Exercising muscle hypoperfusion stimulates afferents (metaboreceptors) involved in the regulation of ventilation. Atrial fibrillation (AF), particularly when combined with diseases causing endothelial (ED) impairment, like hypertension (HP) and diabetes mellitus (DM), depresses the ED activity and enhances exercise hyperventilation. The relationship between these two functions, and the underlying mechanisms are unexplored. In AF lone or associated with HP or DM (12 subjects in each cohort), we investigated the brachial artery flow-mediated dilatation (FMD) (ED function) and ventilation during the recovery phase of handgrip (metaboreflex, MTR), while on placebo or oral vitamin C (double-blind crossover), both before and after cardioversion (CV) to sinus rhythm. Baseline ED impairment was increasingly more severe and ergoreflex activity more pronounced in AF+HP and AF+DM compared with lone AF. Vitamin C and CV significantly improved both FMD and MTR activity in lone AF and AF+HP, and vitamin C did not produce any additive effect when administered after CV. In AF+DM, neither vitamin C nor CV were effective. This study provides the following information: AF generates oxidative injury, which is less when the arrhythmia is lone and greater when associated with HP; in DM, the oxidative injury generated by AF is refractory to a rather weak antioxidant, like vitamin C, or the baseline damage is such as to prevent any additive influence of AF; in AF a cause-effect link exists between ED dysfunction and MTR activity; ventilatory advantages of CV seem to be inversely related with the extension of the underlying ED oxidative impairment.