Differential Regulation of Membrane Guanylyl Cyclases in Congestive Heart Failure: Natriuretic Peptide Receptor (NPR)-B, Not NPR-A, Is the Predominant Natriuretic Peptide Receptor in the Failing Heart

Abstract

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) bind natriuretic peptide receptor (NPR)-A and decrease blood pressure and cardiac hypertrophy by elevating cGMP concentrations. Physiological responses to ANP and BNP are diminished in congestive heart failure (CHF) by an unknown mechanism. C-type natriuretic peptide (CNP) binding to NPR-B decreases cardiac hypertrophy, but the effect of CHF on NPR-B is unknown. Here, we measured ANP/NPR-A-dependent and CNP/NPR-B-dependent guanylyl cyclase activities in membranes from failing and nonfailing hearts. Transaortic banding of mice resulted in marked CHF as indicated by increased heart/body weight ratios, increased left ventricular diameters, and decreased ejection fractions. In nonfailed hearts, saturating ANP concentrations increased particulate guanylyl cyclase activity almost 10-fold, whereas saturating CNP concentrations increased activity 6.9-fold, or to about 70% of the ANP response. In contrast, in failed heart preparations, CNP elicited twice as much activity as ANP due to dramatic reductions in NPR-A activity without changes in NPR-B activity. For the first time, these data indicate that NPR-B activity represents a significant and previously unappreciated portion of the natriuretic peptide-dependent guanylyl cyclase activity in the normal heart and that NPR-B accounts for the majority of the natriuretic peptide-dependent activity in the failed heart. Based on these findings, we suggest that drugs that target both NPRs may be more beneficial than drugs like nesiritide (Natrecor) that target NPR-A alone.

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…Membrane preparations from mouse hearts subjected to pressure overload show slightly higher guanylyl cyclase activity in response to saturating concentrations of ANP than upon stimulation by CNP 76. However, in preparations from failing mouse heart, the response elicited by CNP is 2‐fold compared to the response of ANP, thus suggesting marked reduction in NPRA activity, but no change in NPRB activity 76. CNP levels are substantially increased in myocardial tissue in patients with HF 77.…”

Use of C-type natriuretic peptide as an indicator in detection of inducible peripheral ischemia

“…[2,13] Additionally, NPR-B, a receptor of CNP, has demonstrated various effects on the blood vessel wall upon its expression and cell surface localization in the vascular smooth muscle. [3,14] Moreover, CNP also shows anti-atherogenic properties on vessel walls with the inhibition of leukocyte migration and suppression of P-selectin expression. [14,15] Furthermore, Costa et al [16] demonstrated that infusion of CNP increases inducible nitric oxide synthase (iNOS) expression.…”

“…[22] Furthermore, CNP has a regulatory effect on the GC enzyme system via the NPR-B, one of the seven particulate GCs cloned from mammalian tissue, and it has an autocrine/paracrine role in vasorelaxation and vascular remodeling because it affects this system. [3,23] Unfortunately, we could not find sufficient data regarding CNP and its relationship with peripheral ischemia, and relatively little data is available in reference to CNP and cardiac events, including heart failure. For example, Passino et al [24] studied CNP levels in patients with chronic heart failure during physical exercise and claimed that alterations in the levels of CNP from plasma after physical exercise might reflect an enhancement in endothelial function.…”

“…Natriuretic peptide receptors (NPRs) have two forms that have been designated as A and B, and studies that have focused on the vascular smooth muscles suggest that CNP is a potent agonist of NPR-B. [1,3] Previous reports have examined the effects of natriuretic peptides in different types of ischemia. [4][5][6] Swärd et al [4] studied the recombinant human atrial natriuretic peptide (h-ANP) with regard to ischemic acute renal failure and reported that infusion of h-ANP improves the renal excretory function.…”

Visinin-like protein 1 regulates natriuretic peptide receptor B in the heart

“…These effects are mediated by NPR-A and B. The cardioprotective role of NPR-A has been recognized many years ago but the knowledge about NPR-B is still evolving [31]. By overexpressing a dominant-negative mutant of NPR-B (NPR-BΔKC), we have recently demonstrated a antihypertrophic function of NPR-B in cardiomyocytes in vitro and in vivo [17].…”