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 re ceptor-C (NPR-C), which plays a role in peptide clearance. Rat ANP (rA NP) mutants that bind rat NPR-A selectively over rat NPR-C were isolat ed from randomized libraries of rANP-display phage by differential pan ning. One variant was identified with reduced NPR-C binding; rANP (G16 R, A17E, Q18A) [rANP(REA18)]. Synthetic rANP(REA18) was equipotent wit h rANP in stimulating cGMP production from cloned rat NPR-A (ED(50) = 1.8 nM) and was reduced in NPR-C binding by similar to 200-fold. When infused into conscious rats at 0.325 mu g/min for 30 min rANP elicited an identical decrease in blood pressure compared with 0.25 mu g/min o f rANP(REA18), however the natriuretic (P < 0.05) and diuretic (P = 0. 07) responses to rANP(REA18) were greater. These data are consistent w ith a role for NPR-C as a local decoy receptor attenuating NPR-A effec ts in the kidney, where these receptors are coexpressed. Improved NPR- A specificity could provide more effective natriuretic peptides for tr eatment of acute renal failure or heart failure.