Visualizing the basis for paracrine natriuretic peptide signaling in human heart.

Since the discovery of atrial natriuretic factor 25 years ago,1 there has been an explosion of research elucidating the basic biology of endogenous natriuretic peptides. Among other things, this work has established atrial natriuretic factor as one of a family of structurally similar endogenous natriuretic peptides with complex and distinct functional roles in maintaining normal homeostasis and responding to pathological circumstances. The first identified member of this family, atrial natriuretic peptide (ANP), is synthesized and secreted in the cardiac atria under normal conditions and by the ventricular myocardium during fetal development, hypertrophy, or heart failure. BNP, a distinct natriuretic peptide first isolated from the porcine brain, is preferentially synthesized and secreted by ventricular cardiac myocytes and, like ANP, exhibits increased expression during hypertrophy and heart failure. In contrast, C-type natriuretic peptide (CNP) is mainly produced by vascular endothelial cells and neurons, whereas urodilatin is synthesized and secreted by renal cells. The last identified member of this peptide family is dendroaspis natriuretic peptide (DNP), which was first isolated from the venom of the Green Mamba snake.2 Although immunoreactivity to DNP has been identified in several human tissues3 and circulating plasma,4 the gene encoding this natriuretic peptide has not yet been identified within the human genome. Actions of natriuretic peptides are mediated through binding to 3 distinct natriuretic peptide receptors (NPRs) that are located on the cell surface and bind endogenous ligands with varying specificities and affinities (Figure).5 Two of the receptors, NPR-A and NPR-B, have an extracellular (ligandbinding) domain linked to an intracellular (catalytic) domain with guanylate cyclase activity. Consequently, binding to NPR-A and NPR-B triggers increases in guanylate cyclase activity, increased intracellular cGMP, and downstream signaling and responses. The third natriuretic peptide receptor, NPR-C, has no catalytic domain or guanylate cyclase activity, and contributes to the clearance of natriuretic peptides from the circulation. NPR-A receptors exhibit high affinity for ANP, BNP, and DNP, but have relatively low affinity for CNP. In contrast, NPR-B receptors bind with high affinity to CNP, but not ANP or BNP. The NPR-C receptor binds ANP, BNP, and CNP with approximately equal affinity. Differences in the tissue distributions of NPR subtypes and the potential for disease-related alterations further complicate the biology of endogenous natriuretic peptides.5 Early work examining the functional biology of ANP and BNP focused on their roles as endocrine substances. In these constructs, increases in natriuretic peptide synthesis and secretion in response to acute or chronic cardiac chamber distension resulted in increased circulating levels of the secreted peptides and effects at remote target organs such as the kidney, adrenal, or vasculature. Though paracrine effects were implicated when CNP and NPR-B receptors were both found within the vasculature,6 there was initially little support for functionally significant local cardiac effects of cardiac derived ANP or BNP. Indeed, during infusions of exogenous natriuretic peptides, decreases in cardiac output and preload were attributed to natriuresis, venodilation, and decreases in systemic vascular resistance. An absence of data indicating expression of NPR-A receptors in the heart supported the impression that endogenous natriuretic peptides had no direct effects on the myocardium. However, the later advent of pharmacologic and genetic NPR-A inhibition implicated paracrine and autocrine actions of cardiac natriuretic peptides, even when data supporting myocardial NPR-A were lacking.7 Studies using a specific NPR-A receptor antagonist (HS-142) suggested direct cardiac actions of natriuretic peptides. In cultured myocytes, HS-142 modulated secretion of ANP8 and increased cellular hypertrophy, particularly in the setting of 1-adrenergic stimulation via phenylephrine.9 In vivo, HS-142 blocked coronary vasodilation responses to exogenous ANP10 and induced immediate slowing of ventricular relaxation and decreases in coronary blood flow suggesting direct lusitropic and vasodilating actions of NPR-A binding by endogenous natriuretic peptides.11 Complementing pharmacological approaches, transgenic mice lacking NPR-A receptor exhibit increases in cardiac mass out of proportion to their degree of hypertension,12 and cultured myocytes from NPR-A / mice are hypertrophied.13 Together, these studies suggested functionally important autocrine and paracrine cardiac actions of endogenous natriuretic peptides despite the lack of direct evidence for expression and cellular localization for NPR-A receptors in the heart. In this context, the article by Singh et al in the current issue of Circulation Research examines the distribution and binding kinetics of the natriuretic peptide type A (NPR-A) receptor in human heart tissue.14 The authors developed a novel radiolabeled DNP analogue, I-DNP, and used this to The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the University of Pennsylvania School of Medicine (K.B.H.), Heart Failure and Transplantation, Philadelphia; and the Mayo Clinic (J.C.B.), Rochester, Minn. Correspondence to Dr Kenneth B. Margulies, University of Pennsylvania School of Medicine Heart Failure and Transplantation, 709 Stellar Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104. E-mail [email protected] (Circ Res. 2006;99:113-115.) © 2006 American Heart Association, Inc.