Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats.
Atrial natriuretic peptide (ANP) binds to natriuretic peptide receptor-A (NPR-A), a membrane guanylyl cyclase, and to natriuretic peptide receptor-C (NPR-C), which plays a role in peptide clearance. Rat ANP (rANP) mutants that bind rat NPR-A selectively over rat NPR-C were isolated from randomized libraries of rANP-display phage by differential panning. One variant was identified with reduced NPR-C binding; rANP (G16R, A17E, Q18A) [rANP(REA18)]. Synthetic rANP(REA18) was equipotent with rANP in stimulating cGMP production from cloned rat NPR-A (ED50 = 1.8 nM) and was reduced in NPR-C binding by approximately 200-fold. When infused into conscious rats at 0.325 microg/min for 30 min rANP elicited an identical decrease in blood pressure compared with 0.25 microg/min of rANP(REA18), however the natriuretic (P < 0.05) and diuretic (P = 0.07) responses to rANP(REA18) were greater. These data are consistent with a role for NPR-C as a local decoy receptor attenuating NPR-A effects in the kidney, where these receptors are coexpressed. Improved NPR-A specificity could provide more effective natriuretic peptides for treatment of acute renal failure or heart failure.
Jin
H
H
Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.
Li
B
B
Cunningham
B
B
Tom
J
J
Yang
R
R
Sehl
P
P
Thomas
G R
GR
Ko
A
A
Oare
D
D
Lowe
D G
DG
D000595:Amino Acid Sequence; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000737:chemistry*; D001483:Base Sequence; D001667:Binding, Competitive; D001794:Blood Pressure; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004231:Diuresis; D006162:Guanylate Cyclase / Q000378:metabolism*; D006339:Heart Rate; D006801:Humans; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D009318:Natriuresis; D015260:Neprilysin / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000737:chemistry
D017931:DNA Primers; D014665:Vasodilator Agents; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; C073616:atrial natriuretic factor receptor C; D006152:Cyclic GMP