic division of the ipsilateral trigeminal nerve in cats did not modify the magnitude of arteriolar responses to perivascular microapplication of either vasoconstrictor or vasodilator agents, but the duration of vasoconstrictor responses to norepinephrine (0.1 mM) or alkaline solutions (pH 7.6) was significantly increased. The cerebrovascular trigeminal neuronal system, in which CGRP is the most potent vasoactive constituent, may participate in a reflex or local response to excessive cerebral vasoconstriction that restores normal vascular diameter.     

Calcitonin gene-related peptide modulates adrenal hormones in conscious dogs.

The effects of a small dose (2 pmol/kg) of human calcitonin gene-related peptide I on plasma renin activity and hormones, including, aldosterone, ACTH, cortisol, AVP and ANH, were investigated in 14 conscious dogs. In addition, we studied the effects of calcitonin gene-related peptide on aldosterone secretion when it is stimulated by angiotensin II and ACTH. An intravenous bolus injection of 2 pmol/kg of calcitonin gene-related peptide raised plasma renin activity (by 216%, p less than 0.05), ACTH (by 85%, p less than 0.05), AVP (by 89%, p less than 0.05), and ANH (by 36%, p less than 0.05). Despite the elevation of plasma renin activity, aldosterone was decreased (by 52%, p less than 0.05). Cortisol did not change significantly. Infusion of 1 pmol.kg-1.min-1 of angiotensin II produced an elevation of aldosterone (by 186%, p less than 0.01), which was completely inhibited by pretreatment with an injection of 2 pmol/kg of calcitonin gene-related peptide. On the other hand, aldosterone secretion stimulated by ACTH was not altered significantly by pretreatment with an injection of 2 pmol/kg of calcitonin gene-related peptide. These results suggest that calcitonin gene-related peptide inhibits aldosterone secretion, especially when aldosterone is stimulated by angiotensin II. In addition, calcitonin gene-related peptide may be involved as an endocrine modulator in the physiological control of other several hormones closely related to the hemodynamics.     

Calcitonin gene-related peptide in small cell lung carcinomas

OBJECTIVE Calcitonin gene-related peptide (CGRP) is a regulatory peptide encoded by the calcitonin gene. CGRP is expressed in increased amounts by the cells of medullary thyroid carcinomas and has been demonstrated by immunohistochemistry to occur in neuroendocrine cells and nerve fibres of lung tissue. MEASUREMENTS Serum CGRP levels were measured in patients with small cell lung carcinomas before treatment (n= 74) and immediately before the second course of chemotherapy (n= 30). In-situ hybridization and immunohistochemistry were performed on tumour tissue and CGRP was extracted from two tumours and characterized by gel chromatography and high pressure liquid chromatography. RESULTS Serum CGRP levels were elevated in small cell lung carcinomas when compared with healthy controls of similar age and sex (median values 55.0 vs 36.6 pmol/l, P<0.001), and 27% had levels above the upper normal range. Serum CGRP levels decreased following the initial course of chemotherapy (P < 0.05) but remained elevated when compared to the controls (P < 0.001). In-situ hybridization for CGRP mRNA was positive in three of 17 tumours and immunohistochemistry was positive in seven of 31 tumours investigated. CGRP immunoreactivity extracted from two tumours was characterized by gel chromatography and high pressure liquid chromatography. A major part of the immunoreactivity was demonstrated to represent the intact molecule. CONCLUSIONS We found that patients with small cell lung carcinomas had elevated concentration of serum calcitonin gene-related peptide but only 27% had values above the upper normal range. Serum CGRP is therefore of limited value as a tumour marker. Intact CGRP can be extracted from tumour tissue, but in-situ hybridization and immunohistochemistry showed positive reactions in only a few of the tumours investigated. The elevated serum CGRP levels are therefore likely to be largely of extratumoral origin.     

Calcitonin gene-related peptide in pregnancy and its emerging receptor heterogeneity.

Calcitonin gene-related peptide (CGRP) is the most potent vasodilator, and there is a growing body of evidence that this peptide might have multiple other functions. During pregnancy, circulating CGRP levels in rats increase up to the time of delivery, followed by a sharp decline at term and postpartum. In addition, the sensitivity of various vascular beds to CGRP in rats appears to increase with advancing pregnancy. This increased sensitivity might be involved in regulating uteroplacental blood flow, in addition to other vascular adaptations that occur during normal pregnancy. Furthermore, the uterine relaxation response to CGRP is elevated during pregnancy and decreased at term. Sex steroid hormones, estrogens and progesterone, regulate CGRP synthesis and its effects on both myometrial and uterine vascular tissues. These changes in smooth muscle relaxation sensitivity to CGRP appear to be a consequence of changes in CGRP-receptor levels in these tissues. There appear to be two receptors for CGRP: the CGRP-A receptor, a well-characterized receptor consisting of calcitonin receptor-like receptor and receptor activity modifying protein 1, and the CGRP-B receptor. The CGRP system might play a role in the maintenance of normal pregnancy, and a defect in this system might lead to complications.     

