Hemodynamic and hormonal responses to captopril were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25-mg dose, stroke volume (SV) increased from 53 ± 7 to 63 ± 9ml(p < 0.05), while pulmonary wedge pressure (PWP) decreased from 20 ± 2 to 14 ± 2 mm Hg (p < 0.01). The hemodynamic changes were associated with increases in plasma renin activity (PRA; p < 0.05) and in plasma levels of a novel bicyclo-prostaglandin E<sub>2</sub> metabolite (bicycle-PGE-m; p < 0.01), whereas norepinephrine (NE) showed a falling tendency. In general, basal hemodynamic and basal hormonal levels did not correlate. Captopril-induced changes in mean artery pressure (MAP) and mean pulmonary artery pressure (mPAP) were positively correlated to pre-captopril PRA (r = 0.74, p < 0.01; r = 0.64, p < 0.05) and to changes in PRA (r = 0.85, p < 0.01;r = 0.80, p < 0.01) with a similar trend for angiotensin II (All); decreases of systemic vascular resistance were more pronounced in patients with higher control NE levels (r = 0.62, p < 0.05), the reduction of NE levels being highest in patients with higher basal concentrations (p < 0.001); the captopril-induced decreases of mPAP and PWP were inversely related to basal bicyclo-PGE-m levels (r = 0.60, p < 0.05; r = 0.61, p < 0.05), and changes in mPAP were closely related to basal ratios of All/bicyclo-PGE-m (r = 0.67, p < 0.01). Thus, captopril exerts its acute beneficial hemodynamic effect by inhibiting the generation of All, associated with toning down of sympathetic stimulation and increased production of vasodilating prostaglandins, such as PGE<sub>2</sub>The relation between All and PGE<sub>2</sub> – counteracting substances – might determine the hemodynamic response to captopril in the patients.