Prior work in animals and humans suggests that muscle mechanoreceptor control of sympathetic activation(MSNA) during exercise in heart failure(HF) is heightened compared to healthy humans, and that muscle mechanoreceptors are sensitized by metabolic byproducts. We sought to determine if cyclooxygenase products and/or endogenous adenosine, two metabolites of ischemic exercise, sensitize muscle mechanoreceptors during rhythmic handgrip(RHG) exercise in HF patients. Indomethacin, which inhibits the production of prostaglandins, and saline control, was infused in 12 HF patients. In a different protocol, aminophylline, which inhibits adenosine receptors, and saline control was infused in 12 different HF patients. MSNA was recorded (microneurography). During exercise following saline, MSNA increased in the first minute of exercise consistent with baseline heightened mechanoreceptor sensitivity. MSNA continued to increase during 3 minutes of RHG, indicative that muscle mechanoreceptors are sensitized by ischemia metabolites. Indomethacin, but not aminophylline, markedly attenuated the increase in MSNA during the entire 3 minutes of low-level rhythmic exercise, consistent with the sensitization of muscle mechanoreceptors by cyclooxygenase products. Interestingly, even the early increase in MSNA was abolished by indomethacin infusion, indicative of very early generation of cyclooxygenase products after the onset of exercise in HF patients. In conclusion, muscle mechanoreceptors mediate the increase in MSNA during low-level RHG exercise in HF. Cyclooxygenase products, but not endogenous adenosine, play a central role in muscle mechanoreceptor sensitization. Finally, muscle mechanoreceptors in patients with HF have heightened basal sensitivity to mechanical stimuli, which appears to be also mediated by the early generation of cyclooxygenase products, resulting in exaggerated early increases in MSNA.