The relationship of plasma norepinephrine levels to the adaptational changes in ventricular-load coupling were studied at rest and during exercise in subjects with variably depressed ventricular function. Peak body oxygen consumption (VO2) and gas exchange anaerobic threshold (ATge) were measured to assess exercise capacity. Ventricular contractile properties were expressed by the slope (Ees) of the end-systolic pressure-volume relation and mechanical arterial properties were expressed by the slope (Ea) of the end-systolic pressure-stroke volume relation. Resting plasma norepinephrine was significantly elevated in patients with severe heart failure (New York Heart Association class III, IV) and correlated well with the magnitude of reduction in peak VO2 and ATge. In these patients, Ea/Ees ratio was also increased and correlated with the levels of resting plasma norepinephrine. Although pump efficiency of the left ventricle progressively fell with the development of heart failure, stroke volume was maintained within normal range by virtue of a compensatory increase in end-diastolic volume. Sympathetic activity was much higher in anaerobic exercise than in aerobic exercise. However, Ees (ventricular contractility) remained at the same value throughout the exercise period. Thus, an increase in stroke volume during anaerobic exercise was caused more by an increase in end-diastolic volume than by an enhanced contractility. Our results suggest that the level of resting plasma norepinephrine can be a good predictor of the modulation of ventricular-load coupling in patients with heart failure and that when contractile reserve is decreased, the Frank-Starling mechanism plays an important role in the control of stroke volume.