Calcitonin gene-related peptide stimulates proliferation of human endothelial cells.

The effects of the vasoactive perivascular neuropeptides calcitonin gene-related peptide (CGRP), neurokinin A (NKA), neuropeptide Y (NPY), and vasoactive intestinal polypeptide (VIP) on proliferation of cultured human umbilical vein endothelial cells (HUVECs) were investigated. CGRP was shown to increase both cell number and DNA synthesis, whereas NKA, NPY, and VIP were ineffective. 125I-labeled CGRP was shown to bind to HUVECs and this binding was displaced by addition of unlabeled CGRP, suggesting the existence of specific CGRP receptors. The effect of CGRP on formation of adenosine 3',5'-cyclic monophosphate (cAMP) and inositol phosphates (InsP), two intracellular messengers known to be involved in regulation of cell proliferation, was investigated. CGRP stimulated cAMP formation but was without effect on the formation of InsP. Proliferation, as well as cAMP formation, was also stimulated by cholera toxin. Basic fibroblast growth factor stimulated growth without affecting cAMP or InsP formation, whereas thrombin, which increased InsP formation, did not stimulate proliferation. We thus suggest that CGRP may act as a local factor stimulating proliferation of endothelial cells; that the mechanism of action is associated with cAMP formation; and that this effect of CGRP may be important for formation of new vessels during physiological and pathophysiological events such as ischemia, inflammation, and wound healing.     

Calcitonin gene-related peptide: a haemodynamic study of a novel vasodilator in patients with severe chronic heart failure.

The haemodynamic and neurohumeral response to a novel vasodilator calcitonin gene-related peptide was assessed in 11 patients with severe chronic heart failure. To assess tolerance, a continuous 48-h infusion (n = 6) was compared with a regimen of two successive 8-h infusions (n = 5). Haemodynamic response profiles were similar for both regimens, though the continuous infusion was poorly tolerated. Reductions in afterload reflected by changes in systemic vascular resistance and systemic blood pressure led to increases in cardiac index of at least 24%. Increments in heart rate accounted for much of the increase in cardiac output, there being no significant change in stroke volume index. The response was maintained over the 48-h study period with no tachyphylaxis. Renin and angiotensin levels increased significantly after 24 h. Calcitonin gene-related peptide exerts a favourable haemodynamic response in patients with severe heart failure. The dose used in this study, however, caused troublesome side-effects, particularly when given by continuous infusion. Further studies are required to establish the therapeutic range of this new peptide.     

Calcitonin gene-related peptide in normotensive and spontaneously hypertensive rats

Using specific radioimmunoassay, radioimmunoreceptor analysis and gel filtration, we found that calcitonin gene-related peptides (CGRP) were distributed in various tissues of normotensive rat (WKY) and spontaneously hypertensive rat (SHR), the highest content was in the lumbar spinal cord (1197 +/- 94.8 pg/mg tissue), the lowest in the auricle (15.0 +/- 2.1 pg/mg tissue). Compared with WKY, the plasma CGRP concentration decreased and the CGRP content in abdominal aorta and hypothalamus increased in SHR. By gel filtration, it showed that only one major molecular form of CGRP was present in the tissues. The CGRP specific binding sites were present both in SHR and WKY hearts, but the number of CGRP binding sites in SHR heart was higher and the binding affinity lower than those in WKY heart. Besides, CGRP can reduce the mean arterial pressure (MAP) in the SHR in a dose-dependent way. The above data indicated that CGRP may play an important role in the pathogenesis of hypertension and exert possibly a therapeutic effect on hypertension.     

Calcitonin gene-related peptide mediates acid-induced lung injury in mice

BACKGROUND AND OBJECTIVE: Acid-induced lung injury from aspiration is one of the most important causes of ARDS. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. The current study investigated whether CGRP might have pathophysiological roles in acid-induced lung injury. METHODS: The investigations employed CGRP gene-disrupted mice--mutant mice (CGRP(-/-)) and their littermate controls (CGRP(+/+)). Anaesthetized and mechanically ventilated mice received 2 mL/kg HCl (pH = 1.5) intratracheally. Lung wet-to-dry weight ratios were calculated to assess pulmonary oedema, total and differential cell counts of the BALF were determined, and measurements of myeloperoxidase activity were performed. RESULTS: Acid-induced lung injury was characterized by an increase in lung permeability and respiratory failure. Disruption of the CGRP gene significantly attenuated acid-induced injury, oedema and respiratory failure. CONCLUSIONS: This study suggests that CGRP is involved in the pathogenesis of acute lung injury caused by acid aspiration and CGRP mutant mice may provide an appropriate model to study molecular mechanisms in this context.     

