CYP450 Inhibition on Cerebral Hemodynamics in Healthy, Young Males and Females During Simulated Hypovolemia

Abstract

Animal models have shown that cytochrome P450 2C9 (CYP450) is involved in vascular control within the cerebrovasculature. However, the role sex plays on CYP450 within human cerebral circulation has not been examined. PURPOSE: To determine the contribution of CYP450 to cerebrovascular hemodynamics between healthy young males and females at rest and during mild simulated hypovolemia. METHODS: 18 subjects (9 females, tested during days 1-5 of early follicular phase) participated in 1 familiarization and 2 experimental visits. During experimental visits, subjects ingested a CYP450 inhibitor (fluconazole, FLZ 150mg) or placebo (PLC, 250mg microcrystalline cellulose) in a randomized, single-blind, crossover design. Following ingestion and 120 minutes of supine rest, middle cerebral artery velocity (MCAv, cm/s, Transcranial Doppler) and mean arterial pressure (MAP, mmHg, finger photoplethysmography) were continuously measured during 5 minutes of supine rest and 5 minutes of lower-body negative pressure (LBNP, -20mmHg). Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. RESULTS: Means ± SD. Resting values for all variables were not different between treatments (p > 0.05). Therefore, all data are presented as a change (Δ) from rest to LBNP. There was no treatment*time*sex effect for MCAv or CVCi (p = 0.52, pη2 = 0.08; p = 0.34, pη2 = 0.06, respectively). MCAv responded similarly to LBNP between sexes within PLC and FLZ with a low-to-moderate effect (M -4.2 ± 5.2 vs. F -2.4 ± 7.3, p = 0.63, r = 0.11; M -4.2 ± 6.2 vs. F -8.1 ± 6.3, p = 0.06, r = 0.45, respectively). Similarly, male and female CVCi responses to LBNP were similar within treatments with a low effect (PLC M -0.04 ± 0.05 vs. -0.02 ± 0.08, p = 0.69, r = 0.09; FLZ M -0.06 ± 0.06 vs. -0.08 ± 0.05, p = 0.31, r = 0.24). Two one-sided testing (TOST) analysis, used to assess equivalence between groups (1), revealed that the differences between PLC and FLZ ΔMCAv and ΔCVCi were non-equivalent between the sexes (Mean = 5.67, t(13.84) = 0.42, p = 0.55; Mean = 0.05, t(15.02) = 0.34, p = 0.63, respectively). CONCLUSION: Although no significant differences were seen between sexes, small-to-moderate effect sizes and TOST analysis suggest male and female hemodynamic responses to LBNP are not equal following CYP450 inhibition. These data argue that CYP450 may have differential contributions to cerebral vascular control between the sexes and further exploration is warranted. 1. O’Brien MW, Kimmerly DS. Is “not different” enough to conclude similar cardiovascular responses across sexes? American Journal of Physiology-Heart and Circulatory Physiology 322: H355–H358, 2022. doi: 10.1152/ajpheart.00687.2021. 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.