To study the metabolism and production of angiotensin I, highly purified monoiodinated [125I] angiotensin I was given by constant systemic intravenous infusion, either alone (n = 7) or combined with unlabeled angiotensin I (n = 5), to subjects with essential hypertension who were treated with the angiotensin converting enzyme inhibitor captopril (50 mg b.i.d.). Blood samples were taken from the aorta and the renal, antecubital, femoral, and hepatic veins. [125I]Angiotensin I and angiotensin I were extracted from plasma, separated by high-performance liquid chromatography, and quantitated by gamma counting and radioimmunoassay. Plasma renin activity was measured at pH 7.4. The plasma decay curves after discontinuation of the infusions of [125I]angiotensin I and unlabeled angiotensin I were similar for the two peptides. The regional extraction ratio of [125I]angiotensin I was 47 +/- 4% (mean +/- SEM) across the forearm, 59 +/- 3% across the leg, 81 +/- 1% across the kidneys, and 96 +/- 1% across the hepatomesenteric vascular bed. These results were not different from those obtained for infused unlabeled angiotensin I. Despite the rapid removal of arterially delivered angiotensin I, no difference was found between the venous and arterial levels of endogenous angiotensin I across the various vascular beds, with the exception of the liver where angiotensin I in the vein was 50% lower than in the aorta. Thus, 50-90% of endogenous angiotensin I in the veins appeared to be derived from regional de novo production. The blood transit time is 0.1-0.2 minute in the limbs and in the kidneys and 0.3-0.5 minute in the hepatomesenteric vascular bed. This is too short for plasma renin activity to account for the measured de novo angiotensin I production. It was calculated that less than 20-30% in the limbs and in the kidneys and approximately 60% in the hepatomesenteric region of de novo-produced angiotensin I could be accounted for by circulating renin. These results indicate that a high percentage of plasma angiotensin I may be produced locally (i.e., not in circulating plasma).