Renin Inhibition in Hypertension
Alan H. Gradman, MD1,* and
Rishi Kad, MD
Division of Cardiovascular Diseases, The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania.
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Figure 1 The Renin–Angiotensin Cascade and the 3 Available Approaches to Pharmacologic Inhibition of Production or Action of Angiotensin II
Direct renin inhibitors (DRI), angiotensin-converting enzyme inhibitors (ACEI), and angiotensin (AT) type 1 receptor blockers (ARB).
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Figure 2 X-Ray Crystallographic Representation of Aliskiren in the Binding Complex With Human Renin
Renin molecule consists of 2 homologous lobes with the active site located in the cleft between the 2 lobes. Aliskiren occupies a specific subpocket in the cleft and blocks the enzymatic function of renin.
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Figure 3 Direct Intracellular Effects Mediated Via (Pro)Renin Receptors
Renin and pro-renin directly activate intracellular signaling pathways, including mitogen-activated protein kinases (MAPK), leading to generation of transforming growth factor-beta (TGF-β), plasminogen activator inhibitor-1 (PAI-1), and heat shock protein 27 (Hsp27). Activation is independent of angiotensin II. Reprinted with permission from Nguyen and Danser (27).
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Figure 4 Antihypertensive Effects of Aliskiren Compared With Placebo
Results of the pooled analysis in 8,481 patients treated with aliskiren 150 and 300 mg compared with placebo. ***p < 0.0001 versus placebo. Values under the bars represent least-squares mean reduction ± standard error of the mean; values in the arrows represent placebo-subtracted reductions. DBP = diastolic blood pressure; SBP = systolic blood pressure. Data from Dahlöf et al. (63).
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Figure 5 Persistent PRA Suppression After Aliskiren Withdrawal
Measurements of plasma renin activity (PRA) after withdrawal of aliskiren in patients on long-term aliskiren therapy showed a persistent >50% reduction in PRA during a 4-week double-blind withdrawal phase.  End point is defined as the end of the 1-month withdrawal period or the last visit carried forward. Data from Pool et al. (70).
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Figure 6 Possible Effects of Renin Inhibitors on Receptor-Bound Renin and Pro-Renin
Potential sites of inhibition of the enzymatic activity and direct intracellular effects of receptor-bound renin and pro-renin. ERK1/2 = extracellular signal-regulated kinase 1/2; PAI-1 = plasminogen activator inhibitor-1; TGF-β = transforming growth factor-beta. Reprinted with permission from Nguyen (74).
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