RAAS Pathway

The renin-angiotensin-aldosterone system (RAAS) is a hormonal cascade governing blood pressure, fluid balance, and electrolyte homeostasis. Reduced renal perfusion pressure triggers juxtaglomerular cells to secrete renin, which cleaves hepatically-derived angiotensinogen to angiotensin I (Ang I). Angiotensin-converting enzyme (ACE), expressed predominantly in pulmonary vascular endothelium, converts Ang I to the bioactive angiotensin II (Ang II). Ang II acts on AT1 receptors to cause vasoconstriction, aldosterone secretion from the adrenal cortex, sodium and water retention, and sympathetic nervous system activation — all elevating blood pressure and cardiac afterload.

Chronic RAAS overactivation drives maladaptive cardiac remodelling, including myocardial hypertrophy, fibrosis, and ventricular dilation, contributing to the progression from hypertension to overt heart failure. In the kidney, Ang II-mediated efferent arteriolar constriction increases intraglomerular pressure, accelerating nephron loss in CKD and diabetic nephropathy. RAAS blockade via ACE inhibitors, ARBs, or the neprilysin-inhibitor/ARB combination (sacubitril/valsartan) attenuates these processes, with ARNI therapy demonstrating superior outcomes to ACE inhibition alone in HFrEF in the PARADIGM-HF trial.

Aldosterone, the terminal effector of the RAAS, exerts genomic effects via mineralocorticoid receptors in the kidney (sodium retention), heart (fibrosis), and blood vessels (endothelial dysfunction). Mineralocorticoid receptor antagonists (MRAs) — spironolactone and eplerenone — block these effects and have demonstrated mortality benefit in HFrEF and post-MI LV dysfunction. The RAAS also interfaces with neprilysin (which degrades natriuretic peptides, bradykinin, and Ang II fragments), providing the pharmacological rationale for sacubitril/valsartan, which simultaneously augments natriuretic peptide signalling while blocking AT1R.