Plasma Concentrations Of Calcitonin Gene-related Peptide Research Articles

Circadian Profile of Plasma Calcitonin Gene-Related Peptide in Healthy Man*

Calcitonin gene-related peptide (CGRP) is known to exert potent cardiovascular effects and is presumed to participate in the neural control of circulation and blood flow. It has been assayed in many physiological and disease conditions, yet virtually nothing is known of the normal fluctuations in its circulating levels. We have studied the variability throughout a 24-h period of plasma concentrations of CGRP in eight recumbent healthy volunteers (four men and four women, 25-37 yr old), after careful standardization of their daily diet and routine schedules. A correlation with the circadian rhythms of blood pressure (BP), heart rate (HR), and plasma aldosterone (PA), PRA, plasma cortisol (PC), and atrial natriuretic peptide (ANP) was also made. Plasma CGRP concentrations ranged from a mean peak value of 18.1 +/- 1.5 pmol/L to a mean lowest value of 11.7 +/- 0.4 pmol/L (P less than 0.05). The mean circadian acrophase of CGRP (calculated by cosinor analysis to occur at 2314 h) anticipated the corresponding acrophases of the other hormones (0122, 0528, 0809, and 0840 h for ANP, PRA, PA, and PC, respectively). Instead, BP and HR rhythms seemed to be antiphasic with the ANP rhythm (calculated acrophases occurred at 1356, 1339, and 1314 h for systolic BP, diastolic BP, and HR, respectively). Our data demonstrate that, like many other hormones, CGRP circulates in plasma with a circadian rhythm. There seems to be a temporal sequence starting with the nocturnal rise in plasma CGRP concentrations and progressing with the ensuing elevations of ANP, PRA, PA, and PC, whereas BP and HR are kept to their lowest values. These findings are in favor of a physiological role of CGRP in the complex regulation of BP homeostasis.

Plasma concentrations of calcitonin gene-related peptide in fluid overload

To investigate the hypothesis that calcitonin gene-related peptide (CGRP), a potent vasodilator, is an important physiological defence against fluid overload, plasma CGRP concentrations were measured in various degrees of fluid overload in 26 haemodialysis patients, for whom diuresis, mediated by atrial natriuretic peptide (ANP), is not a possible defence mechanism. Plasma CGRP concentrations were positively correlated with the degree of fluid excess (r = 0·815, p = 0·0001) and were significantly higher in 5 patients with severe fluid overload than in those less severely affected (143 [SE 14] vs 52 [11] pmol/l; p<0·001). CGRP may be an effective defence against complications of fluid overload since it can increase capitance by vasodilatation.

Calcitonin gene-related peptide in human obesity

We studied plasma calcitonin gene-related peptide (CGRP) levels in obese women before ( n=24 ) and after ( n=13 ) weight loss, and in normal weight controls ( n=15 ). Furthermore, the influence of two isocaloric meals (high carbohydrate vs. high fat) on plasma CGRP concentrations was studied. The CGRP concentration in the obese group ( 32.26±2.01 pg/ml ) was significantly ( p<0.0001) higher than in the control group ( 21.64±0.15 pg/ml ). After weight loss ( 14.3±0.72% of original weight) CGRP concentrations remained unchanged. Only the high-fat meal caused a significant ( p<0.02) rise in CGRP levels. Our results indicate that elevated plasma CGRP levels may constitute a primary phenomenon in obese women, and that fat intake may be associated with increased CGRP secretion.

