To investigate the mechanism of pharmacodynamic tolerance reported to occur during prazosin therapy of chronic congestive heart failure, we measured plasma norepinephrine, plasma epinephrine, plasma renin activity (PRA) and plasma aldosterone, as well as hemodynamics in eight patients with chronic congestive heart failure, functional class III and IV (NYHA), before and during 10 weeks of prazosin therapy. Initially, prazosin therapy produced significant hemodynamic improvement, but no significant changes were noted in norepinephrine, epinephrine, plasma renin activity or aldosterone. During ambulatory therapy, fluid retention developed in four patients, and three of them had symptoms or clinical evidence of congestive heart failure for which they required an increase in diuretic or prazosin therapy. Plasma norepinephrine levels for the whole group were significantly higher after four weeks of therapy (p less than 0.01). Repeat inpatient studies after 10 weeks showed a persistent hemodynamic response to prazosin in seven patients. One patient demonstrated complete hemodynamic tolerance whereas three others showed partial tolerance. In these four patients the cardiac output increased only to 3.78 +/ 1.17 liters/min compared to 5.04 +/- 2.11 liters/min during initial prazosin therapy. Plasma norepinephrine increased further and levels were significantly higher for the whole group than before prazosin therapy (p less than 0.05). No significant changes in epinephrine, plasma renin activity or aldosterone were demonstrated. This increase in plasma norepinephrine suggests that the sympathetic nervous system could be involved in the pharmacodynamic tolerance to prazosin therapy in congestive heart failure. Further studies are necessary to extend these results.