Calcitonin gene-related peptide terminates long-lasting vasopressor responses to endothelin 1 in vivo

Slow dissociation of endothelin 1 from its endothelin A receptors is responsible for the long-lasting vasoconstrictor effects of the peptide. We showed recently that calcitonin gene-related peptide selectively terminates long-lasting contractile responses to endothelin 1 in isolated rat mesenteric arteries. Here we assessed whether the antiendothelinergic effect of calcitonin gene-related peptide is vascular bed specific and may terminate long-lasting pressor responses to exogenous and locally produced endothelin 1 in vivo. Regional heterogeneity of the calcitonin gene-related peptide/endothelin A receptor cross-talk was explored in arteries isolated from various rat organs. Endothelin A receptor-mediated arterial contractions were terminated by calcitonin gene-related peptide in rat mesenteric, renal, and spermatic arteries but not in basilar, coronary, epigastric, gastric, splenic, and saphenous arteries. Endothelin A receptor antagonism only ended endothelin 1-induced contractions in spermatic arteries. In anesthetized rats, instrumented with Doppler flow probes to record regional blood flows, long-lasting pressor and vasoconstrictor responses to an intravenous bolus injection of endothelin 1 or big endothelin 1 were transiently reduced by sodium nitroprusside (NO donor) but terminated by intravenously administered calcitonin gene-related peptide. In conscious rats, calcitonin gene-related peptide but not sodium nitroprusside terminated prolonged (>60-minute) pressor responses to endothelin 1 but not those to intravenous infusion of phenylephrine. In conclusion, pressor responses to circulating and locally produced endothelin 1 that are resistant to endothelin receptor antagonism and NO can be terminated by a regionally selective effect of calcitonin gene-related peptide. Calcitonin gene related peptide receptor agonism may represent a novel strategy to treat endothelin 1-associated cardiovascular pathologies.     

Calcitonin gene-related peptide in patients with and without early reperfusion after acute myocardial infarction.

Plasma concentrations of calcitonin gene-related peptide (CGRP), a potent regulator of vascular tone, creatine kinase, myoglobin, and cardiac troponin T were assessed in 31 patients with acute myocardial infarction. In patients who had sustained acute myocardial infarctions, maximum CGRP concentrations (median, 3.2 pmol/L; interquartile range, 1.5 to 4.8 pmol/L) were markedly elevated as compared with healthy control subjects (n = 23; median, 1.02 pmol/L; p = 0.02). However, no marked differences in CGRP levels were observed between patients with early reperfusion (n = 19; median, 3.5 pmol/L) and patients without early reperfusion (n = 12; median, 2.6 pmol/L; p = 0.96), as well as between those with congestive heart failure (n = 8; median, 3.9 pmol/L) and those without congestive heart failure (n = 23; median, 3.2 pmol/L; p = 0.62). CGRP did not correlate closely with myocardial protein release or hemodynamic parameters (heart rate and blood pressure) or the occurrence of arrhythmias. Therefore we conclude that elevated peripheral venous CGRP concentrations in patients who have sustained an acute myocardial infarction are independent of successful reperfusion and hemodynamic state. Although the cause of CGRP increase is not yet identified, CGRP may play a role in the regulation of coronary vascular tone in patients after acute myocardial infarction.     

Calcitonin gene-related peptide in neural tissues: a phylogenetic study

A heterologous radioimmunoassay using a rabbit antiserum raised against human calcitonin gene-related peptide (CGRP) was used to measure levels of immunoreactive CGRP (IR-CGRP) in the brain, pituitary, and spinal cord in species representing all classes of vertebrates from cyclostomes to mammals, except amphibians. All the brain extracts except those from the trout, goldfish, and iguana demonstrated the presence of IR-CGRP. Pituitary extracts from all animals, except the ratfish, goldfish and trout, contained IR-CGRP. CGRP was present in all classes of animals tested and seems to be highly conserved in the nervous system, where it may act as a neurotransmitter or neuromodulator.     

Calcitonin gene-related peptide is an inhibitor of aldosterone secretion

This study examined the effects of calcitonin gene-related peptide (CGRP) on aldosterone secretion both in vivo and in vitro. Intravenous administration of CGRP (0.01 micrograms/kg) in 6 conscious dogs produced a significant decrease in plasma aldosterone concentration from 68 +/- 12 pg/ml to 28 +/- 11 pg/ml (p less than 0.05) despite a mild but significant elevation of plasma renin activity. In an in vitro study using isolated rabbit adrenal glomerulosa cells CGRP reduced the basal aldosterone secretion in a dose-related manner and furthermore 10(-9) M CGRP inhibited the aldosterone secretion stimulated by 10(-8) M angiotensin II. From these results it is suggested that CGRP has an inhibitory effect on aldosterone secretion.     

