Natriuretic peptide receptors and heart failure: to B or not to B blocked?

Abstract

The role of natriuretic peptides in the dynamic regulation ofblood volume and pressure is now well established and com-prises the complementary endocrine actions of atrial (ANP)and brain (BNP) natriuretic peptides, with the more local,paracrine bioactivity of C-type natriuretic peptide (CNP).This family of mediators also coordinates to maintain cardiacfunction and integrity (Potter et al. 2009). However, muchof the information pertaining to the physiological functionsof these peptides has not been garnered via the use ofselective pharmacological tools. Indeed, there are a paucityof such reagents and this has been the bane of researchersin the field for their inception with the identification ofANP in 1981(de Bold et al. 1981). Several selective agonistsand antagonists at natriuretic peptide receptors (NPRs), themembrane spanning proteins that transduce signals conveyedby natriuretic peptides, have been described, but the vastmajority are high molecular weight, often peptide-based,molecules with suboptimal pharmacodynamic and pharma-cokinetic properties.Perhaps the most useful tool to date has been HS-142-1, apolysaccharide extracted from Aureobasidium sp. (Morishitaet al. 1991).This reagent inhibitsactivationof bothguanylatecyclase-coupled NPRs (i.e. NPR-A and NPR-B) through anallosteric interaction, but does not bind NPR-C (Poirier et al.2002). It has therefore been an ideal intervention to definemechanisms reliant on the activation of particulate guanylatecyclases(andtodifferentiate between these membrane-boundisoforms and the NO-sensitive soluble guanylate cyclase).Regrettably, the production of HS-142-1 has now beenhalted and is no longer available. Several additional moleculeshave been reported to selectively inhibit NPR-A (the cognatereceptorforANPandBNP,e.g.A71915(Delporteetal. 1992),S-28-Y (Minamitake et al. 1990), anantin (Weber et al. 1991;Wyssetal. 1991)andPL-3994(Edelsonetal. 2013))orNPR-B(the cognate receptor for CNP, e.g. a monoclonal antibody3G12 (Drewett et al. 1995) and P19 (Deschenes et al. 2005)).A truncated, modified natriuretic peptide, cANF