Inhibition of CYP450 pathways reduces functional sympatholysis in healthy young adults

Functional sympatholysis, the blunting of sympathetic vasoconstriction during exercise, is critical for regulating exercise hyperemia. The role of cytochrome P450-2C9 (CYP450) pathways in functional sympatholysis remains unclear. A total of 21 participants (11 females) completed three study visits (2 experimental). Participants ingested a placebo (PLA) or CYP450 inhibitor fluconazole (FLZ) 120 min before testing in a double-blind, randomized, crossover design. Forearm blood flow (FBF) and mean arterial pressure (MAP) were continuously measured to calculate forearm vascular conductance (FVC) during baseline, -20 mmHg lower body negative pressure (LBNPrest), rhythmic handgrip exercise (Ex) at 20% maximum voluntary contraction, and exercise with LBNP (LBNPex). FLZ did not change FVC at baseline or during Ex (<i>P</i> > 0.05). However, adding LBNPex to Ex reduced FVC in the FLZ condition compared with PLA (PLA: 2 ± 12 Δ% vs. FLZ: -12 ± 13 Δ%, <i>P</i> < 0.001, <i>d</i>: 0.9). A significant change in FVC across time (baseline + LBNPrest vs. Ex + LBNPex) was observed (<i>P</i> < 0.001, [Formula: see text]: 0.8), along with significant effects of condition (PLA vs. FLZ) (<i>P</i>: 0.003, [Formula: see text]: 0.4) and their interaction (<i>P</i>: 0.05, [Formula: see text]: 0.2). Functional sympatholysis magnitude differed between conditions (PLA: 107 ± 41% vs. FLZ: 67 ± 50%, <i>P</i>: 0.001, <i>r</i>: 0.7). Therefore, CYP450 pathways are mechanistically involved in functional sympatholysis. However, CYP450 inhibition does not augment resting or exercising vascular responses without constrictor stimuli.<b>NEW & NOTEWORTHY</b> Evidence suggests that functional sympatholysis is an endothelial-dependent, nitric oxide and prostaglandin-independent process. We found that cytochrome P450-2C9 (CYP450-2C9) inhibition attenuated sympatholytic responses during dynamic handgrip exercise with superimposed lower body negative pressure. These data indicate that CYP450 pathways contribute to functional sympatholysis in young healthy humans.