Nineteen hypertensive patients were treated with increasing doses of the new angiotensin-converting enzyme inhibitor MK 421. Twenty milligrams orally reduced blood pressure from 180/112+/-6.8/3.6 (mean+/-SEM) to 160/100+/-6.5/3.3 mm Hg (p< 0.005) while heart rate increased from 75+/-2 to 87+/-3 beats/min (p< 0.005). Plasma converting enzyme activity was still markedly reduced 24h following 2.5. 5, 10, or 20 mg MK 421 po (p< 0.001). In nine patients treated with 20 mg bid for up to 10 months, blood pressure was controlled, with the association of hydrochlorothiazide 50 mg qd in five. However, 12 to 16 h following the preceding drug administration, plasma angiotensin II and aldosterone were back to base-line levels. Analysis of plasma angiotensin II-renin relationships strongly suggests that converting enzyme blockade is not complete even 4 h after 20 mg MK 421 and starts to wear off already at 12 h. Thus, MK 421 20 mg taken orally twice daily, effectively reduces blood pressure, but does not constantly suppress plasma angiotensin II and aldosterone. Whether its long duration of action makes once daily administration possible has not yet been established.