Renin Inhibition in Hypertension
Fifty 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 physiological effects occur when renin and pro-renin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive. Molecular modeling was used to develop aliskiren, a potent, low-molecular-weight, nonpeptide, direct renin inhibitor with sufficient bioavailability to produce sustained suppression of plasma renin activity after oral administration. In patients with hypertension, aliskiren produces dose-dependent blood pressure (BP) reduction and 24-h BP control up to a dose of approximately 300 mg once daily; at these doses, aliskiren shows placebo-like tolerability. Its antihypertensive potency is approximately equivalent to that of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics. After abrupt withdrawal, persistent BP reduction and prolonged suppression of plasma renin activity is observed. When combined with diuretics, fully additive BP reduction is seen. When given with an angiotensin receptor blocker, aliskiren produces significant additional BP reduction indicative of complimentary pharmacology and more complete renin-angiotensin system blockade. Clinical trials are currently underway assessing the effects of aliskiren combined with an angiotensin receptor blocker on intermediate markers of end organ damage, and long-term end point trials are planned. The results of these studies will ultimately determine the place of renin inhibition and aliskiren in the treatment of hypertension and related cardiovascular disorders. The effect of aliskiren on receptor-bound renin and pro-renin is the subject of active investigation.
In 1957, Skeggs et al. with rather remarkable foresight postulated 3 possible approaches to pharmacologic inhibition of the renin-angiotensin system (RAS) (Fig. 1): 1) inhibition of angiotensin-converting enzyme (ACE); 2) direct interference with the action of angiotensin II (A II); and 3) inhibition of the circulating enzyme, renin. "Since renin is the initial and rate-limiting substance," these authors observed, "the last approach would be the most likely to succeed." In the intervening 50 years, ACE inhibition and angiotensin II receptor type 1 (AT1) blockade have indeed become integral components of cardiovascular pharmacotherapy, compiling an impressive track record in reducing blood pressure (BP), changing the natural history of heart failure and proteinuric renal disease, and conferring cardiovascular protection in a variety of clinical circumstances.
(Enlarge Image)
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).
The development of clinically effective renin inhibitors has, however, remained elusive because of difficulties in identifying suitable agents with the required combination of high affinity for renin's active site and sufficient bioavailability to permit chronic oral administration. The recent U.S. Food and Drug Administration approval of the first direct renin inhibitor, aliskiren, thus constitutes an important milestone in the history of RAS blockade, making it possible for the Skeggs et al. theoretically preferred approach to receive widespread clinical application and testing.
The Skeggs et al. preference for renin inhibition was based on the fact that the reaction catalyzed by renin is the first and rate-limiting step in the synthesis of A II, which was by then recognized as the primary effector hormone of the RAS. The discovery of the (pro)renin receptor constitutes an additional reason to focus attention on renin inhibition. When bound to the (pro)renin receptor, the enzymatic activity of renin is amplified and renin exerts physiological effects that are entirely independent of A II production. In addition, pro-renin, long thought to be merely an inactive precursor of renin, becomes biologically active when bound to this receptor. The expanding physiological role ascribed to renin and pro-renin and the possibility that renin inhibitors could interfere with both suggests that these agents could ultimately prove to have very different tissue effects compared with earlier RAS blockers.
In this review we will discuss the structure and function of renin and pro-renin, recent discoveries relevant to their physiological actions, and available data regarding the effects of the renin inhibitor aliskiren in the treatment of hypertension and related cardiovascular disorders.
Fifty 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 physiological effects occur when renin and pro-renin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive. Molecular modeling was used to develop aliskiren, a potent, low-molecular-weight, nonpeptide, direct renin inhibitor with sufficient bioavailability to produce sustained suppression of plasma renin activity after oral administration. In patients with hypertension, aliskiren produces dose-dependent blood pressure (BP) reduction and 24-h BP control up to a dose of approximately 300 mg once daily; at these doses, aliskiren shows placebo-like tolerability. Its antihypertensive potency is approximately equivalent to that of angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and diuretics. After abrupt withdrawal, persistent BP reduction and prolonged suppression of plasma renin activity is observed. When combined with diuretics, fully additive BP reduction is seen. When given with an angiotensin receptor blocker, aliskiren produces significant additional BP reduction indicative of complimentary pharmacology and more complete renin-angiotensin system blockade. Clinical trials are currently underway assessing the effects of aliskiren combined with an angiotensin receptor blocker on intermediate markers of end organ damage, and long-term end point trials are planned. The results of these studies will ultimately determine the place of renin inhibition and aliskiren in the treatment of hypertension and related cardiovascular disorders. The effect of aliskiren on receptor-bound renin and pro-renin is the subject of active investigation.
In 1957, Skeggs et al. with rather remarkable foresight postulated 3 possible approaches to pharmacologic inhibition of the renin-angiotensin system (RAS) (Fig. 1): 1) inhibition of angiotensin-converting enzyme (ACE); 2) direct interference with the action of angiotensin II (A II); and 3) inhibition of the circulating enzyme, renin. "Since renin is the initial and rate-limiting substance," these authors observed, "the last approach would be the most likely to succeed." In the intervening 50 years, ACE inhibition and angiotensin II receptor type 1 (AT1) blockade have indeed become integral components of cardiovascular pharmacotherapy, compiling an impressive track record in reducing blood pressure (BP), changing the natural history of heart failure and proteinuric renal disease, and conferring cardiovascular protection in a variety of clinical circumstances.
(Enlarge Image)
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).
The development of clinically effective renin inhibitors has, however, remained elusive because of difficulties in identifying suitable agents with the required combination of high affinity for renin's active site and sufficient bioavailability to permit chronic oral administration. The recent U.S. Food and Drug Administration approval of the first direct renin inhibitor, aliskiren, thus constitutes an important milestone in the history of RAS blockade, making it possible for the Skeggs et al. theoretically preferred approach to receive widespread clinical application and testing.
The Skeggs et al. preference for renin inhibition was based on the fact that the reaction catalyzed by renin is the first and rate-limiting step in the synthesis of A II, which was by then recognized as the primary effector hormone of the RAS. The discovery of the (pro)renin receptor constitutes an additional reason to focus attention on renin inhibition. When bound to the (pro)renin receptor, the enzymatic activity of renin is amplified and renin exerts physiological effects that are entirely independent of A II production. In addition, pro-renin, long thought to be merely an inactive precursor of renin, becomes biologically active when bound to this receptor. The expanding physiological role ascribed to renin and pro-renin and the possibility that renin inhibitors could interfere with both suggests that these agents could ultimately prove to have very different tissue effects compared with earlier RAS blockers.
In this review we will discuss the structure and function of renin and pro-renin, recent discoveries relevant to their physiological actions, and available data regarding the effects of the renin inhibitor aliskiren in the treatment of hypertension and related cardiovascular disorders.
SHARE
