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.