Novel RAAS agonists and antagonists: clinical applications and controversies

Abstract

The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure homeostasis and vascular injury and repair responses. The RAAS was originally thought to be an endocrine system critically important in regulating blood pressure homeostasis. Yet, important local forms of the RAAS have been described in many tissues, which are mostly independent of the systemic RAAS. These systems have been associated with diverse physiological functions, but also with inflammation, fibrosis and target-organ damage. Pharmacological modulation of the RAAS has brought about important advances in preventing morbidity and mortality associated with cardiovascular disease. Yet, traditional RAAS blockers such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) only reduce the risk of disease progression in patients with established cardiovascular or renal disease by ∼20% compared with other therapies. As more components of the RAAS are described, other potential therapeutic targets emerge, which could provide improved cardiovascular and renal protection beyond that provided by an ACE inhibitor or ARB. This Review summarizes the present and future pharmacological manipulation of this important system.

Figure 1. Components of the renin–angiotensin–aldosterone system and main classes of pharmacological activators and inhibitors of the system.

Prorenin can be activated proteolytically in the kidneys (by neuroendocrine convertase 1 or cathepsin B) or nonproteolitically by the renin receptor in many tissues. Circulating renin can also bind to the renin receptor, which increases its enzymatic activity. Renin converts angiotensinogen to Ang I, which can then enter three main pathways. These three axes, ACE–Ang II–AT1–aldosterone, ACE2–Ang 1-7–MAS1 and Ang IV–IRAP, are highlighted. Activation of the AT1 receptor in the adrenal gland results in production of aldosterone, which can then bind to the mineralocorticoid receptor. Abbreviations: ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; Ang, angiotensin; ARB, angiotensin receptor blocker; ARN, angiotensin receptor–neprilysin; AT1, type-1 Ang II receptor; AT2, type-2 Ang II receptor; IRAP, leucyl-cystinyl aminopeptidase (also known as insulin-regulated membrane aminopeptidase or insulin-responsive aminopeptidase); MAS1, proto-oncogene Mas; rh, recombinant human. PowerPoint slide