The effects on cytochrome P450 pathway inhibition on reactive hyperemia in healthy young adults
Authors: Skillett Sarah , Mixon Chris , Buelow Alexander , Matney Jacob , Ashley John , Song Jiwon , Sun Jongjoo , McKenzie Nathan , Kellawan Mikhail 
Published: May 2023

Reactive hyperemia (RH) is typically used as an assessment of cardiovascular risk from observing microvasculature reperfusion following induced ischemia from arterial occlusion. It is unknown if Cytochrome P450 (CYP450) pathways have any contribution to the microcirculatory response to RH PURPOSE: To test the hypothesis that inhibition of CYP450 would decrease RH in healthy young adults. METHODS: 23 healthy young adults (23±3 years, 12 females, tested in days 1-5 of menstrual cycle) participated in a randomized, single blind, counter-balanced protocol. 2 hours prior to experiments, participants ingested either a placebo (PLA, 250 mg microcrystalline cellulose) or CYP450 inhibitor, fluconazole (FLZ, 150 mg fluconazole) and rested in the supine position. From this position with limbs at heart-level, participants rested for 5 minutes prior to 5-minute recording of baseline values. Then using a rapid inflation/deflation device (Hokanson) a blood pressure cuff was inflated to 230 mmHg on the upper portion of their non-dominate arm for 5-minutes to occlude forearm blood flow. Following 5 min of occlusion, the cuff was rapidly deflated. Frequency-domain Near-infrared spectroscopy (NIRS) was secured over the flexor digitorum muscles to continuously measure oxy, deoxy, and total hemoglobin [Hb]+myoglobin [Mb]. Tissue saturation index was calculated (TSI% = oxy[Hb+Mb]/total[Hb+Mb]). The reperfusion rate (RR, slope of TSI increase, %/s) following the release of occlusion was calculated. The ischemic stimulus was also characterized for each participant in each trial as the integral of TSI desaturation during the 5-minute occlusion (Δ%TSI x Min). Significance was set to ≤0.05. RESULTS: All data are presented as mean ±SD. Sex as a biological variable was also assessed (males, M vs females, F). There was no effect of CYP450 inhibition, but a fairly large effect size (η2) was observed (PLA, M:1.91±0.71 vs F:1.44±0.49, FLZ, M:2.36±1.05 vs F:1.24±0.54, p=0.11, η2=0.12). Interestingly, M were found to have a larger RR than F (p≤0.001, η2=0.92). However, when data were normalized to the ischemic stimulus, the effect size of FLZ was drastically reduced (PLA, M:0.01±0.01 vs F:0.04±0.09, FLZ, M:0.02±0.004 vs F:0.04±0.10, p=0.68, η2=0.01) and sex differences remained (p=0.05, η2=0.17). CONCLUSION: These data indicate that inhibition of CYP450 pathways do not affect microvascular RH in healthy young adults. Further, our data indicate that men have a greater microvascular RH response than women with no contribution of CYP450 pathways. These data highlight the importance of including sex as a biological variable and incorporating a measure of the ischemic stimulus when reporting reactive hypermia data. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.