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SUMMARY An assay of plasma prorenin was developed in which the conversion to renin occurred under apparently optimal conditions. Some characteristics of the assay were 1) prorenin was activated by Sepharose-bound trypsin at 4°C; 2) the concentration of activator was not critical provided that incubation was prolonged until renin activity had reached a plateau; and 3) this plateau was stable and had the same height as after maximal activation with acid, pepsin, plasmin or urokinase. Maximal activity with Sepharose-bound trypsin at 4°C was higher than with cryoactivation, and optimal conditions were more readily reproduced than with trypsin at 37°C or with acid-activation. The assay was used for measurements in peripheral and renal vein plasma after captopril in hypertensive patients with unilateral renal artery stenosis. Peripheral renin rose within 30 minutes after a first dose of captopril, 50 mg orally, and it remained high with chronic treatment. In contrast, peripheral prorenin fell initially and rose after 4 hours. These changes in peripheral plasma were related to changes in the secretion rates of the two forms of renin from the affected kidney. Thus chronic, but not acute, stimulation of renin release was associated with an increased secretion rate of prorenin. The late rise in prorenin is probably an indication of enhanced synthesis in the kidney, so that more prorenin is available for conversion. The data suggest that prorenin is indeed a biosynthetic precursor of renin and that, at least under certain circumstances, a major proportion of circulating prorenin originates from the kidney. (Hypertension 5: 244-256, 1983) KEY WORDS • captopril • converting enzyme • prorenin renal artery stenosis * renin A BOUT 80% of the renin in normal human plasma is thought to circulate in an inactive form.

1. Human plasma contains two types of renin: one is active in its native form (active renin), the other has renin-like activity after exposure to low pH (inactive renin). Reactions of acid-activated plasma renin and kidney renin with either homo logous or heterologous substrate showed identical K m values.2. Peripheral venous values for active and inactive renin in essential hypertension (n = 22), renovascular hypertension (n = 14), primary aldosteronism (n = 12), adrenal insufficiency (« = 6) and control subjects (n = 13) were directly correlated. But the percentage of renin that was active varied widely.3. After bilateral nephrectomy in 12 patients both active and inactive plasma renin fell, but did not completely disappear. Estimates of half-life in two patients were 30-80 min for active renin and 150-165 min for inactive renin.4. Renal vein to peripheral vein ratios of active and inactive renin in ten patients with essential hypertension (19 determinations) ranged from 0-96 to 1·60 and from 0-68 to 1-44 respectively with mean values (±SEM) of 1-21 ± 0-04 and 1·06 ± 0-05.5. The renal vein to peripheral vein ratio of active renin on the affected side in 13 out of 17 patients with renovascular hypertension was above the range found in essential hypertension. Six of them also had an elevated ratio of inactive renin on that side, which indicated renal release of this form of renin into the circulation. But, in contrast to the renal vein to peripheral vein ratio of active renin, the mean value of the ratio of inactive renin on the affected side was not significantly higher than on the contralateral side. The results suggest a renal mechanism not only for controlling the total quantity of circulating renin but also for modulat ing its degree of activation.