Ligand and redox - interactions of adrenaline with iron at physiological pH

Abstract

Adrenaline (Adr) is catecholamine that is released by the sympathetic nervous system and adrenal medulla. It is involved in several physiological functions, including regulation of blood pressure, vasoconstriction, cardiac stimulation, and regulation of the blood glucose levels 1 . Transients of high levels of Adr in the bloodstream have been recognized for a long time as a cause of cardiovascular problems that develop under chronic exposure to psychosocial and physical stress 2,3. A number of studies have found a connection between the excess of Adr, cardiotoxic effects, and oxidative stress, that is irrespective of adrenergic receptors stimulation 2-4. The mechanism behind this involves Adr (coordinate and redox) interactions with iron, which are still not clear. Two main concepts have been proposed - Adr autooxidation and redox interactions with iron, the most abundant transition metal in human plasma 5 . Fe3+ is known to build complexes with catechols 6 , but data on Fe3+ coordinate interactions with Adr at physiological pH are missing. In addition to its (patho)physiological role, Adr is of interest from the aspect of development of catecholamine-rich biopolymers with adhesive properties and metelloorganic frameworks 7,8. The adhesion and other properties materials are based on the cross-linking via coordinate bonds with Fe3+ at pH > 7. Finally, ligands might dramatically alter the redox potential of Fe3+/Fe2+ couple 9 . It has been shown that specific ligands with high affinity for Fe3+, including some catechols, might promote the oxidation and increase the reactivity of Fe2+ with molecular oxygen 10. The aim of our study was to examine the nature of Adr interactions with Fe3+ and Fe2+: stoichiometry, sites of coordinate bonds formation and structure of complex(es), and redox activity, at pH 7.4 and different concentration ratios. The coordinate and redox interactions were investigated using UV/Vis spectrophotometry, low temperature EPR, Raman 143 spectroscopy, cyclic voltammetry, and oximetry. The stability of Adr in the studied reactions was monitored by HPLC. At pH 7.4, Adr forms complexes with Fe3+, in the 1:1, and 3:1 stoichiometry, depending on (high or low) Adr/Fe3+ concentration ratio. The high-spin Fe3+ 1:1 and 3:1 complexes show different symmetries, with the 3:1 complex displaying higher EPR spectral anisotropy. Raman spectroscopy showed that oxygen atoms on the catechol ring represent the sites of coordinate bond formation in the bidentate Adr-Fe3+ complex. The bonds appear to be stronger in the 1:1 complex, and not to share the same plane with the ring. On the other hand, Adr and Fe2+ build a complex that acts as a strong reducing agent. In the presence of O2, this leads to the production of H2O2, and to a facilitated formation of Adr/Fe3+ complexes. Adr is not oxidized in this process, i.e. iron is not an electron shuttle but electron donor. Catalyzed oxidation of Fe2+ in the presence of Adr represents a plausible chemical basis of stress-related damage of heart cells. In addition, our results imply that the application/pre-binding of Fe2+ followed by oxidation at pH > 7 might be a simple alternative strategy for promotion of cross-linking in catecholamine-rich biopolymers frameworks.