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), 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.