Angiotensin II Blockade Compared with Other Pharmacological Methods of Inhibiting the Renin-angiotensin System

Aim: To compare angiotensin II receptor blockade, angiotensin converting enzyme (ACE) inhibition and renin inhibition as pharmacological methods of inhibiting the renin-angiotensin system.

Method: Review of published results of studies using the three methods, with a particular emphasis on measurement problems.

Results: Whenever an attempt is made to block the renin-angiotensin system, by whatever approach, there is a compensatory rise in renin secretion which determines the effect of the drug. Accurate biochemical methods must be available to assess the efficacy of each approach. ACE inhibitors have been very successful and are generally well tolerated but cough is a common side effect, possibly related to their lack of specificity. High doses stimulate renin secretion. Renin inhibitors are theoretically more attractive than ACE inhibitors because of their specificity, and renin inhibitors with adequate oral bioavailability are now available. Due to the reactive rise in renin, however, the effects of the renin inhibitors so far available appear to be very short in duration. There is insufficient evidence to show whether prolonged administration may be successful. With present methods, only circulating angiotensin I and II levels can give an accurate indication of the effectiveness of the drug. The first non-peptide angiotensin II inhibitor, losartan (DuP753, MK 954), is still undergoing clinical trials. Dose-dependent inhibition of the pressor response to exogenous angiotensin II has been obtained in normotensive volunteers, the effect being closely related to circulating levels of the active metabolite E 3174. The reactive rise in plasma renin activity and angiotensin II was highly variable. A preliminary study in hypertensive patients showed effective blood pressure reduction at doses based on the results obtained in normotensive volunteers.

Conclusions: Renin inhibitors and angiotensin antagonists represent potentially exciting alternatives to the ACE inhibitors. At present, only orally active angiotensin II antagonists are available for extensive clinical evaluation, and the results so far look promising. Whether these compounds will compare favourably with ACE inhibitors requires further investigation.