Angiotensin converting enzyme during acute and chronic enalapril therapy in essential hypertension.

The acute and chronic effects of enalapril (MK421) were assessed in a double-blind randomized trial in subjects with essential hypertension. In acute studies, twelve subjects received enalapril (10 mg p.o.), following which there was a fall in blood pressure, maximal at 6 h and lasting for 24 h. Serum MK422 (enalaprilic acid, the bioactive form of enalapril) and serum angiotensin converting enzyme (ACE) inhibition had a similar time course with good correlation between drug levels and ACE inhibition (P less than 0.001, r = 0.98, n = 16) and between ACE inhibition and the hypotensive effect (P less than 0.001, r = 0.84, n = 16). In chronic studies enalapril was titrated from 5 mg to 20 mg twice a day in eleven hypertensive patients to achieve a diastolic blood pressure less than 90 mmHg. Treatment continued for 3-12 months. Increasing serum MK422 was correlated with reducing serum ACE activity (P less than 0.001, r = 0.8, n = 104). The fall in blood pressure correlated both with serum MK422 level (P less than 0.05, r = 0.37, n = 39) as well as ACE inhibition (P less than 0.01, r = 0.45, n = 42). The drug level:ACE inhibition curve was shifted to the right during chronic enalapril treatment. ID50 for serum ACE was 32 ng MK422/ml following the single 10 mg dose of MK421 and 70 ng MK422/ml during chronic treatment. Blood pressure falls during acute and chronic treatment were similar over the range of serum MK422 levels achieved. The shift in the drug level:ACE inhibition curve suggests induction of ACE during chronic treatment with enalapril in man.