Circadian Variation of Plasma Calcitonin Gene‐Related Peptide in Man

Abstract Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilator peptides known so far. Almost all clinical studies using or measuring CGRP are conducted during the day, and hence this study was carried out to see any variations of CGRP levels in the circulation during this period. Three separate studies were conducted. In the first study, following an overnight fast, sequential samples of blood were taken from six healthy volunteers between 0900 and 2100 h and were assayed for CGRP using a highly sensitive and specific radioreceptor assay. A diurnal variation of CGRP in the circulation (P<0.0001) was demonstrated. No difference in the diurnal pattern of CGRP in plasma was seen between males and females. The range of plasma receptor-active CGRP was 2.8 to 13.0 pmol/l (mean +/-SEM, 7.03+/-0.28 pmol/l). Two peaks of CGRP were observed in the circulation (increases of approximately 100% from the basal levels obtained at 0900 h), one around midday (P<0.0001) and the other in the late afternoon (P< 0.005). To assess the contribution of CGRP released from the gut following food, a second study was carried out in which the protocol of the first study was repeated in three volunteers but avoiding any food during the day. Although a similar diurnal variation of receptor-recognized CGRP was seen in this study (P<0.01), the changes observed were significantly lower than those observed in the first study, suggesting that the effect of a meal exaggerates the response of diurnal variation of plasma CGRP. In a third study, circadian variation of receptor-recognized CGRP was examined in three volunteers over a 24 h period. In addition to the diurnal pattern seen with the first study, the plasma CGRP levels continued to decrease up to early morning. The lowest levels of CGRP were detected between 0300 and 0600 h. After this time the levels gradually rose towards midday. It is well accepted that the incidence of cardiovascular episodes is high during the early hours of the morning. Separate studies are necessary to determine if these low levels of 'biologically-active CGRP' in the early hours of the morning are a coincidence, or whether they play a role (e.g. relative deficiency of CGRP) in contributing to the occlusion of already diseased arteries. Furthermore, the diurnal variations of monomeric CGRP demonstrated here imply that, with any experiments relying on the measurement or infusion of CGRP, timing of blood sampling and relationship to meals are important and should be strictly adhered to in most physiological studies with CGRP. This is the first study which demonstrates the circadian variation in plasma concentrations of CGRP.

Calcitonin Gene-Related Peptide: 24-Hour Profile and Responses to Volume Contraction and Expansion in Normal Men*

Plasma immunoreactive calcitonin-gene related peptide (CGRP) concentrations were measured in 10 normal male subjects, aged 23-34 yr, who were studied under 3 separate conditions at intervals of at least 1 week. In phase 1, plasma CGRP concentrations were measured hourly for 24 h during normal activity; in phase 2, the CGRP response to diuretic-induced volume depletion and upright posture was measured over 3 h; in phase 3, the CGRP response to volume loading and supine posture was measured over 4 h. During phase 1, the mean 24-h plasma CGRP concentration averaged 30 +/- 16 pmol/L; hourly CGRP concentrations ranged from 25-37 pmol/L over 24 h and oscillated from 16% below to 27% above the mean 24-h CGRP value, changes that were highly significant (P = 0.005). The peaks were at 0600 and 0700 h, while the nadirs were at 1200 and 2000 h. No significant difference was found between fasting CGRP at 0800 h and levels taken 1, 2, and 3 h postprandially (P = 0.68). During phase 2 (volume depletion and upright) mean plasma CGRP rose significantly, going from a baseline of 42 +/- 8 pmol/L at 0800 h to a peak of 60 +/- 10 pmol/L at 1100 h (P = 0.0005). The percent CGRP increment was relatively small (26% to 42%) compared to the rise in PRA (518% to 1033%) and aldosterone concentrations (333% to 465%). Hematocrit increased from 40.5 +/- 0.7% to 45.8 +/- 0.7% (P = 0.0001) in phase 2, while serum osmolality did not change significantly. In phase 3 (volume loading and supine), plasma CGRP did not change significantly, while PRA and aldosterone concentrations fell significantly (P = 0.0001); neither serum osmolality nor hematocrit changed significantly. We conclude that plasma CGRP concentrations fluctuate spontaneously and significantly during the day, and rise in response to volume depletion. The reasons for the CGRP fluctuations seen over 24 h, which are not apparent from this study, may be related to changes in vascular volume or other as yet unidentified factors. These studies are consistent with the concept that CGRP, acting either directly or through the renin-aldosterone system, may have a role in regulating peripheral vascular tone or controlling vascular volume.

