Effect of antihistamines on the heavy-severe exercise domain boundary and time to fatigue when exercising in the severe domain

Histamine is released in exercising skeletal muscle and is important in exercise responses. Blocking histamine’s actions via antihistamine administration impairs exercise performance, but the reasons are poorly understood. One explanation may be a metabolism-perfusion mismatch impairing the balance of oxygen supply and utilization required for sustainable exercise. Histamine is an intrinsic regulator of the microvasculature and blocking its actions with antihistamines may alter the balance of muscle oxygen supply and demand. However, the effects of antihistamines on muscle oxygenation in conjunction with exercise performance have not been investigated.Portable near-infrared spectroscopy (NIRS) devices have emerged as a reliable tool to measure muscle oxygenation and evaluate oxygen supply and demand balance during exercise. This information can be used to identify the heavy–severe domain boundary, which is important for determining the sustainability of an exercise intensity. We employed a novel protocol for assessing the effect of antihistamines on oxygen supply-demand balance and determining the heavy-severe domain boundary in conjunction with exercise performance. We hypothesized that antihistamine administration would lower power associated with the heavy-severe domain boundary and reduce time to fatigue. Following screening, a graded exercise test, and a familiarization trial, 10 subjects (7M/3F, age 31 [25, 36] yrs, height 173 [164, 181] cm, weight 69.2 [62.9, 75.5] kg, VO 2peak 62.3 [57.9, 66.6] ml/kg/min) reported to the laboratory on two occasions to perform cycle ergometer exercise. Each bout was preceded by the ingestion of antihistamines or placebo in a randomized order with double-blind administration. Exercise consisted of a 20-minute warm-up followed by five stages of increasing intensity, the first four lasting three minutes and the fifth being a time to fatigue trial. Stage intensities were relative to the gas exchange threshold and peak power spanning the moderate, heavy, and severe domains. All stages were separated by periods of active recovery (cycling at 50 W), with the first through fourth separated by two minutes and the fourth and fifth separated by five minutes. Muscle oxygenation was measured using portable NIRS sensors, and expired gasses were analyzed continuously throughout exercise. Heart rate and rating of perceived exertion were recorded at the end of each stage and recovery period. There were no differences between antihistamines and placebo in power associated with the heavy-severe domain boundary (234 [210, 257] vs 235 [212, 258] W, P=0.84) and time to exhaustion (458 [335, 581] vs 479 [373, 584] s, P=0.51). The slope of muscle oxygen saturation, an indicator of oxygen supply and demand balance, decreased with increasing intensity (p<0.05) but was not different between antihistamines and placebo (P=0.51). Heart rate, rating of perceived exertion, and oxygen uptake all increased with intensity (p<0.01) but were not affected by blockade. This novel protocol employs muscle oxygenation to estimate power associated with the heavy-severe domain boundary and determine time to fatigue in men and women. These variables do not appear to be sensitive to antihistamine administration. Nonetheless, the investigation establishes a benchmark protocol for future studies using muscle oxygenation to evaluate exercise responses. Supported by NIH grant R01 AG072805, the Wu Tsai Human Performance Alliance and the Joe and Clara Tsai Foundation, the Eugene and Clarissa Evonuk Memorial Graduate Fellowship. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.