title: Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice.
abstract: OBJECTIVE
  To investigate how permanent inhibition of guanylyl cyclase A receptor (GC-A) affects cardiac function.
  
  
  METHODS
  Hearts of GC-A-/- and corresponding wild type mice (GC-A+/+) were characterised by histological, western blotting, and northern blotting analyses. Cardiac function was evaluated in isolated, working heart preparations.
  
  
  RESULTS
  At 4 months of age, GC-A-/- mice had global cardiac hypertrophy (about a 40% increase in cardiac weight) without interstitial fibrosis. Examination of heart function found a significant delay in the time of relaxation; all other parameters of cardiac contractility were similar to those in wild type mice. At 12 months, the hypertrophic changes were much more severe (about a 61% increase in cardiac weight), together with a shift in cardiac gene expression (enhanced concentrations of atrial natriuretic peptide (3.8-fold), B type natriuretic peptide (2-fold), beta myosin heavy chain (1.6-fold) and alpha skeletal actin (1.7-fold) mRNA), increased expression of cytoskeletal tubulin and desmin (by 29.6% and 25.6%, respectively), and pronounced interstitial fibrosis. These changes were associated with significantly impaired cardiac contractility (+dP/dt decreased by about 10%) and relaxation (-dP/dt decreased by 21%), as well as depressed contractile responses to pressure load (all p < 0.05).
  
  
  CONCLUSIONS
  Chronic hypertension in GC-A-/- mice is associated with progressive cardiac changes--namely, initially compensated cardiomyocyte hypertrophy, which is complicated by interstitial fibrosis and impaired cardiac contractility at later stages.
authors.affiliation: Institute of Pharmacology and Toxicology, Westfälische Wilhelms-Universität Münster, Münster, Germany. mkuhn@uni-muenster.de
authors.forename: M
authors.initials: M
authors.lastname: Kuhn
authors.forename: R
authors.initials: R
authors.lastname: Holtwick
authors.forename: H A
authors.initials: HA
authors.lastname: Baba
authors.forename: J C
authors.initials: JC
authors.lastname: Perriard
authors.forename: W
authors.initials: W
authors.lastname: Schmitz
authors.forename: E
authors.initials: E
authors.lastname: Ehler
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D006332:Cardiomegaly / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004719:Endomyocardial Fibrosis / Q000209:etiology; D006162:Guanylate Cyclase; D006973:Hypertension / Q000209:etiology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D017461:Receptors, Atrial Natriuretic Factor; D011956:Receptors, Cell Surface / Q000172:deficiency*; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D011956:Receptors, Cell Surface; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A