The Role of Cytochrome P-450 2C9 Pathway in Flow-Mediated Dilation in Young Healthy Adults

Endothelium-derived hyperpolarizing factors (EDHF) produced via the cytochrome P-450 2C9 (CYP2C9) pathways are known to influence vascular function, but their role in flow-mediated dilation (FMD) remains unclear. Purpose: To determine whether CYP2C9 pathways contribute to brachial artery FMD in young, healthy adults Methods: Thirty healthy young adults (15 males 22±2.9 yrs, 15 females 22±3.3 yrs with regular menstruation cycle and examined during days 1-5 of their cycle) completed two randomized, single-blinded, counterbalanced experimental visits separated by ≥72hrs. Before laboratory arrival, all participants refrained from caffeine ≥12hrs, and vigorous exercise, alcohol, and NSAIDs ≥24 hrs. Two hours before experiments, participants randomly ingested 150 mg of fluconazole (FLZ, CYP2C9 inhibitor) or placebo (250 mg microcrystalline cellulose, PLA). All study visits were completed in a quiet, temperature-controlled (20-22°C), and dark environment with the participant in a supine position and arms at heart level. FMD was induced via proximal upper arm brachial artery occlusion for 5 min and pneumatic rapid cuff release. Brachial artery diameter and mean blood velocity were recorded by duplex ultrasound for offline analysis. FMD responses were reported as maximal absolute (FMD, Δmm) and percent changes (FMD, Δ%) within 3 min post-occlusion diameter relative to 1 min pre-occlusion baseline diameter (BLD).The cumulative shear rate area under the curve (SR AUC , a.u.) was calculated until the peak diameter. Peak velocity (PV), time-to-peak velocity (TPV), and time-to-peak diameter (TPD) were also determined after cuff deflation. Results: Means ±SD. BLD did not differ between conditions (PLA:3.7±0.6 mm vs. FLZ:3.6±0.6 mm, p =0.4, d: 0.14). Absolute and relative FMD was significantly higher in PLA (mm, PLA: Δ0.4±0.1 vs. FLZ: Δ0.3±0.1, p =0.04, d=0.4; %, PLA: Δ10.1±3.4 vs. FLZ: Δ8.9±3.8, p =0.05, d=0.37). SR AUC , PV, TPV, and TPD showed no significant differences between conditions. Further, our data confirms the known sex differences in BLD (mm, PLA; M: 4.2±0.3 vs. F: 3.1±0.3, FLZ; M: 4.1±0.4 vs F: 3.1±0.3, p <0.001, η 2 =0.71) and relative FMD (%, PLA; M: Δ8.4±2.1 vs. F: Δ11.8±3.8, FLZ; M: Δ6.8±2.6 vs. F: Δ11.0±3.7, p <0.001, η 2 =0.35). No significant differences or sex*treatment interaction were found in absolute FMD, SR AUC , PV, TPV, or TPD. Interestingly, if treatment is compared separately within sex, males present an attenuated FMD in FLZ (%, PLA; M: Δ8.4±2.1 vs. FLZ; M: Δ6.8±2.6, p=0.049; mm, PLA, M: Δ0.4±0.1 vs. FLZ, M: Δ0.3±0.1, p =0.031) whereas, females do not (%, PLA, vs. FLZ, p =0.2, mm PLA, vs. FLZ, p =0.2). Conclusion: Our findings indicate that CYP2C9 pathways contribute to FMD in young, healthy adults. Furthermore, our data provides evidence that CYP2C9 pathways may have differing contributions to FMD between sexes. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.