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Several sports have been associated with a postexercise increase of cardiac, liver, and skeletal muscle biomarkers of injury. Exhaustive or acute physical exercise causes an increased generation of reactive oxygen species, resulting in cellular injury. Thus, exercise and training may trigger pathophysiological changes in serum concentrations of a variety of biomarkers. In this study, we aimed to evaluate the variation of novel biomarkers of stress and cardiovascular disease such as copeptin, midregional part of proadrenomedullin (MR-proADM), growth differentiation factor 15 (GDF15), soluble vascular endothelial growth factor receptor, and placental growth factor along with uric acid before and after acute high-intensity exercise and allopurinol administration. We also assessed whether allopurinol administration may affect the circulating levels of these biomarkers by inhibition of XO activity. This is a double-blind, placebo-controlled study in which 12 professional football players were divided into 2 experimental groups. An oral dose of 300 mg of allopurinol was administered to one group of six participants 4 hours before a match of the Spanish Football League, whereas the other 6 participants received placebo (cellulose). Venous blood samples were obtained before the match (baseline) and twelve hours afterwards (post-match). Serum MR-proADM levels increased significantly in the placebo group, whereas serum GDF15 levels increased significantly in both the placebo and allopurinol group after the match. No differences in the other parameters tested were found after the match in any experimental group. The trend toward postexercise increase of serum MR-proADM and GDF15 levels shows that the metabolism of these proteins is clearly imbalanced after exercise, which thereby represents a potential source of biological variability in their clinical assessment.