To determine whether prostaglandins are involved in circulatory homeostasis in congestive heart failure, we measured plasma levels of the metabolites of vasodilator prostaglandins I2 and E2 in 15 patients with severe chronic heart failure. Mean circulating levels of both metabolites were 3 to 10 times higher than those in normal subjects. Plasma levels of both metabolites correlated directly with plasma renin activity and plasma angiotensin II concentrations (r = 0.64 and 0.84, respectively). Individual serum sodium concentrations were inversely correlated with levels of prostaglandin E2 metabolites (r = -0.92, P less than 0.001) and plasma renin activity (r = -0.69, P less than 0.02). Of 23 patients with severe heart failure challenged with indomethacin (an inhibitor of prostaglandin synthesis), the 9 with hyponatremia had significant decreases in the cardiac index (1.99 +/- 0.12 to 1.72 +/- 0.13 liters per minute per square meter of body-surface area, P less than 0.001) and significant increases in the pulmonary capillary wedge pressure (17.4 +/- 2.0 to 24.0 +/- 1.9 mm Hg, P less than 0.001) and systemic vascular resistance (1882 +/- 239 to 2488 +/- 315 dyn x sec x cm-5, P less than 0.001), whereas the 14 patients with a normal serum sodium concentration had no significant hemodynamic changes. We conclude that both vasoconstrictor (renin-angiotensin) and vasodilator (prostaglandin) mechanisms are operative in patients with heart failure complicated by hyponatremia and that these mechanisms interact to modulate circulatory homeostasis.