Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy

Abstract

The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in the physiology of blood pressure control and the pathophysiology of hypertension (HTN) with effects on vascular tone, sodium retention, oxidative stress, fibrosis, sympathetic tone, and inflammation. Fortunately, RAAS blocking agents have been available to treat HTN since the 1970s and newer medications are being developed. In this review, we will (1) examine new anti-hypertensive medications affecting the RAAS, (2) evaluate recent studies that help provide a better understanding of which patients may be more likely to benefit from RAAS blockade, and (3) review three recent pivotal randomized trials that involve newer RAAS blocking agents and inform clinical practice.

Keywords: anti-hypertensive drugs; blocking agents; blood pressure control; hypertension; renin-angiotensin-aldosterone system.

Figure 1.. New and existing drugs interfering with the renin-angiotensin (Ang) system cascade.

Classically, interference occurs at the level of renin, angiotensin-converting enzyme (ACE), the Ang II type 1 (AT ₁) receptor (R), or the mineralocorticoid receptor (MR), with renin inhibitors, ACE inhibitors, AT ₁ receptor blockers (ARBs), or MR antagonists. Novel enzyme inhibitors now target aminopeptidase A (APA), which generates Ang III (=Ang-[1–7]) from Ang II (=Ang-[1–8]), or aldosterone synthase (CYP11B2). Activators of ACE2 (XNT and diminazene), which generates Ang-(1–7) from Ang II, were recently found to act equally well in ACE2 knockout animals, thus questioning their mechanism of action. Numerous agonists for both the AT ₂ receptor and Mas receptor are being developed. Aminopeptidase N (APN) degrades Ang III to Ang IV (=Ang-[3–8]), which may act on the AT ₄ receptor, also known as insulin-regulated aminopeptidase (IRAP). Figure reprinted with permission of the American Heart Association .