Alexander A. Buelow

Rapid onset vasodilation (ROV) is the immediate, transient increase in muscle blood flow following contraction and is mediated by chemical, mechanical, and, potentially, neural mechanisms. Although exercise training has been shown to preserve ROV in older adults, it remains unclear whether training promotes adaptation in specific contributing mechanisms. This study tested the hypothesis that a history of forearm training increases ROV. Sixteen healthy young males (8 trained, 8 sedentary) completed two trials of 1s voluntary forearm contractions (5, 10, 15kg; 20% and 100% of maximal voluntary contraction), electrically-stimulated involuntary contractions (5 and 10mA), and mechanical forearm compression (50, 200, 300mmHg) (randomly ordered). Forearm blood flow (ultrasound) and mean arterial pressure (finger photoplethysmography) were measured beat-to-beat and used to calculate Forearm vascular conductance (FVC). Data from the two trials of each contraction/compression were averaged together to form a singular response. Forearm and hand lean mass, as measured via dual-energy X-ray absorptiometry (DXA), did not differ between groups. Trained participants displayed greater absolute ROV responses to voluntary and involuntary contractions (p ≤ 0.05 for all), as well as to higher-intensity mechanical compressions (p ≤ 0.05 for 300mmHg ΔFVC _total , 200mmHg and 300mmHg ΔFVC _peak ). Additionally, ROV responses increased disproportionately with absolute voluntary contraction intensity in trained participants (Training Status x Intensity interaction ΔFVC _total : p = 0.02, η _p ² = 0.29). These findings extend upon previous research which has demonstrated training-related preservation of ROV and indicate that exercise training enhances rapid vascular responsiveness across multiple stimulus modalities, providing new insight into training-induced adaptations in vascular regulation.

Cerebrovascular CYP450 is underexplored in humans. Twenty‐three participants (12 females) completed familiarization and two experimental visits utilizing double‐blind, randomized, crossover design. Participants ingested fluconazole (150 mg; FLZ, CYP450 inhibitor) or placebo (PLC, microcrystalline cellulose) followed by 120 min of supine rest. Five minutes of middle cerebral artery velocity (MCAv) and mean arterial pressure (MAP) were collected during rest (PLC/FLZ _BASE ) and lower body negative pressure (LBNP; −20 mmHg; PLC/FLZ _LBNP ). There was no interaction for MCAv, cerebrovascular conductance index (CVCi), resistance area product (RAP), critical closing pressure (CrCP), or transfer function variables. Bonferroni tests revealed only FLZ attenuated MCAv (FLZ _BASE 75.2 ± 11.3 cm•s ⁻¹ vs. FLZ _LBNP 70.6 ± 11.2 cm•s ⁻¹ , p = 0.015, d = 0.713) and CVCi (FLZ _BASE 0.76 ± 0.12 cm•s ⁻¹ •mmHg ⁻¹ vs. FLZ _LBNP 0.71 ± 0.11 cm•s ⁻¹ •mmHg ⁻¹ , p = 0.003, d = 0.865) during LBNP. LBNP lowered CrCP (PLC _BASE 29.7 ± 9.3 mmHg vs. PLC _LBNP 25.1 ± 11.3 mmHg, p = 0.002, d = 0.940) within PLC. RAP increased during LBNP (PLC _BASE 0.96 ± 0.29 vs. PLC _LBNP 1.08 ± 0.32, p = < 0.001, d = 1.28; FLZ _BASE 0.98 ± 0.24 vs. FLZ _LBNP 1.07 ± 0.23, p = < 0.001, d = 1.10). These data suggest a participatory, nonobligatory role of CYP450 in human cerebrovascular control.

This study demonstrates that inhibiting CYP2C9 significantly reduces brachial artery flow-mediated dilation (FMD) in young, healthy adults, implicating CYP2C9-derived metabolites as a mediator of endothelium-dependent vasodilation. Notably, CYP2C9 inhibition attenuated FMD in males, whereas females maintained their vasodilatory response, suggesting sex-specific reliance on CYP2C9 signaling. These findings enhance our understanding of sex differences in vascular regulation and may inform future strategies for preserving endothelial health.

Evidence suggests that functional sympatholysis is an endothelial-dependent, nitric oxide and prostaglandin-independent process. We found that cytochrome P450-2C9 (CYP450-2C9) inhibition attenuated sympatholytic responses during dynamic handgrip exercise with superimposed lower body negative pressure. These data indicate that CYP450 pathways contribute to functional sympatholysis in young healthy humans.