Alexander A Buelow, Jacob E Matney, Sarah M Skillett, John D Ashley, Jiwon Song, Chris Mixon, Amir Akbari Fakhrabadi, Matthew Stanford, Debra A Bemben, Daniel J Larson, J Mikhail Kellawan
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Forearm blood flow (FBF) and mean arterial pressure (MAP) were continuously measured to calculate forearm vascular conductance (FVC) during baseline, -20 mmHg lower body negative pressure (LBNPrest), rhythmic handgrip exercise (Ex) at 20% maximum voluntary contraction, and exercise with LBNP (LBNPex). FLZ did not change FVC at baseline or during Ex (<i>P</i> > 0.05). However, adding LBNPex to Ex reduced FVC in the FLZ condition compared with PLA (PLA: 2 ± 12 Δ% vs. FLZ: -12 ± 13 Δ%, <i>P</i> < 0.001, <i>d</i>: 0.9). A significant change in FVC across time (baseline + LBNPrest vs. Ex + LBNPex) was observed (<i>P</i> < 0.001, [Formula: see text]: 0.8), along with significant effects of condition (PLA vs. FLZ) (<i>P</i>: 0.003, [Formula: see text]: 0.4) and their interaction (<i>P</i>: 0.05, [Formula: see text]: 0.2). Functional sympatholysis magnitude differed between conditions (PLA: 107 ± 41% vs. FLZ: 67 ± 50%, <i>P</i>: 0.001, <i>r</i>: 0.7). Therefore, CYP450 pathways are mechanistically involved in functional sympatholysis. However, CYP450 inhibition does not augment resting or exercising vascular responses without constrictor stimuli.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":7630,"journal":{"name":"American journal of physiology. 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Participants ingested a placebo (PLA) or CYP450 inhibitor fluconazole (FLZ) 120 min before testing in a double-blind, randomized, crossover design. Forearm blood flow (FBF) and mean arterial pressure (MAP) were continuously measured to calculate forearm vascular conductance (FVC) during baseline, -20 mmHg lower body negative pressure (LBNPrest), rhythmic handgrip exercise (Ex) at 20% maximum voluntary contraction, and exercise with LBNP (LBNPex). FLZ did not change FVC at baseline or during Ex (<i>P</i> > 0.05). However, adding LBNPex to Ex reduced FVC in the FLZ condition compared with PLA (PLA: 2 ± 12 Δ% vs. FLZ: -12 ± 13 Δ%, <i>P</i> < 0.001, <i>d</i>: 0.9). A significant change in FVC across time (baseline + LBNPrest vs. Ex + LBNPex) was observed (<i>P</i> < 0.001, [Formula: see text]: 0.8), along with significant effects of condition (PLA vs. FLZ) (<i>P</i>: 0.003, [Formula: see text]: 0.4) and their interaction (<i>P</i>: 0.05, [Formula: see text]: 0.2). 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引用次数: 0
摘要
功能性交感神经溶解，即运动过程中交感血管收缩的减弱，对调节运动性充血至关重要。细胞色素P450-2C9 （CYP450）通路在功能性交感神经溶解中的作用尚不清楚。共有21名参与者（11名女性）完成了3次研究访问（2次实验访问）。在双盲、随机、交叉试验设计中，受试者在试验前120分钟服用安慰剂（PLA）或CYP450抑制剂氟康唑（FLZ）。连续测量前臂血流量（FBF）和平均动脉压（MAP），以计算基线、-20 mmHg下体负压（LBNPrest）、20%最大自愿收缩的有节奏握力运动（Ex）和LBNPex运动时前臂血管传导（FVC）。FLZ对FVC无显著影响（P < 0.05）。然而，与PLA相比，在FLZ条件下，在Ex中添加LBNPex降低了FVC （PLA: 2±12 Δ% vs. FLZ: -12±13 Δ%, P < 0.001, d: 0.9）。观察到FVC随时间的显著变化（基线+ LBNPrest vs. Ex + LBNPex） （P < 0.001，[公式：见文]:0.8），以及状态的显著影响（PLA vs. FLZ） （P: 0.003，[公式：见文]:0.4）及其相互作用（P: 0.05，[公式：见文]:0.2）。两种情况下功能性交感神经溶解的幅度存在差异（PLA: 107±41% vs. FLZ: 67±50%,P: 0.001, r: 0.7）。因此，CYP450通路在机制上参与功能性交感神经溶解。然而，在没有收缩刺激的情况下，CYP450抑制不会增强静息或运动血管反应。新的和值得注意的证据表明，功能性交感神经溶解是一个内皮依赖、一氧化氮和前列腺素独立的过程。我们发现细胞色素P450-2C9 （CYP450-2C9）抑制在伴有下体负压叠加的动态握力运动中减弱交感神经溶解反应。这些数据表明，CYP450通路有助于年轻健康人群的功能性交感神经溶解。
Inhibition of CYP450 pathways reduces functional sympatholysis in healthy young adults.
Functional sympatholysis, the blunting of sympathetic vasoconstriction during exercise, is critical for regulating exercise hyperemia. The role of cytochrome P450-2C9 (CYP450) pathways in functional sympatholysis remains unclear. A total of 21 participants (11 females) completed three study visits (2 experimental). Participants ingested a placebo (PLA) or CYP450 inhibitor fluconazole (FLZ) 120 min before testing in a double-blind, randomized, crossover design. Forearm blood flow (FBF) and mean arterial pressure (MAP) were continuously measured to calculate forearm vascular conductance (FVC) during baseline, -20 mmHg lower body negative pressure (LBNPrest), rhythmic handgrip exercise (Ex) at 20% maximum voluntary contraction, and exercise with LBNP (LBNPex). FLZ did not change FVC at baseline or during Ex (P > 0.05). However, adding LBNPex to Ex reduced FVC in the FLZ condition compared with PLA (PLA: 2 ± 12 Δ% vs. FLZ: -12 ± 13 Δ%, P < 0.001, d: 0.9). A significant change in FVC across time (baseline + LBNPrest vs. Ex + LBNPex) was observed (P < 0.001, [Formula: see text]: 0.8), along with significant effects of condition (PLA vs. FLZ) (P: 0.003, [Formula: see text]: 0.4) and their interaction (P: 0.05, [Formula: see text]: 0.2). Functional sympatholysis magnitude differed between conditions (PLA: 107 ± 41% vs. FLZ: 67 ± 50%, P: 0.001, r: 0.7). Therefore, CYP450 pathways are mechanistically involved in functional sympatholysis. However, CYP450 inhibition does not augment resting or exercising vascular responses without constrictor stimuli.NEW & NOTEWORTHY 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.
期刊介绍：
The American Journal of Physiology-Regulatory, Integrative and Comparative Physiology publishes original investigations that illuminate normal or abnormal regulation and integration of physiological mechanisms at all levels of biological organization, ranging from molecules to humans, including clinical investigations. Major areas of emphasis include regulation in genetically modified animals; model organisms; development and tissue plasticity; neurohumoral control of circulation and hypertension; local control of circulation; cardiac and renal integration; thirst and volume, electrolyte homeostasis; glucose homeostasis and energy balance; appetite and obesity; inflammation and cytokines; integrative physiology of pregnancy-parturition-lactation; and thermoregulation and adaptations to exercise and environmental stress.
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