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.

Fig. 1.

Schematic showing cleavage of BNP 1-32 to BNP 8-32 by the metalloprotease meprin A. BNP, B-type natriuretic peptide.

Fig. 2.

BNP 8-32 and BNP 1-32-induced changes from preinfusion levels of mean arterial pressure (A), renal blood flow (B), urine flow (C), and urinary sodium excretion (D). *P < 0.05 vs. respective preinfusion level. #P < 0.05 BNP 8-32 vs. BNP 1-32. Levels during the first preinfusion clearance were (means ± SE): Mean arterial pressure: 131 ± 5 mmHg; renal blood flow: 312 ± 20 ml/min; urine flow: 0.28 ± 0.04 ml/min; urinary sodium excretion: 21 ± 5 μEq/min. BNP, B-type natriuretic peptide; MAP, mean arterial pressure; RBF, renal blood flow; UNaV, urinary sodium excretion; UVolR, urine flow.

Fig. 3.

BNP 8-32 and BNP 1-32 induced changes from preinfusion levels of urinary cGMP excretion (A), human B-type natriuretic peptide plasma immunoreactivity (B), and plasma cyclic guanosine monophosphate (C). *P < 0.05 vs. respective preinfusion level. #P < 0.05 BNP 8-32 vs. BNP 1-32. Levels during the first preinfusion clearance were urinary cGMP excretion: 988 ± 132 pmol/min; cGMP: 9.7 ± 1.0 pg/ml. BNP, B-type natriuretic peptide; cGMP, cyclic guanosine monophosphate; UcGMPV, urinary cGMP.

Fig. 4.

BNP 1-32 (dashed line) and BNP 8-32 (solid line) significantly increased cGMP generation in human aortic endothelial cells (HAEC) with no difference between peptides (A). Cyclic GMP generation by BNP 8-32 was significantly reduced when the natriuretic peptide receptor blocker HS-142-1 was present (B). *P < 0.05 vs. control. cGMP, cyclic guanosine monophosphate, HS, HS-142-1, NS, nonsignificant.