Contribution of cytochrome P450 2C9 pathways to functional sympatholysis in healthy young adults

In humans exercise hyperemia is adequately maintained despite elevated sympathetic outflow through an endothelium dependent, yet nitric oxide and prostaglandin independent mechanism(s) known as functional sympatholysis. Evidence suggests that functional sympatholysis has an endothelium-dependent hyperpolarization-like component, however, investigations into hyperpolarization pathways, such as, cytochrome P450 2C9 are scant. PURPOSE: To determine if cytochrome P450 inhibition attenuates functional sympatholysis in healthy young adults. METHODS: 21 participants (23 ± 3 years, 11 Females, tested in early follicular phase) participated in three study visits (1 familiarization, 2 experimental visits, random, single blind, counter-balanced) separated by ≥72 hours. Participants completed 5min baseline, 2min resting lower body negative pressure (LBNP, -20mmHg, to elevate sympathetic outflow), 7min of dynamic handgrip exercise at 20% effort with minutes 5-7 having LBNP stimulus superimposed (Ex+LBNP) in the supine position, exercising limb at heart-level. 10 min of rest separated each event. 120min prior to testing a placebo (PLA, 250 mg microcrystalline cellulose) or cytochrome P450 2C9 inhibitor (150 mg fluconazole, FLZ) were ingested. Forearm blood flow (FBF, Echo and Doppler ultrasound) and mean arterial pressure (MAP, finger photoplethysmography) were measured continuously and use to calculate forearm vascular conductance (FVC= FBF/MAPx100mmHg). RESULTS: All data are mean percent change in FVC (%Δ) ± SD. FVC decreased (p<0.001) from baseline during LBNP with no effect of FLZ (PLA: -31.8 ± 19.4 vs. FLZ: -36.1 ± 25.1 p:0.53, d: 0.17). Interestingly, FVC increased from baseline to exercise (p<0.001) with no effect of FLZ (PLA: 819.6 ± 503.9 vs. FLZ: 709.1 ± 459.2 p: 0.36, d: 0.20). However, FVC was unaltered during Ex+LBNP in PLA from steady-state exercise (4.5 ± 13.9, p:0.32) but was significantly reduced with FLZ (–11.5 ± 13.3, p>0.001) with a large effect size between conditions (p>0.001, d: 1.1). All responses were similar between the sexes (p:0.5, d:0.3). CONCLUSION: Our results indicate that in young healthy adults, inhibition of cytochrome P450 pathways attenuated vascular opposition to superimposed sympathetic stress during dynamic handgrip exercise. Thus, cytochrome P450 pathways are mechanistically involved in functional sympatholysis in young healthy 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.