Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats.

H Jin; B Li; B Cunningham; J Tom; R Yang; P Sehl; G R Thomas; A Ko; D Oare; D G Lowe

doi:10.1172/JCI118881

Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

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Published in Volume 98, Issue 4 on August 15, 1996
J Clin Invest. 1996;98(4):969–976. https://doi.org/10.1172/JCI118881.
© 1996 The American Society for Clinical Investigation

Published August 15, 1996 - Version history

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.

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Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats.

H Jin, B Li, B Cunningham, J Tom, R Yang, P Sehl, G R Thomas, A Ko, D Oare, and D G Lowe

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Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats.

H Jin, B Li, B Cunningham, J Tom, R Yang, P Sehl, G R Thomas, A Ko, D Oare, and D G Lowe

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