Sex Difference in Reliance on CYP450 Contribution to Functional Sympatholysis in Healthy, Young Adults
Authors: Buelow Alexander A. , Matney Jacob E. , Skillett Sarah , Song Jiwon , Mixon Chris , Ashley John , Bemben Debra A. 
Published: May 2024

Sex differences in functional sympatholysis have provided conflicting results, in both animal and human models. Further, investigations into underlying functional sympatholysis mechanisms between the sexes are largely unexplored. PURPOSE: To investigate if functional sympatholysis differs between biological sexes and to explore whether CYP450 inhibition alters functional sympatholysis between sexes. METHODS: Healthy males (n=12, 21±2 years) and females (n=12, 23±3 years, tested in early follicular phase) participated in three study visits (2 experimental). 120min prior to experimental testing, a placebo (PLA, 250 mg microcrystalline cellulose) or CYP450 2C9 inhibitor (150 mg fluconazole, FLZ) were ingested in a randomized, counter-balanced design. Beat-to-beat forearm muscle blood flow (FBF, doppler ultrasound) and mean arterial pressure (MAP, finger photoplethysmography), were measured continuously to calculate vascular conductance (FVC= FBF/MAPx100mmHg). Measurements were taken during 5 minutes of rest and lower body negative pressure (LBNP; -20mmHg) in resting conditions for 2 minutes. Following 10 minutes of rest, steady state rhythmic handgrip exercise (EX; 20% maximum voluntary contraction; 2 sec contraction, 1 sec relaxation duty cycles) was applied for 7 minutes with LBNP added for the last 2 minutes (Ex+LBNP). The magnitude of functional sympatholysis (%) was calculated as (functional sympatholysis (%) = Δ%FVC Ex+LBNP - Δ%FVC LBNP). Impairment to functional sympatholysis in response to CYP450 inhibition was calculated as the difference in functional sympatholysis (%) between the PLA and the FLZ condition. Results: Data are means ± SD. The magnitude of functional sympatholysis was not different between sexes in either PLA (Males: 33.91±20.91 % vs. Females: 38.43±21.71 %, P: 0.61 d: 0.21) nor FLZ (Males: 30.83±29.95 % vs. Females: 18.40±26.56 %, P: 0.23 r: 0.026). The impairment to functional sympatholysis in response to CYP450 inhibition was not different between sexes (Males: -3.07±20.02% vs. Women: -20.02±39.80%, P: 0.23, d: 0.5) with a moderate to large effect size. However, a two one-sided test (TOST) was used to test whether sexes had equivalent in responses to CYP450 inhibition and revealed non-significance ( t(18.86) = 0.574, p = 0.714) and thus non-equivalence. CONCLUSION: Our findings support previous investigation confirming no sex differences in functional sympatholysis in humans. However, our results indicate that sexes did not show equivalent responses to CYP450 inhibition despite non-significance. These findings advocate that females may be more reliant of CYP450 pathways for functional sympatholysis then men and future exploration is warranted. This is the full abstract presented at the American Physiology Summit 2024 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.