%0 Journal Article %1 Engelhardt2002 %A Engelhardt, S. %A Hein, L. %A Keller, U. %A Klambt, K. %A Lohse, M. J. %D 2002 %J Circ Res %K & Administration Administration, Animal Animals Antiporter/*antagonists Blotting, Body Cardiomegaly/complications/physiopathology/*prevention Contraction/drug Disease Drug Dysfunction, Enzyme Expression Failure/complications/physiopathology/*prevention Fibrosis/complications/metabolism/*prevention Gene Guanidines/administration Heart Humans Inhibitors/administration Left/pathology/physiopathology/prevention Messenger/analysis/metabolism Mice Models, Myocardial Myocardium/metabolism/pathology Oral Organ RNA, Schedule Size/drug Sodium-Hydrogen Sulfones/administration Transgenic Ventricular Weight/drug Western beta-1/genetics/*metabolism control dosage effects effects/genetics inhibitors/genetics/metabolism Receptor Adrenergic %N 7 %P 814-9 %T Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis, and heart failure in beta(1)-adrenergic receptor transgenic mice %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11964375 %V 90 %X 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.

@article{Engelhardt2002, abstract = {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.}, added-at = {2010-12-14T18:12:02.000+0100}, author = {Engelhardt, S. and Hein, L. and Keller, U. and Klambt, K. and Lohse, M. J.}, biburl = {https://www.bibsonomy.org/bibtex/2433ab839404e83e4937a1320b1ddafac/pharmawuerz}, endnotereftype = {Journal Article}, interhash = {f3ca17468460baa35384642e12ef7d49}, intrahash = {433ab839404e83e4937a1320b1ddafac}, issn = {1524-4571 (Electronic) 1524-4571 (Linking)}, journal = {Circ Res}, keywords = {& Administration Administration, Animal Animals Antiporter/*antagonists Blotting, Body Cardiomegaly/complications/physiopathology/*prevention Contraction/drug Disease Drug Dysfunction, Enzyme Expression Failure/complications/physiopathology/*prevention Fibrosis/complications/metabolism/*prevention Gene Guanidines/administration Heart Humans Inhibitors/administration Left/pathology/physiopathology/prevention Messenger/analysis/metabolism Mice Models, Myocardial Myocardium/metabolism/pathology Oral Organ RNA, Schedule Size/drug Sodium-Hydrogen Sulfones/administration Transgenic Ventricular Weight/drug Western beta-1/genetics/*metabolism control dosage effects effects/genetics inhibitors/genetics/metabolism Receptor Adrenergic}, month = {Apr 19}, note = {Engelhardt, Stefan Hein, Lutz Keller, Ursula Klambt, Kerstin Lohse, Martin J Research Support, Non-U.S. Gov't United States Circulation research Circ Res. 2002 Apr 19;90(7):814-9.}, number = 7, pages = {814-9}, shorttitle = {Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis, and heart failure in beta(1)-adrenergic receptor transgenic mice}, timestamp = {2010-12-14T18:22:39.000+0100}, title = {Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis, and heart failure in beta(1)-adrenergic receptor transgenic mice}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11964375}, volume = 90, year = 2002 }