Abstract 3478: Evidence for Differential Modulation of the Cardiorenal Actions of B-Type Natriuretic Peptide by the Peptidases Dipeptidyl Peptidase IV and Meprin A
B-type natriuretic peptide (BNP), a 32-amino acid hormone, plays an important role in cardiorenal regulation. It has vasodilating and natriuretic properties via the natriuretic peptide A receptor (NPR-A), which generates the second messenger cyclic guanosine monophosphate (cGMP). The amino terminus of BNP 1–32 is cleaved by dipeptidyl peptidase IV (DPP4) to BNP 3–32 and by meprin A to BNP 8 –32. We hypothesized that BNP 3–32 and BNP 8 –32 would differ in their bioactivity. The cardiorenal actions of BNP 3–32 and BNP 8 –32 as compared to equimolar BNP 1–32 (30 ng/kg/min IV) were assessed in two separate crossover studies in healthy anesthetized canines (n=8 each). Parameter changes were compared to BNP 1–32 by paired t-test and between BNP 3–32 and BNP 8 –32 with unpaired t-test. BNP 1–32 increased plasma cGMP and urinary cGMP excretion, diuresis, natriuresis, and renal blood flow, and decreased mean arterial pressure. BNP 3–32 and BNP 8 –32 significantly increased plasma cGMP, urinary cGMP excretion, urine flow, and urinary sodium excretion but to a significantly lesser degree than BNP 1–32. Also, cGMP increased more with BNP 8 –32 as compared to BNP 3–32. BNP 3–32 did not reduce mean arterial pressure (−0.2±1.2 mmHg; p<0.05 vs BNP 1–32 and BNP 8 –32), whereas BNP 8 –32 (−8.2±2.5 mmHg) did to a similar degree as BNP 1–32 (−6.8±1.4 mmHg). Renal blood flow increased with BNP 8 –32, but less compared to BNP 1–32. There were no differences between the three peptides with regard to the renin-angiotensin-aldosterone system. Compared to BNP 1–32, plasma BNP immunoreactivity (Biosite assay) was reduced with BNP 3–32 and absent with BNP 8 –32. BNP 3–32 and BNP 8 –32, cleavage products of BNP 1–32 by DPP4 and meprin A, respectively, have reduced renal activity compared to BNP 1–32. The hypotensive actions of BNP 1–32 were preserved with BNP 8 –32 but absent with BNP 3–32. These findings suggest that local peptidase activity may provide a mechanism to modify the activity profile of BNP 1–32 in individual tissues. Further studies are warranted to investigate peptidase activity in different regions in health and disease, which is of special interest as peptidase inhibitors are already available (e.g. sitagliptin for DPP4) or in development (for meprin A).