Clinical meaning
Brain natriuretic peptide (BNP) and its inactive N-terminal fragment (NT-proBNP) are neurohormonal biomarkers secreted by ventricular cardiomyocytes in response to myocardial wall stress from volume overload or pressure overload. Understanding the synthesis, release, clearance, and clinical significance of these biomarkers is essential for the NP in diagnosing and managing heart failure.
Synthesis and release: When ventricular cardiomyocytes are stretched (increased wall stress from volume or pressure overload), the proBNP gene is activated, producing a 108-amino acid prohormone (proBNP). The enzyme corin (a serine protease on the cardiomyocyte surface) cleaves proBNP into two fragments: the biologically active BNP (32 amino acids, C-terminal fragment) and the inactive NT-proBNP (76 amino acids, N-terminal fragment). Both are released into the circulation proportionally.
Physiological actions of BNP: BNP binds to natriuretic peptide receptor A (NPR-A), activating guanylyl cyclase and increasing intracellular cGMP. This produces: natriuresis and diuresis (antagonizing sodium and water retention by RAAS and ADH), vasodilation (reducing preload and afterload), suppression of RAAS (inhibiting renin and aldosterone secretion), inhibition of sympathetic nervous system activation, and antifibrotic/antihypertrophic effects on the myocardium. Essentially, BNP is the body's counter-regulatory mechanism against the volume-retaining effects of RAAS and sympathetic activation in heart failure.
Clearance differences (clinically critical): BNP is cleared by NPR-C receptor-mediated internalization AND by enzymatic degradation by neprilysin (neutral endopeptidase). Its half-life is approximately 20 minutes. NT-proBNP is cleared passively by the kidneys. Its half-life is approximately 120 minutes (6 times longer than BNP). This has major clinical implications: NT-proBNP is more affected by renal function (falsely elevated in CKD), but its longer half-life provides a more stable measurement. BNP levels are reduced by sacubitril/valsartan (Entresto) because sacubitril inhibits neprilysin, the enzyme that degrades BNP — so BNP levels RISE on sacubitril/valsartan and cannot be used for monitoring. NT-proBNP is NOT affected by sacubitril because neprilysin does not degrade NT-proBNP — use NT-proBNP to monitor patients on Entresto.