The Virtually Mature BNP (BNP1-32) is a Precursor for the More Effective BNP1-30.

BACKGROUND AND PURPOSE: The B-type natriuretic peptide (BNP1-32) exerts vasorelaxing and cardioprotective activity. BNP is used as a biomarker for the diagnosis of cardiopathological conditions and recombinant BNP1-32 as a drug for the treatment of such. BNP1-32 has a short half-life time and thus, similar to other vasoactive peptides like angiotensin II and bradykinin, can be enzymatically truncated forming bioactive metabolites. We aimed to investigate the metabolism of BNP1-32 in mouse lung, to identify potential new BNP metabolites and to disclose their biological activity compared to the BNP1-32, in vitro and in vivo.

EXPERIMENTAL APPROACH: Using High Performance Liquid Chromatography and Mass-Spectrometry, we identified a new BNP metabolite, BNP1-30, in the lung being generated by endothelin-converting enzyme-1.

KEY RESULTS: BNP1-30 is more efficient in stimulating the guanylyl cyclase receptor A (GC-A) and, in contrast to BNP1-32, is also able to profoundly stimulate the GC-B. In vivo, BNP1-30 reduced the mean arterial blood pressure of normotensive mice after acute infusion significantly more than BNP1-32. In a model of severe hypertension, a 3-day infusion of BNP1-30 was able to reduce systolic blood pressure by 30 mmHg and to improve markers of heart failure, while BNP1-32 was without significant effect.

CONCLUSION AND IMPLICATIONS: Our results suggest that BNP1-32 is the precursor for the biologically more active BNP1-30 leading to a fundamental extension of the natriuretic-peptide system. Due to expanded activity, BNP1-30 might be a promising treatment option for cardiovascular diseases. Furthermore, its potency as a new diagnostic marker of specific cardiac diseases should be evaluated.