1. The relationship between the antihypertensive action of captopril and its inhibitory effect on angiotensin I(ANG I)-converting enzyme has been investigated. Converting enzyme was measured in plasma by its ability to generate hippuric acid from the synthetic substrate hippuryl-l-histidyl-l-leucine. Inhibition by captopril appeared transient on storage of the plasma samples at −20°C, so that measurements in such samples were not a valid index of the effect in vivo.
2. Rapid reversal of captopril's inhibitory effect on ANG I-converting enzyme in plasma was achieved by the addition of N-ethylmaleimide (0.1 mmol/l). In this way an estimate of converting enzyme ‘concentration’ was obtained both in stored and in freshly prepared plasma samples. Measurements of converting enzyme ‘activity’ in freshly prepared samples, in the absence of N-ethylmaleimide, were used as an index of inhibition in vivo.
3. In eight hypertensive subjects ANG I-converting enzyme ‘concentration’ did not change after a single oral 100 mg dose of captopril. Long-term treatment of 10 hypertensive subjects with captopril was associated with a gradual increase in converting enzyme ‘concentration’ from 29 ± 2 to 47 ± 3 m-units/ml (mean ± sem) over a period of several weeks. In contrast, captopril caused a rapid fall of converting enzyme ‘activity’.
4. Abrupt withdrawal of captopril after long-term treatment caused a gradual decrease in ANG I-converting enzyme ‘concentration’ to the control value. In contrast, converting enzyme ‘activity’ rose rapidly and became equal to enzyme ‘concentration’ 2 days after the drug had been stopped.
5. The concentration of enzymatically active renin in plasma rose from 13 ± 3 to 81 ± 34 μ-units/ml during long-term captopril treatment (mean ± sem). Blood pressure fell from 168 ±4/108 ± 3 to 140 ± 3/90 ± 3 mmHg and had not returned to the control value in the first week after the drug had been stopped, despite the fact that circulating active renin and ANG I-converting enzyme ‘activity’ were elevated.
6. It is concluded that long-term inhibition of ANG I-converting enzyme by captopril is associated with an increased plasma concentration of this enzyme. The results also suggest that the level of converting enzyme ‘activity’ in plasma is not the only factor that determines the long-term effect of captopril on blood pressure.