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BACKGROUND B-type natriuretic peptide (BNP) compensates for the failing heart and is synthesized as a 108-residue prohormone that is cleaved to a 32-residue C-terminal maximally active peptide. During heart failure, serum concentrations of proBNP1–108 exceed concentrations of BNP1–32. The aim of this study was to determine why the proBNP1–108/BNP1–32 ratio increases and whether proBNP1–108 is bioactive. METHODS Using cGMP elevation and 125I-ANP binding assays, we measured binding and activation of individual human natriuretic peptide receptor populations by recombinant human proBNP1–108 and human synthetic BNP1–32. Using receptor bioassays, we measured degradation of recombinant proBNP1–108 and BNP1–32 by human kidney membranes. RESULTS ProBNP1–108 stimulated guanylyl cyclase-A (GC-A) to near-maximum activities but was 13-fold less potent than BNP1–32. ProBNP1–108 bound human GC-A 35-fold less tightly than BNP1–32. Neither proBNP1–108 nor BNP1–32 activated GC-B. The natriuretic peptide clearance receptor bound proBNP1–108 3-fold less tightly than BNP1–32. The half time for degradation of proBNP1–108 by human kidney membranes was 2.7-fold longer than for BNP1–32, and the time required for complete degradation was 6-fold longer. BNP1–32 and proBNP1–108 were best fitted by first- and second-order exponential decay models, respectively. CONCLUSIONS ProBNP1–108 activates GC-A with reduced potency and is resistant to degradation. Reduced degradation of proBNP1–108 may contribute to the increased ratio of serum proBNP1–108 to BNP1–32 observed in patients with congestive heart failure.

ProBNP1–108 Is Resistant to Degradation and Activates Guanylyl Cyclase-A with Reduced Potency