Published Online
on March 19, 2007

A more recent version of this article appeared on May 1, 2007

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Submitted on October 5, 2006
Revised on October 24, 2006

Immunoreactivity and Guanosine 3',5'-Cyclic Monophosphate Activating Actions of Various Molecular Forms of Human B-Type Natriuretic Peptide

Denise M. Heublein^*; Brenda K. Huntley; Guido Boerrigter; Alessandro Cataliotti; Sharon M. Sandberg; Margaret M. Redfield; and John C. Burnett Jr

From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, Minn.

^* To whom correspondence should be addressed. E-mail: dheublein{at}mayo.edu.

Abstract--Recent studies support the speculation that different molecular forms of the cardiac hormone BNP with differential biological activity may circulate in heart failure and be detected by conventional assays. In the current study we determined the ability of 3 widely used conventional assays to detect these different forms thought to circulate in heart failure. We also evaluated the ability of pro-BNP (1-108), N-terminal peptide (NT)-pro-BNP (1-76), and BNP 3-32, the latter a cleavage product of BNP 1-32 by dipeptidyl peptidase IV, on an equimolar basis to activate cGMP in cultured cardiac fibroblasts and cardiomyocytes compared with the biologically active mature BNP 1-32. Specifically, we observed that the Roche NT-pro-BNP assay detected both NT-pro-BNP 1-76 and pro-BNP 1-108 and that Biosite Triage and Shionogi detected both mature BNP 1-32 and the shortened BNP 3-32. Moreover, in cultured cardiac fibroblasts and cardiomyocytes, BNP 1-32 (10^-6 mol/L) activated cGMP. BNP 3-32 demonstrated a similar cGMP activating property in both cardiac cell types. In contrast, the cGMP response to pro-BNP 1-108 and NT-pro-BNP 1-76 was not significantly greater than no treatment alone. We conclude that widely used commercial assays for NT-pro-BNP 1-76 and BNP 1-32 cannot differentiate among pro-, processed, or degraded forms and, thus, may not thoroughly identify circulating BNP forms in heart failure patients. These findings also demonstrate differential cGMP activating properties of BNP forms and, importantly, that pro-BNP 1-108 and NT-pro-BNP 1-76 have reduced cGMP activity in vitro that may have biological relevance to human heart failure.

Key words: peptides • natriuretic peptides • cGMP • heart failure • biomarkers

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