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Abstract
Epoxides derived from arachidonic acid (AA) are released during exercise and may contribute to vasodilation. However, exercise may also affect circulating levels of other epoxides derived from cytochromes P450 (CYP) monooxygenase and lipoxygenase (LOX) pathways, many of whose exhibit cardiovascular activity in vitro. The effects of exercise on their levels have not been documented. We tested the hypothesis that acute, maximal exercise would influence the plasma concentrations of these vasoactive substances. We measured plasma CYP and LOX mediators derived from both the n − 3 and n − 6 fatty acid (FA) classes in healthy volunteers before, during and after short‐term exhaustive exercise. Lipid mediators were profiled by means of LC–MS/MS tandem mass spectrometry. A maximal Bruce treadmill test was performed to voluntary exhaustion. Exhaustive exercise increased the circulating levels of epoxyoctadecenoic (12,13‐EpOME), dihydroxyeicosatrienoic (5,6‐DHET), dihydroxyeicosatetraenoic acids (5,6‐DiHETE, 17,18‐DiHETE), but had no effect on the majority of CYP and LOX metabolites. Although our calculations of diol/epoxide ratios revealed preferred hydrolysis of epoxyeicosatrienoic acids (EEQs) into their diols (DiHETEs), this hydrolysis was resistant to maximal exercise. Our study is the first documentation that bioactive endogenous n − 3 and n − 6 CYP lipid mediators are released by short‐term exhaustive exercise in humans. In particular, the CYP epoxy‐metabolite status, 12,13‐EpOME/DiHOME, 5,6‐EET/DHET, 5,6‐EEQ/DiHETE and 17,18‐EEQ/DiHETE may contribute to the cardiovascular response during maximal exercise.
Highlights
Vasoactive substances, including prostaglandins, nitric oxide (NO), adenosine, adenosine 50-triphosphate (ATP), are released from contracting skeletal muscle and vascular endothelium and may contribute to vascular relaxation (Clifford and Hellsten 2004)
The cytochromes P450 (CYP) epoxy-metabolite status, 12,13-EpOME/ DiHOME, 5,6-EET/DHET, 5,6-EEQ/dihydroxyeicosatetraenoic acids (DiHETEs) and 17,18-EEQ/DiHETE may contribute to the cardiovascular response during maximal exercise
We found that exercise increased the levels of 12,13-EpOME plus 12,13DiHOME (12,13-EpOME/DiHOME), 5,6-EET plus 5,6DHET (5,6-EET/DHET), 8,9-EET plus 8,9-DHET (8,9EET/DHET), and 5,6-EEQ plus 5,6-DiHETE (5,6-EEQ/ DiHETE) levels, but not of the majority of metabolites (Table 2)
Summary
Vasoactive substances, including prostaglandins, nitric oxide (NO), adenosine, adenosine 50-triphosphate (ATP), are released from contracting skeletal muscle and vascular endothelium and may contribute to vascular relaxation (Clifford and Hellsten 2004). In this regard, arachidonic acid (AA) can be converted into vasoactive metabolites via the cytochromes P450 (CYP) mono-oxygenase and lipoxygenase (LOX) pathways (Fig. 1). EETs can cause hyperpolarization of smooth muscle cells and relaxation by opening of Ca2+-activated K+ (BK) channels (Zhu et al 1995; Spector 2009). Activation of this pathway is partially or totally unresponsive to inhibitors of cyclo-oxygenases that metabolize AA to 5-, 12, and 15-hydroxyeicosatetraenoic acid (HETE) (Fig. 1), prostaglandins, prostacyclin (PGI2), thromboxane and leukotrienes and inhibitors of NO synthase
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