Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications  Gunter Wolf, Eberhard Ritz  Kidney International  Volume 67, Issue 3, Pages 799-812 (March 2005) DOI: 10.1111/j.1523-1755.2005.00145.x Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 1 Differences between angiotensin II type 1 (AT1) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors. Since AT1 receptor blockers increase the local angiotensin II (Ang II) concentration (interruption of negative feedback at the juxtaglomerular apparatus), Ang II could either bind to AT2 receptors or, after conversion to Ang IV, interact with AT4 receptors. Obviously, binding of excess Ang II to AT2 and AT4 receptors is not antagonized by AT1 blockers. In contrast, inhibition of ACE reduces the Ang II concentrations resulting in less agonistic stimulation of both for AT1 and AT2 receptors. Furthermore, ACE inhibitor increase bradykinin levels through inhibition of its breakdown by the kinase activity of ACE. Kidney International 2005 67, 799-812DOI: (10.1111/j.1523-1755.2005.00145.x) Copyright © 2005 International Society of Nephrology Terms and Conditions

Figure 2 Overview of angiotensin-converting enzyme (ACE) and ACE2 functions. The “classic” ACE1 leads to the formation of the octapeptide angiotensin II that is further metabolized by aminopeptidase A into angiotensin III and finally angiotensin IV. The recently discovered ACE2 enzyme cleaves one amino acid less, forming angiotensin 1-9. This intermediate without known function is subsequently converted by the “classic” ACE inhibition into angiotensin 1-7. The effects of angiotensin 1-7 are opposite to those of angiotensin II such as vasodilatation and also down-regulates angiotensin II type 1 (AT1) receptors. It has been hypothesized that it is an endogenous antagonist of angiotensin II. Some data suggest that ACE2 is influenced by ACE inhibitors. ACE inhibition causes less formation of less angiotensin II but possibly also less conversion of angiotensin 1-9 to angiotensin 1-7. The result would be less antagonism to the activity of angiotensin II by reduced availability of its endogenous antagonist. Kidney International 2005 67, 799-812DOI: (10.1111/j.1523-1755.2005.00145.x) Copyright © 2005 International Society of Nephrology Terms and Conditions