The role of the pulmonary autonomic nerves in the mediation of respiratory sensation is unclear. Pulmonary neurogenic mechanisms may contribute to dyspnea either directly or indirectly via an influence on the pattern of ventilation. Using human heart-lung transplantation as a model of pulmonary denervation, we studied the ventilatory response, respiratory drive (P0.1), and sensation of breathlessness (modified Borg scale) during maximal incremental bicycle exercise. The subjects were four female heart-lung transplant recipients 3 to 9 months post-transplant and 10 age-matched control subjects. The ventilatory response to increasing CO2 output (VCO2) was higher (p less than 0.001) in transplant recipients than in control subjects, such that ventilation at peak exercise was similar in the two groups despite a lower peak VCO2 in transplant recipients. The ratio of tidal volume to inspiratory capacity increased with increasing ventilation in a similar fashion in both groups. Although the respiratory rate increased more quickly in transplant recipients, it was similar at peak ventilation in the two groups. Ventilatory timing and duty cycle at half-peak and peak ventilation were similar in transplant recipients and control subjects. Dyspnea ratings were not different between the two groups at similar levels of ventilation. Dyspnea as a function of P0.1 was also similar in transplant and control groups. These results indicate that pulmonary neurogenic mechanisms play a role in determining the level, but not the pattern, of ventilation during exercise. Furthermore, these pathways do not appear to contribute significantly to the perception of breathlessness in normal humans.