In an attempt to evaluate deficiencies of renin activation and adrenal zona glomerulosa biosynthesis in hyporeninemic hypoaldosteronism (HH), we studied active and inactive renin (AR and IR, respectively) responses to the dopamine antagonist metoclopramide, furosemide, and graded dose infusion of ACTH in 10 HH patients and 6 normal subjects. In HH patients, AR levels, but not IR levels, were decreased relative to normal values. While normal subjects had an AR response to metoclopramide, the HH patients did not. The AR response to furosemide in HH patients was markedly diminished compared to that in normal subjects. Plasma cortisol and corticosterone levels were in the normal range, but the zona glomerulosa products 18-hydroxycorticosterone (18-OHB) and aldosterone (Aldo) were low in HH patients. Plasma 18-OHB and Aldo responses to metoclopramide and furosemide were diminished, but cortisol and 18-OHB responses to ACTH were normal in the HH patients. Our observation that 18-OHB and Aldo responses to metoclopramide were diminished refutes the possibility that excessive adrenal zona glomerulosa dopaminergic activity could account for reduced biosynthesis of 18-OHB and Aldo in HH patients. Our results appear most consistent with the concept that the primary etiological factor in the HH syndrome is impairment of renal activation of renin.