Exercise tolerance improves within a few weeks after prostacyclin initiation in patients with primary pulmonary hypertension even in the absence of significant changes in resting pulmonary vascular resistance and/or in patients who fail to respond to an acute vasodilator challenge. We tested the hypothesis that this early effect of prostacyclin may be ascribable to an improved pressure-flow response of the pulmonary circulation to exercise. Pulmonary hemodynamic variables at rest and during exercise and the 6-min walking distance were determined before and after 6 wk of continuous intravenous prostacyclin treatment (11 +/- 1.5 ng/kg/min) in seven patients unresponsive to an acute nitric oxide vasodilator test. Mean pulmonary arterial pressure/cardiac index coordinates obtained during exercise were pooled, and the slopes of these plots were compared using covariance analysis. All hemodynamic variables at rest were unchanged after prostacyclin. By contrast, the 6-min walking distance improved in all patients (mean increase, 81 m) and the slope of the mean pulmonary artery pressures/cardiac indexes plot decreased with prostacyclin, from 18.2 to 13.1 mm Hg/L/min/m(2) (p < 0.01). These results suggest that the improvement in exercise tolerance seen after 6 wk of prostacyclin therapy may be ascribable to a decrease in incremental pulmonary vascular resistance during exercise.