Sex-related differences in cough reflex sensitivity in patients with chronic cough

Among patients attending specialist cough clinics there is an excess of females, but the reason for this sex difference is unknown. We tested the hypothesis that the sensitivity of the cough reflex is greater in female compared with male patients with chronic cough. Inhalation cough challenges with capsaicin and citric acid were performed in a large group of patients with chronic cough. The concentrations of tussive agent causing two (C2) and five (C5) coughs were calculated. Measurements of capsaicin cough reflex sensitivity (median [interquartile range]) were significantly lower for female patients compared with male patients (C2: 1.9 [0.5 to 5.5] versus 5.3 [2.2 to 11.5] micro M, p = 0.0026; C5: 8.6 [2.2 to 34.0] versus 51.2 [7.2 to > 100] micro M, p = 0.0007). Similarly for citric acid challenge, values were significantly lower for female compared with male patients (C2: 53.5 [17.3 to 145.4] versus 118.1 [41.4 to 381.7] mM, p = 0.0064; C5: 300.0 [97.1 to > 1,000] versus 830.4 [300.0 to > 1,000] mM, p = 0.032). There were significant correlations between capsaicin and citric acid C2 values (r(s) = 0.54, p < 0.0001) and C5 values (r(s) = 0.57, p < 0.0001). These findings indicate a sex difference in cough sensitivity in patients with chronic cough, as previously reported in healthy volunteers. This may explain the female preponderance in cough clinics.     

Calcitonin gene-related peptide immunoreactivity in a crustacean Nephrops norvegicus and correlation with calcitonin

Immunoreactive calcitonin-gene-related peptide (ir-CGRP) was detected in the crustacean Nephrops norvegicus. High levels of ir-CGRP were present in the foregut and hepatopancreas (3 +/- 0.7 and 4.6 +/- 1.0 micrograms eq per 100 mg of fresh organ, respectively). Molecular sieving of acidic extracts of anterior gut of Nephrops norvegicus showed a high molecular weight immunoreactive peptide in the range 15,000 to 25,000 Da. Immunoreactivity related to salmon calcitonin was present in the high molecular weight fraction.     

急性脑梗死患者血浆降钙素基因相关肽分析

目的　了解急性脑梗死患者血浆降钙素基因相关肽 ( CGRP)动态变化及与病情的关系。方法　脑梗死患者按病情分为轻、中、重三组 ,分别在发病 3d内、 2 w末、 4 w末采血 ,放免法测定血浆 CGRP浓度 ,并与对照组比较。　结果　血浆 CGRP浓度脑梗死发病 3d内显著降低 ,2 w末、 4 w末依次增高接近对照组 ,急性期病情重者比轻者的 CGRP浓度低。　结论　脑梗死患者存在着血浆 CGRP水平的规律性变化 ,其浓度与脑梗死病理过程以及病变程度有关。     

血糖波动及降钙素基因相关肽对糖尿病微血管病变影响的研究进展

随着动态血糖监测系统（CGMS）的广泛使用,使人们注意到波动性高血糖比持续性高血糖更易促进糖尿病微血管病变的发生和发展。降钙素基因相关肽是目前知道的舒血管活性最强的多肽,在糖尿病微血管病变中起着重要的作用。相信对血糖波动危害的正确认识及降钙素基因相关肽对糖尿病微血管病变影响机制的深入研究,能够为糖尿病（DM）的诊治提供依据和手段,改善患者的预后。     

Calcitonin gene-related peptide in hepatorenal syndrome. A possible mediator of peripheral vasodilation?

In advanced cirrhosis and hepatorenal syndrome, peripheral vasodilation is a prominent feature and may be pathophysiologically relevant. To determine whether the potent vasodilator, calcitonin gene-related peptide (CGRP), circulates at abnormal levels in patients with these disorders, we observed eight patients with alcoholic cirrhosis and hepatorenal syndrome, seven with alcoholic cirrhosis and ascites without hepatorenal syndrome, and 10 healthy controls. Plasma CGRP levels were higher in patients with alcoholic cirrhosis and hepatorenal syndrome (364 +/- 166 pg/ml) than in healthy controls (143 +/- 54 pg/ml, p less than 0.01). In patients with cirrhosis and ascites without hepatorenal syndrome, plasma CGRP levels were less elevated (291 +/- 257 pg/ml, NS). The identity of immunoreactive CGRP and synthetic hCGRP was confirmed by high performance liquid chromatography. These results suggest that CGRP may play a role in hepatorenal syndrome. However, to establish whether circulating CGRP contributes to the hemodynamic change in hepatorenal syndrome requires study of a larger number of patients and additional control groups.