title: B-type natriuretic peptide 8-32, which is produced from mature BNP 1-32 by the metalloprotease meprin A, has reduced bioactivity.
abstract: 32-amino acid B-type natriuretic peptide (BNP 1-32) plays an important role in cardiovascular homeostasis. Recently, it was reported that BNP 1-32 is cleaved by the metalloprotease meprin A to BNP 8-32, the bioactivity of which is undefined. We hypothesized that BNP 8-32 has reduced vasodilating and natriuretic bioactivity compared with BNP 1-32 in vivo. Human BNP 8-32 and BNP 1-32 were compared in a crossover study in eight anesthetized normal canines. After a preinfusion clearance, BNP 1-32 was infused at 30 ng.kg(-1) x min(-1) for 45 min followed by a 60-min washout and a second preinfusion clearance. Then, equimolar BNP 8-32 was infused. In half of the studies, the peptide sequence was reversed. Changes with peptides from the respective preinfusion clearance to infusion clearance were compared with paired tests. Mean arterial pressure was reduced by both BNP 8-32 and BNP 1-32 (-8 +/- 3 vs. -6 +/- 2 mmHg, P = 0.48). Changes in right atrial pressure, pulmonary capillary wedge pressure, heart rate, cardiac output, and glomerular filtration rate were similar. However, urinary sodium excretion increased less with BNP 8-32 than with BNP 1-32 (+171 +/- 24 vs. +433 +/- 43 muEq/min; P = 0.008), as did urinary potassium excretion, urine flow, and renal blood flow. While BNP 8-32 has similar vasodilating actions as BNP 1-32, its diuretic and natriuretic actions are reduced, suggesting a role for meprin A in the regulation of BNP 1-32 bioactivity in the kidney. Meprin A inhibition may be a potential strategy to increase the bioactivity of endogenous and exogenous BNP 1-32 in cardiovascular diseases.
authors.affiliation: Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic and Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA. boerrigter.guido@mayo.edu
authors.forename: Guido
authors.initials: G
authors.lastname: Boerrigter
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Costello-Boerrigter
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Harty
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Huntley
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cataliotti
authors.forename: Harald
authors.initials: H
authors.lastname: Lapp
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002319:Cardiovascular System / Q000378:metabolism*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004231:Diuresis; D004285:Dogs; D042783:Endothelial Cells / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009318:Natriuresis; D020097:Natriuretic Peptide, Brain / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D010446:Peptide Fragments; D020097:Natriuretic Peptide, Brain; D008666:Metalloendopeptidases; C053833:meprin A; D006152:Cyclic GMP