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-Atrial Natriuretic Polypeptide (
ANP)-Derived Peptides in Human Plasma: Cosecretion of N-Terminal
ANP Fragment and
ANP*
Second Division, Department of Medicine, Kyoto University School of Medicine (H.I., K.N., A.S., Y.S., M.M., N.M., T. Y., S.S., H.A., K.H., H.I.) Kyoto 606, Japan
The Radioisotope Research Center, Kyoto University (K.N.) Kyoto 606, Japan
Address all correspondence and requests for reprints to: Dr. Kazuwa Nakao, Second Division, Department of Medicine, Kyoto University School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan 606.
Using RIAs for the N- and C-terminal fragments of the human atrial natriuretic polypeptide (ANP) precursor
ANP, that is
ANP-(1–25), and
ANP[
ANP-(99–126)], we studied the secretion of
ANP-derived peptides from the heart in normal subjects and patients with heart disease, chronic renal failure, and cirrhosis. We detected
ANP-(1–25)-like im-munoreactivity (-LI) in plasma from normal subjects (n = 17) in considerable amounts [mean, 510 ± 62 (±SE) pg/mL (174 ± 21 pmol/L)]; the mean plasma
ANP-LI level at the same time in these subjects was 32.8 ± 4.4 pg/mL (10.7 ± 1.4 pmol/L). Gel permeation chromatographic analysis of plasma samples from normal subjects and patients with heart disease and chronic renal failure revealed two major components; one was aANP, and the other was the 10K N-terminal
ANP fragment (N-peptide) resulting from the removal of
ANP (3K) from
ANP (13K). In addition,
ANP (13K), which possessed both
ANP-(1–25)-LI and
ANP-LI, and βANP, an antiparallel dimer of
ANP, were detected in some patients as minor components. A significant positive correlation between plasma levels of the N-terminal
ANP fragment and
ANP (P < 0.01) and almost equal step-ups in the coronary sinus plasma levels of the N-terminal
ANP fragment and
ANP suggest that they are cosecreted in equimolar amounts. The high molar ratio of plasma
ANP-(1–25)-LI to
ANP-LI (17.4 ± 1.4) in normal subjects and the significantly higher ratio in patients with chronic renal failure (36.9 ± 7.1; P < 0.01) suggest the slower clearance of the N-terminal
ANP fragment than
ANP and a role for the kidney in its degradation. Since the molar ratio of plasma
ANP-(1–25)-LI to
ANP-LI in patients with cirrhosis (20.7 ± 2.7) was similar to that in normal subjects, it is unlikely that the N-terminal
ANP fragment is metabolized by the liver. In patients with heart disease, plasma
ANP-(1–25)-LI and
ANP-LI levels were higher in those with cardiac decompensation and were positively correlated with right atrial pressure, pulmonary arterial pressure, and pulmonary capillary wedge pressure, indicating cosecretion of the N-terminal
ANP fragment and
ANP in response to atrial stretch. The molar ratio of plasma
ANP-U-25)-LI to
ANP-LI in patients with severe congestive heart failure (8.0 ± 1.2) was significantly lower than that in normal subjects (P
0.05), suggesting an alteration in the secretion and/or metabolism of
ANP-derived peptides in these patients. These results indicate that the simultaneous determination of the plasma levels of the N-terminal
ANP fragment and
ANP would serve as a clinical indicator of cardiac or renal function and posssess potential usefulness for detecting abnormalities in the structure, secretion, and metabolic clearance of ANP.
* This work was supported in part by research grants from the Japanese Ministry of Education, Science, and Culture; the Japanese Ministry of Health and Welfare "Disorders of Adrenal Hormone" Research Committee, Japan, 1987; Life Science Research Project of Institute of Physical and Chemical Research (RIKEN); Japan Tobacco, Inc.; Yamanouchi Foundation for Research on Metabolic Disorders; and research grants for cardiovascular diseases (60A-3 and 62A'-1) from the Japanese Ministry of Health and Welfare.
Received December 29, 1987.
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