Do cytochrome P450 2C9 pathways contribute to the cerebrovascular response to small muscle exercise?

Cytochrome P450 2C9 (CYP450) contributes to regulation of cerebral blood flow in animal models, however, the involvement of CYP450 in human cerebrovascular control is under researched. To this effect, small muscle exercise has been utilized as a model to evaluate cerebral flow in humans, but whether CYP450 contributes to that response is unknown. PURPOSE: To determine if CYP450 contributes to cerebrovascular response during small muscle exercise. METHODS: 16 healthy young adults (10 females tested only in the first 5 days of their menstrual cycle) participated in a familiarization visit followed by 2 experimental visits separated by ≥72hrs. Participants received either a microcrystalline cellulose placebo (PLA 250mg) or the CYP450 inhibitor fluconazole (FLZ 150mg) in a single-blind, randomized, crossover design. After ingestion, participants rested for 120 minutes prior to the experiment. After which, mean arterial pressure (MAP, mmHg, finger photoplethysmography) and middle cerebral artery velocity (MCAv, cm/s, Transcranial Doppler) were measured continuously for 5 minutes of supine rest followed by 5 minutes of dynamic hand grip exercise (contraction/relaxation cycle 1:2 seconds) at heart level at resistance 20% of their maximal voluntary contraction. Cerebrovascular conductance index was calculated as CVCi = MCAv/MAP (cm/s/mmHg). RESULTS: Data was averaged as 3 second intervals to match the contraction rate and presented as change (Δ) from rest to exercise, reported as mean ± SD. All values were not different between treatments at steady state exercise (MAP PLA Δ 10.9±5.5 vs. FLZ Δ 10.4±3.3 mmHg, p = 0.88, MCAv PLA Δ 0.9±7.7 vs. FLZ Δ 1.2±4.7 cm/s, p = 0.88, CVCi PLA Δ -0.07±0.06 vs. FLZ Δ -0.06±0.06, p = 0.34). Interestingly, at exercise onset (~ 18s or first 6 contraction cycles) MCAv response was blunted with FLZ (PLA Δ 5.2±4.8, FLZ Δ 2.9±3.9 cm/s, p = 0.03, d = 0.51). This attenuation was not due to a change in MAP (PLA Δ 1.2±3.0, FLZ Δ 2.2±4.8 mmHg, p = 0.2, d = -0.25). Thus, attenuation of the MCAv in FLZ was due to a reduction in CVCi response (PLA Δ 0.04±0.04, FLZ Δ 0.009±0.04 cm/s/mmHg, p = 0.003, d = 0.8). CONCLUSION: Our results indicate that CYP450 does not affect MCAv, CVCi, or MAP once steady state is achieved during small muscle exercise. However, CYP450 inhibition attenuates vascular response at exercise onset. Therefore, CYP450 contributes to the cerebrovascular response to small muscle mass exercise, however, compensatory vascular mechanisms can overcome CYP450 inhibition indicating CYP450 has a significant yet non-obligatory role in cerebrovascular regulation during exercise in humans. 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.