ProBNP(1-108) is resistant to degradation and activates guanylyl cyclase-A with reduced potency

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 proBNP(1-108) exceed concentrations of BNP(1-32). The aim of this study was to determine why the proBNP(1-108)/BNP(1-32) ratio increases and whether proBNP(1-108) is bioactive.

Using cGMP elevation and (125)I-ANP binding assays, we measured binding and activation of individual human natriuretic peptide receptor populations by recombinant human proBNP(1-108) and human synthetic BNP(1-32). Using receptor bioassays, we measured degradation of recombinant proBNP(1-108) and BNP(1-32) by human kidney membranes.

ProBNP(1-108) stimulated guanylyl cyclase-A (GC-A) to near-maximum activities but was 13-fold less potent than BNP(1-32). ProBNP(1-108) bound human GC-A 35-fold less tightly than BNP(1-32). Neither proBNP(1-108) nor BNP(1-32) activated GC-B. The natriuretic peptide clearance receptor bound proBNP(1-108) 3-fold less tightly than BNP(1-32). The half time for degradation of proBNP(1-108) by human kidney membranes was 2.7-fold longer than for BNP(1-32), and the time required for complete degradation was 6-fold longer. BNP(1-32) and proBNP(1-108) were best fitted by first- and second-order exponential decay models, respectively.

ProBNP(1-108) activates GC-A with reduced potency and is resistant to degradation. Reduced degradation of proBNP(1-108) may contribute to the increased ratio of serum proBNP(1-108) to BNP(1-32) observed in patients with congestive heart failure.