Modification of endogenous angiotensin II (AngII)-mediated processes by inhibitors of the angiotensin-converting enzyme (ACE) and antagonists of the angiotensin type 1 (AT1) receptor is dependent upon both the levels of each agent in the plasma and tissues and on the concomitant changes in plasma and tissue AngII levels. 2. Both ACE inhibitors and AT1 receptor antagonists increase renin secretion and angiotensin peptide formation in plasma and extrarenal tissues. Clinical doses of ACE inhibitors produce incomplete inhibition of ACE and the increased AngI levels act to restore AngII towards basal levels. Clinical doses of AT1 receptor antagonists produce incomplete blockade of AT1 receptors and the increased AngII levels in plasma and extrarenal tissues counteract (to an unknown degree) the effects of the antagonist. 3. The effects of ACE inhibitors and AT1 receptor antagonists on AngII levels show tissue specificity. Angiotensin II-mediated processes in the kidney are most sensitive to inhibition by these agents. ACE inhibitors reduce renal AngII levels at doses much less than those required to reduce AngII levels in plasma and other tissues. Moreover, in contrast to increased AngII levels in plasma and extrarenal tissues, renal AngII levels do not increase in response to AT1 receptor antagonists. The inhibition of AngII-mediated processes in the kidney may, therefore, play a primary role in mediating the effects of ACE inhibitors and AT1 receptor antagonists on blood pressure and other aspects of cardiovascular function and structure. 4. Combination of an ACE inhibitor with an AT1 receptor antagonist prevents the rise in plasma AngII levels that occurs with AT1 receptor antagonism alone. This combination would, therefore, be predicted to produce more effective inhibition of endogenous AngII-mediated processes than either agent alone. We must await further studies to determine whether the combination of ACE inhibition and AT1 receptor antagonism results in superior clinical outcomes.
