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Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice
  1. M Kuhn1,
  2. R Holtwick1,
  3. H A Baba2,
  4. J C Perriard3,
  5. W Schmitz1,
  6. E Ehler3
  1. 1Institute of Pharmacology and Toxicology, Westfälische Wilhelms-Universität Münster, Münster, Germany
  2. 2Gerhard Domagk Institute of Pathology, Westfälische Wilhelms-Universität Münster, Münster, Germany
  3. 3Institute of Cell Biology, ETH Hoenggerberg, Zürich, Switzerland
  1. Correspondence to:
    Dr M Kuhn, Institute of Pharmacology and Toxicology, Westfälische Wilhelms-Universität Münster, Domagkstrasse 12, D-48129 Münster, Germany;


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), β myosin heavy chain (1.6-fold) and α 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.

  • atrial natriuretic peptide
  • hypertension
  • cardiac hypertrophy
  • fibrosis
  • cardiac function
  • ANP, atrial natriuretic peptide
  • BNP, B type natriuretic peptide
  • GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • GC-A, guanylyl cyclase A receptor
  • MHC, myosin heavy chain

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