The reduced responsiveness of the renin-angiotensin system to hemodynamic changes in patients with congestive heart failure (CHF) could be due to a defect of the juxtaglomerular apparatus. To test this hypothesis, the responses to viprostol, an analog of prostaglandin E2(PGE2) that is known to stimulate both the macula densa and the juxtaglomerular cells, and to nitroprusside were compared in patients with CHF. An average fall in mean arterial pressure (MAP) of 6 mm Hg with viprostol was associated with a fivefold increase in plasma renin activity (PRA) from 11.4 + 6.4 to 47.9 31.0 ng/ml/hr; in contrast PRA did not change with nitroprusside, despite a significant decrease in preload and an average decrease in MAP of 16 mm Hg. These data demonstrate that (1) the reninangiotensin system could be activated by PGE2in patients with CHF, (2) this activation is not related to the global hemodynamic changes induced by PGE2, and (3) the previously reported unresponsiveness of the renin-angiotensin system in patients with CHF cannot be attributed to a defective response of the juxtaglomerular apparatus.