NATRIURETIC PEPTIDE RECEPTOR-B (GUANYLYL CYCLASE-B) MEDIATES C-TYPE NATRIURETIC PEPTIDE RELAXATION OF PRECONTRACTED RAT AORTA

The most potent known agonist for the natriuretic peptide receptor-B ( NPR-B)/guanylyl cyclase-B is C-type natriuretic peptide (CNP). A homol ogous ligand-receptor system consists of atrial natriuretic peptide (A NP) and NPR-A/guanylyl cyclase-A A third member of this family is NPR- C, a non-guanylyl cyclase receptor. Monoclonal antibodies were raised against NPR-B by immunizing mice with a purified receptor-IgG fusion p rotein consisting of the extracellular domain of NPR-B and the Pc port ion of human IgG-gamma(1). One monoclonal antibody, 3G12, did not reco gnize NPR-A or NPR-C and bound to human and rat NPR-B. CNP binding to NPR-B and stimulation of cGMP synthesis were inhibited by 3G12. With c ells isolated from either the media or adventitia layers of rat thorac ic aorta, 3G12 did not interfere with ANP-stimulated cGMP synthesis, b ut it inhibited CNP-stimulated cGMP levels in cells from both layers. CNP (IC50 = 10 nM) and ANP (IC50 = 1 nM) caused relaxation of phenylep hrine-contracted rat aortic rings. 3G12 caused a marked increase in th e IC50 for CNP, from 10 nM to 140 nM, but failed to affect ANP-mediate d relaxation. Therefore, our results for the first time demonstrate th at CNP relaxes vascular smooth muscle by virtue of its binding to NPR- B.