Date Published: May 31, 2019
Publisher: Public Library of Science
Author(s): Milica Popovic, Katharina Timper, Eleonora Seelig, Thierry Nordmann, Tobias E. Erlanger, Marc Y. Donath, Mirjam Christ-Crain, Melissa M. Markofski.
Studies have suggested that arginine vasopressin (AVP) and its surrogate marker copeptin increase during exercise, independently of serum sodium and/or osmolality. In extreme cases, this can lead to runners-induced hyponatremia. Interleukin-1 (IL-1) increases during exercise and induces AVP in animal models. We here therefore investigate whether copeptin (a surrogate marker for AVP) increases upon exercise in young and healthy males, and whether this increase is regulated by IL-1.
In a randomized, placebo-controlled, double-blind, crossover trial in 17 healthy male volunteers, the effect of the IL-1 receptor antagonist anakinra on exercise-induced copeptin was compared with placebo.
Participants exercised for one hour at 75% of VO2max and were not allowed to drink/eat 6 hours before and during the study. Participants received either 100 mg of anakinra or placebo 1h before exercise. Blood was drawn at certain time intervals.
In both groups, copeptin levels were induced by 2.5-fold upon exercise (p<0.001), from 4.5–10.6 pmol/l in the placebo, and 4.3–11.3 pmol/l in the anakinra group, (p = 0.38). One hour after exercise, copeptin levels dropped to 7.7 and 7.9 pmol/l in the placebo and anakinra group, respectively (p = 0.58). The increase of copeptin levels was not explained by sodium concentrations. Exercise induces a continuous rise of plasma copeptin levels in healthy male volunteers independently of sodium levels and fluid intake. This increase is not regulated by the IL-1 pathway.
Copeptin (the C-terminal portion of pre-pro-vasopressin) is secreted together with arginine vasopressin (AVP) in equimolar amounts and serves as a surrogate marker for AVP which is difficult to measure. Elevation in serum osmolality and reduction in blood volume are the classic stimuli for AVP and copeptin production. Another important stimulus is stress and thus copeptin is increased in several acute diseases predicting outcome.[3–11] Additionally, several studies have shown an enhanced AVP production during exercise in different settings, whereby the elevation in AVP levels correlated with the intensity of exercise.[12–18] Few studies have investigated exercise-induced copeptin dynamics. These studies have been performed either in an elderly population with comorbidities, in young volunteers in a hot environment, or under extreme conditions like an ultramarathon.[19–25] Moreover, all of these studies have measured copeptin levels only twice, before and after exercise. Although increasing osmolality and plasma volume loss seem to be potent drivers of AVP/copeptin production in exercising participants, this does not explain the whole effect: Three studies reported increased AVP and copeptin levels after an ultramarathon in spite of decreased sodium values and osmolality.[12,22,26] Furthermore, a recent study showed that at a sodium level of 143 mmol/L or a serum osmolality of 295 mOsm/kg, respectively, led to an absolute increase in copeptin of only 3 pmol/L, i.e. lower levels than achieved during exercise. AVP levels also normalized after exercise without fluid replacement.[13,15] Therefore, other factors seem to be involved in the regulation of AVP/copeptin dynamics upon exercise. The pro-inflammatory cytokine interleukin-1 (IL-1) might play a role in AVP/copeptin production. Specifically, serum IL-1β levels and IL-1β activity were shown to increase upon exercise.[28–30] Furthermore, animal studies reported increased AVP production after administration of IL-1β in freely moving rats in vivo or in the dissected hypothalamus in vitro.[31–33] The fact that administration of dexamethasone abolished the increase in AVP levels in exercising healthy men further supports the inflammatory hypothesis in exercise-stimulated AVP production.
To our knowledge, this is the first study reporting the course of copeptin levels before, during, and after steady-state exercise and investigating the potential role of IL-1 in copeptin regulation. We report two main findings. First, exercise induced a continuous rise of copeptin levels by about 2.5 fold in healthy male volunteers reaching a maximum level of ~11.0 pmol/l at the end of the exercise period. Copeptin levels remained elevated in the first minutes after discontinuing exercise and then dropped gradually within the following hour to a level of ~7.8 pmol/l which was 1.7-fold higher than baseline. Second, our data suggest that exercise-induced copeptin is not regulated via the IL-1 pathway.