Direct Renin Inhibitors as Antihypertensive Agents

Abstract

Hypertension, a serious disease affecting almost a billion people (25% of adults) worldwide, is a major modifiable risk factor for cardiovascular (CV) and renal disease. Despite numerous advances in the pharmacologic treatment of high blood pressure (BP) and availability of several antihypertensive drugs to treat hypertension, a significant proportion of treated hypertensive patients still have uncontrolled high BP, and thus, face serious morbidity and mortality. Furthermore, it is not sufficient to aim for optimum BP control, but to treat all CV risk factors, protect end-organ damage, prevent progression of disease, and prevent long-range adverse effects of the drugs. Therefore, new therapeutic modalities have to be developed to achieve the above objectives. Some years ago, investigators identified renin inhibition as the preferred pharmacologic approach to blockade of the renin-angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additional physiologic effects occur when renin and prorenin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive but molecular modeling was used to develop aliskiren and other renin inhibitors that produce sustained suppression of plasma renin activity after oral administration with a dose-dependent BP. Additional studies will ultimately determine the place of renin inhibition in the treatment of hypertension and related CV disorders.

Structure-Based Analysis of Single Nucleotide Variants in the Renin-Angiotensinogen Complex

“…As such, various classes of drugs have been developed to inhibit this system including ACE inhibitors [3], Angiotensin Receptor Blockers (ARBs) [4], and renin inhibitors [5]. …”

Aliskiren affects fatty-acid uptake and lipid-related genes in rodent and human cardiomyocytes

“…The complexity of RAAS is evidenced by the discovery that binding of (pro)renin to the (pro)renin receptor ((P)RR) [28] can produce non-angiotensin-IImediated effects which are not inhibited by aliskiren [29][30][31]. This latter finding underpins the concept that renin can act not only as an enzyme but also as a hormone [10,20], providing a putative mechanism for non-blood-pressure-related effects of all three classes of RAAS inhibitor, and thus important insights into how to combine different RAAS inhibitors in tailored therapies [3,10,32]. Yet, only five studies to date [7,9,17,32,33] have focussed on the cellular or molecular mechanisms underlying organ protection by aliskiren, and none have directly investigated the role(s) that metabolism might play.…”

“…Activation of (P)Rr induces intracellular signalling by at least two pathways, one leading to angiotensin-II production which is inhibited by aliskiren [1,3], and another which is angiotensin-II-independent, as shown by its not being inhibited by aliskiren [29][30][31]. Igf2/M6P [77] receptor activation does not lead to angiotensin generation [35].…”

“…A recent report shows that aliskiren is able to reduce atherogenesis in mice independent of anti-hypertensive effects [16]. Second, aliskiren also appears to be functionally beneficial or protective in other tissues (pancreatic β-cell epithelium [17,18], white adipose [18], immune and nervous tissues [19]) and might even reverse end-organ damage [3,7,20]. Third, DRI appears to have haemodynamic effects, in spontaneously hypertensive rats [7], in healthy humans on a low-sodium diet [21], and in patients with congestive heart failure [22].…”

“…Aliskiren is the first clinically effective anti-hypertensive agent to have been developed by molecular modelling and to work by direct renin inhibition (DRI) in the renin-angiotensinaldosterone system (RAAS) [1][2][3][4]. Approved by the US FDA in 2007, aliskiren produces sustained suppression of plasma renin activity when used in monotherapy in hypertensive patients [5,6], of cardiac angiotensin in spontaneously hypertensive rats [7], and of renal angiotensin in human renal podocytes [8].…”