We investigated the effect of caffeine and acetaminophen on power output during a 6-min performance test, peripheral fatigue, and muscle protein kinase A (PKA) substrate phosphorylation. Fourteen men [age (means ± SD): 26 ± 6 yr; Vo2max: 63.9 ± 5.0 mL·min-1·kg-1] completed four randomized trials with acetaminophen (1,500 mg), caffeine (5 mg·kg body wt-1), combined caffeine and acetaminophen (caffeine + acetaminophen), or placebo. Mean power output during the 6-min performance test (placebo mean: 312 ± 41 W) was higher with caffeine (+5 W; 95% CI: 1 to 9; P = 0.017) and caffeine + acetaminophen (+6 W; 95% CI: 0 to 12; P = 0.049) than placebo, but not with acetaminophen (+1 W; 95% CI: -4 to 7; P = 0.529). Decline in quadriceps maximal isometric voluntary torque immediately after the performance test was lower (treatment × time; P = 0.035) with acetaminophen (-40 N·m; 95% CI: -53 to -30; P < 0.001) and caffeine + acetaminophen (-44 N·m; 95% CI: -58 to -30; P < 0.001) than placebo (-53 N·m; 95% CI: -71 to -39; P < 0.001) but was similar with caffeine (-54 N·m; 95% CI: -69 to -38; P < 0.001). Muscle phosphocreatine content decreased more during the performance test (treatment × time; P = 0.036) with caffeine + acetaminophen (-55 mmol·kg dry wt-1; 95% CI: -65 to -46; P < 0.001) than placebo (-40 mmol·kg dry wt-1; 95% CI: -52 to -24; P < 0.001). Muscle net lactate accumulation was not different from placebo (+85 mmol·kg dry wt-1; 95% CI: 60 to 110; P < 0.001) for any treatment (treatment × time; P = 0.066), being +75 mmol·kg dry wt-1 (95% CI: 51 to 99; P < 0.001) with caffeine, +76 mmol·kg dry wt-1 (95% CI: 58 to 96; P < 0.001) with acetaminophen, and +103 mmol·kg dry wt-1 (95% CI: 89 to 115; P < 0.001) with caffeine + acetaminophen. Decline in muscle ATP and glycogen content and increase in PKA substrate phosphorylation was not different between treatments (treatment × time; P > 0.1). Thus, acetaminophen provides no additive performance enhancing effect to caffeine during 6-min maximal cycling. In addition, change in PKA activity is likely not a major mechanism of performance improvement with caffeine.
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