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

Endocrinology. 2007 Jul;148(7):3518-22. doi: 10.1210/en.2007-0081. Epub 2007 Apr 5.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Atrial Natriuretic Factor / metabolism
  • Cell Membrane / enzymology
  • Cell Membrane / metabolism
  • Echocardiography
  • Guanylate Cyclase / metabolism*
  • Heart Failure / metabolism*
  • Heart Failure / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Natriuretic Peptide, C-Type / metabolism
  • Rats
  • Receptors, Atrial Natriuretic Factor / metabolism*


  • Natriuretic Peptide, C-Type
  • Atrial Natriuretic Factor
  • Guanylate Cyclase
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor A
  • atrial natriuretic factor receptor B