R E V I E W Aliskiren – an orally active renin inhibitor. Review of pharmacology, pharmacodynamics, kinetics, and clinical potential in the treatment of hypertension Kristina Allikmets Department of Drug Development and Medical Affairs, Nycomed Group, Roskilde, Denmark Correspondence: Kristina Allikmets Senior Director, Medical Scientiﬁc Strategy & Medical Marketing, Nycomed Group, Langebjerg 1, DK-4000 Roskilde, Denmark Tel +45 4677 1655 Fax +45 4675 5999 Email kta@nycomed.com Abstract: The importance of renin-angiotensin-aldosterone system (RAAS) in diseases such as hypertension, congestive heart failure and chronic renal failure has long ago been recognized. It has also been established that inhibition of RAAS, using inhibitors of the angiotensin-converting enzyme (ACE) or angiotensin II receptor blockers (ARB), is an effective way to intervene with the pathogenesis of these disorders. Renin inhibitors block the RAAS at the highest level, at its origin, and might thus offer a new exciting approach for pharmacotherapy of arterial hyperten- sion. Aliskiren is the ﬁrst in a new class of orally active, non-peptide, low molecular weight renin inhibitors, and so far the only renin inhibitor that has progressed to phase III clinical trials. This review summarizes the available data on the pharmacokinetic and pharmacodynamic properties of aliskiren and its clinical development for treatment of arterial hypertension. Keywords: aliskiren, hypertension, renin-angiotensin-aldosterone system, renin inhibition, essential hypertension Introduction The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure (BP) and volume homeostasis. Its importance in diseases such as hypertension, congestive heart failure and chronic renal failure has long ago been recognized and it has also been established that inhibition of RAAS is an effective way to intervene with the pathogenesis of these disorders (Ruggenenti et al 1999; Flather et al 2000; Turnbull 2003). Secretion of renin is the ﬁrst step in RAAS cascade and, importantly, also the rate-limiting step (Skeggs et al 1957). Renin is secreted, in response to a variety of stimuli, from the juxtaglomerular cells in the kidneys. The only known physiological substrate for renin in the plasma is angiotensinogen. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I) which is then converted by angiotensin-converting enzyme (ACE) to the active octapeptide Ang II, the effector enzyme of the cascade. Ang II interacts with type-1 angiotensin receptors (AT-1), inducing vasoconstriction and increase in blood pressure, promoting adrenal aldo- sterone secretion, renal sodium reabsoption and release of catecholamines from the adrenal medulla and prejunctional nerve endings (Kim and Iwao 2000). RAAS may be blocked by pharmacological agents at various sites. Inhibitors of the ACE block the formation of Ang II but also cause a respective increase in the concentrations of Ang I that can subsequently be converted to Ang II by other path- ways, such as the chymase system. Also, ACE inhibitors are not speciﬁc for RAAS, preventing inactivation of bradykinin and substance P that are known to mediate some of the side-effects of ACE inhibitions such as cough and angioedema. Angiotensin-II receptor blockers (ARBs) speciﬁcally block the AT-1 receptors (Brunner et al 1974), Vascular Health and Risk Management 2007:3(6) 809–815 © 2007 Dove Medical Press Limited. All rights reserved 809