Chronic stimulation of the beta(1)-adrenergic receptor leads to
hypertrophy and
heart failure in beta(1)-adrenergic receptor transgenic mice and contributes to
disease progression in
heart failure patients. The cellular mechanisms underlying these detrimental effects are largely unknown. In this study, we have identified the cardiac
Na(+)-H(+) exchanger (NHE1) as a novel mediator of adrenergically induced
heart failure. beta(1)-Adrenergic receptor transgenic mice showed upregulation of both NHE1
mRNA (+140+/-6%) and
protein (+42+/-19%). In order to test whether increased NHE1 is causally related to beta(1)-adrenergic-induced
hypertrophy,
fibrosis, and
heart failure, beta(1)-adrenergic receptor transgenic (TG) and wild-type (WT) littermates were treated with a diet containing 6000 ppm of the NHE1 inhibitor
cariporide or control chow for 8 months. There was significant
hypertrophy of cardiac myocytes in beta(1)-adrenergic receptor transgenic mice (2.3-fold increase in myocyte cross-sectional area), which was virtually absent in
cariporide-fed animals. Interstitial
fibrosis was prominent throughout the left ventricular wall in nontreated beta(1)-adrenergic receptor transgenic mice (4.8-fold increase in
collagen volume fraction);
cariporide treatment completely prevented this development of
fibrosis. Left ventricular catheterization showed that
cariporide also prevented the loss of contractile function in beta(1)-adrenergic receptor transgenic mice: whereas untreated transgenic mice showed a significant decrease in left ventricular contractility (5250+/-570 mm Hg/s TG versus 7360+/-540 mm Hg/s WT, dp/dt(max)), this decrease was completely prevented by
cariporide (8150+/-520 mm Hg/s TG
cariporide). Inhibition of NHE1 prevented the development of
heart failure in beta(1)-receptor transgenic mice. We conclude that the cardiac
Na(+)-H(+) exchanger 1 is essential for the detrimental cardiac effects of chronic beta(1)-receptor stimulation in the heart.