Determination of Plasma Calcitonin Gene-Related Peptide Concentrations by a New Immunochemiluminometric Assay in Normal Persons and Patients with Medullary Thyroid Carcinoma and Other Neuroendocrine Tumors*

There is doubt about concentrations of circulating calcitonin gene-related peptide (CGRP) and the value of plasma CGRP measurements in the detection and follow-up of medullary thyroid carcinoma (MTC). Thus, we developed an immunochemiluminometric sandwich assay for CGRP using antibodies purified from a polyclonal antiserum against human CGRP. The assay was sensitive (limit of detection, 0.4 pmol/L; multiply by 3.7892 to derive nanograms per L) and highly specific [no cross-reaction with human calcitonin (CT)]. Normal plasma CGRP values ranged from less than 0.4 to 4.5 pmol/L (median, 0.8; n = 31), with 61% having detectable levels. Values in samples from patients with MTC were elevated: unoperated patients (n = 10), 4.7-137 pmol/L (median, 7.1); and operated patients with gross persistent or recurrent tumor (n = 14), 4.7-171 pmol/L (median, 23.2). In contrast, CGRP values were normal in 78% of nine postoperative patients with elevated CT, but no detectable tumor (range, less than 0.4 to 6.3 pmol/L; median, 1.6). CGRP levels increased after pentagastrin injection in MTC patients, but less than did CT values. Cultured MTC cells in vitro secreted large amounts of CGRP, and rat nerve root ganglia, human osteoblasts, and microvessel endothelial cells secreted lesser amounts. We conclude that CGRP circulates in normal plasma, but at very low levels. Plasma CGRP concentrations are frequently high in patients with MTC, but primarily in those with gross tumor or metastases. Plasma CT assay is the preferable test for MTC, but CGRP assay deserves prospective study for a possible role in predicting gross metastasis.

Effects of epidural analgesia on plasma calcitonin gene‐related peptide

The effects of epidural analgesia on plasma calcitonin gene-related peptide (CGRP) values during and after hysterectomy were investigated in 14 healthy patients. In seven patients who received general anaesthesia alone for pelvic surgery, there were no significant changes in plasma CGRP concentrations. In the remaining patients, who received extensive epidural blockade in addition to general anaesthesia, there were again no significant changes in plasma CGRP values. This was in spite of profound sympathetic blockade, as shown by marked hypotension and a significant decline in plasma catecholamines. The epidural group of patients showed the expected attenuation of the glucose, cortisol and growth hormone responses to surgery. The results show that circulating CGRP is unlikely to be involved in the modulation of peripheral vascular tone during pelvic surgery under either general or epidural anaesthesia.

Circulating levels of calcitonin gene-related peptide in patients with medullary thyroid carcinoma.

Calcitonin gene-related peptide, originally found in rat medullary thyroid carcinoma cells, was measured by radioimmunoassay in plasma samples with added aprotinin from 17 normal volunteers and 21 patients with medullary thyroid carcinoma. The concentrations were below 75 pmol/l in all 17 normal subjects with a mean of 33 +/- 19 pmol/l plasma. In the patients, the plasma calcitonin gene-related peptide concentrations ranged from below 5 pmol/l to 236 pmol/l, although the mean (36 +/- 48 pmol/l) was not significantly different from the mean normal level. Increase in the plasma calcitonin gene-related peptide level was observed in 2 of 5 patients in response to infusion of 4.3 mg/kg of calcium for 10 minutes and in 3 of 5 patients in response to infusion of 4 micrograms/kg of tetragastrin for 5 minutes. These observations suggest that measurement of calcitonin gene-related peptide level may be helpful in determination of diseases in which the level of calcitonin is of less diagnostic value.