Mechanism for hypotensive action of angiotensin converting enzyme inhibitors.

The mechanism(s) for the hypotensive effect of Angiotensin Converting Enzyme (ACE) inhibitors remains elusive. This is because of the multiplicity of the biological actions of angiotensin, the dual role of ACE and the ability of the inhibitors to induce the enzyme. After a single dose of enalapril (MK421), a new ACE inhibitor, in patients with essential hypertension a close linear relationship between the plasma level of enalaprilic acid (MK422) and the degree of ACE inhibition could be demonstrated. Furthermore the degree of ACE inhibition was linearly related to the hormonal changes and to the fall in blood pressure. After chronic administration of enalapril the plasma levels of MK422 were found to be dose dependent. As in the acute study there was also a linear relationship between the plasma level of MK422 and the degree of ACE inhibition. However, the plasma enalaprilic acid level-ACE inhibition dose response curve after chronic administration was shifted to the right, compared to the dose response curve after acute administration suggesting that ACE had been induced during chronic administration of enalapril in humans. There were direct linear relationships between both the degree of ACE inhibition the plasma and enalaprilic acid (MK422) level to the fall in mean arterial pressure. These results suggest that regardless of the final mechanism for the hypotensive action of ACE inhibitors it is a consequence of their inhibition of the enzyme.