Atrial Natriuretic Peptide

Nesiritide (Natrecor) is an FDA-approved recombinant human B-type natriuretic peptide (BNP-32) structurally identical to the endogenous cardiac hormone. It is used intravenously for the treatment of acutely decompensated heart failure in patients with dyspnea at rest or with minimal activity. As a member of the natriuretic peptide family that includes ANP, it reduces preload, afterload, and promotes natriuresis.

Nesiritide binds to natriuretic peptide receptor A (NPR-A), a transmembrane guanylyl cyclase receptor expressed on vascular smooth muscle, endothelium, kidneys, and cardiac fibroblasts. Ligand binding activates the receptor's intrinsic guanylyl cyclase domain, generating the intracellular second messenger cyclic GMP (cGMP). Elevated cGMP activates protein kinase G (PKG), which phosphorylates myosin light chain phosphatase and reduces intracellular calcium, causing arterial and venous smooth muscle relaxation. This produces balanced vasodilation, reducing both preload (pulmonary capillary wedge pressure) and afterload (systemic vascular resistance) without reflex tachycardia. In the kidney, cGMP-mediated signaling in the collecting duct increases sodium excretion (natriuresis) and promotes diuresis. Nesiritide also suppresses the renin-angiotensin-aldosterone system and attenuates sympathetic nervous system activation, countering the neurohormonal overdrive characteristic of decompensated heart failure.

Nesiritide received FDA approval in 2001 for acutely decompensated heart failure. The VMAC trial demonstrated significant reductions in pulmonary capillary wedge pressure vs. placebo and non-inferiority to nitroglycerin at 3 hours. Later safety concerns arose from a 2005 meta-analysis suggesting increased 30-day mortality, prompting a boxed warning and the large ASCEND-HF trial (7,141 patients), which showed nesiritide provided modest dyspnea relief but did not reduce mortality or rehospitalization. Use has declined substantially; its role is now largely adjunctive when conventional diuretic-based decongestion is insufficient.