Dynamic hyperinflation (DH) is a major pathophysiologic consequence of airflow limitation during exercise in patients with chronic obstructive pulmonary disease (COPD) and an important contributing factor to breathlessness. In this study we aimed to examine the effect of inhaled beta agonist therapy on DH during exercise in these patients and the relationship between changes in DH and breathlessness. In 13 COPD patients (mean age 65.1 +/- 2.0, FEV1 1.20 +/- 0.17, FEV1/FVC 40 +/- 3) we measured pulmonary function tests, exercise breathlessness by Borg score, and exercise flow volume and pressure volume loops on two separate days. Prior to testing, patients randomly received inhaled placebo or albuterol on the first test day and the alternative medication on the second test day. From measurements of exercise inspiratory capacity (IC), we calculated the end-expiratory and end-inspiratory lung volumes (EELV, EILV). We used esophageal pressure recordings to measure peak inspiratory esophageal pressure (Pesins) during exercise and this was related to the maximal capacity for pressure generation taking into account lung volume and airflow changes (Pcapi). Bronchodilator caused significant increase in both FEV1 and FVC (+0.23 and +0.51, p<0.01). Comparisons of breathlessness, exercise volumes, and pressures were made at the highest equivalent work load. There was a significant reduction in the peak exercise EELV/TLC (80 +/- 0.02% to 76 +/- 0.02%, p<0.05) while the peak EILV/TLC decreased by 2% (97 +/- 1% to 95 +/- 1%, p<0.05). The peak Pesins/Pcapi decreased (0.79 +/- 0.10 to 0.57 +/- 0.05, p<0.05), and the Pcapi - Pesins increased (7.4 +/- 3 to 13.0 +/- 3 cm H2O, p<0.05). There was significant improvement in neuroventilatory coupling for volume change (Pesins/Pcapi/VT/TLC 5.45 +/- 0.5 to 3.25 +/- 1.0, p<0.05). There was a significant reduction in breathlessness as measured by Borg score (4.5 +/- 0.7 to 3.1 +/- 0.5, p<0.05) and there was a significant correlation between delta Borg and delta EILV/TLC (r=0.771, p<0.01) with a trend for Pesins/Pcapi/VT/TLC (r=0.544, p=0.067). There was also a significant correlation between delta EELV/TLC and delta Pesins/Pcapi/VT/TLC (r=0.772, p<0.01). The relationships between delta Borg, delta resting volumes, and flow rates were not significant. We conclude that in patients with COPD, inhaled bronchodilator reduces exercise DH and improves inspiratory pressure reserve and neuroventilatory coupling. Changes in DH and neuroventilatory coupling were the main determinants of reduced breathlessness.