title: Inhibition of Na(+)-H(+) exchange prevents hypertrophy, fibrosis, and heart failure in beta(1)-adrenergic receptor transgenic mice.
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.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.forename: Ursula
authors.initials: U
authors.lastname: Keller
authors.forename: Kerstin
authors.initials: K
authors.lastname: Klämbt
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005355:Fibrosis / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D015870:Gene Expression; D006146:Guanidines / Q000008:administration & dosage; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage; D018487:Ventricular Dysfunction, Left / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D012333:RNA, Messenger; D018342:Receptors, Adrenergic, beta-1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; C093373:cariporide