British journal of pharmacology · 2020
The virtually mature B-type natriuretic peptide (BNP1-32) is a precursor for the more effective BNP1-30.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Schwiebs Anja, Wang Yong, Moore Andrew M, Zhu Xudong, Pankow Kristin, Siems Wolf-Eberhard, Walther Thomas
Аннотация
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 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 the 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 HPLC and MS, 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 (GC) receptor A and, in contrast to BNP1-32, is also able to profoundly stimulate the GC-B. In vivo, BNP1-30 reduced the mean arterial BP 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 BP by 30 mmHg and to improve markers of heart failure, while BNP1-32 was without significant effect.
CONCLUSIONS 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.
EXPERIMENTAL APPROACH: Using HPLC and MS, 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 (GC) receptor A and, in contrast to BNP1-32, is also able to profoundly stimulate the GC-B. In vivo, BNP1-30 reduced the mean arterial BP 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 BP by 30 mmHg and to improve markers of heart failure, while BNP1-32 was without significant effect.
CONCLUSIONS 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.