Overexpression of alpha1B-adrenergic receptor induces left ventricular dysfunction in the absence of hypertrophy.
The stimulation of cardiac alpha1-adrenergic receptors (AR) modulates the heart's inotropic response and plays a role in the induction of cardiomyocyte hypertrophy. We have analyzed transgenic mouse lines overexpressing a wild-type alpha1B-AR specifically in the heart. Basal level systolic and diastolic left ventricular (LV) contractile function was depressed both in the anesthetized closed-chest mouse and the perfused working-heart preparation. Intrinsic LV function was further characterized under controlled preload and afterload conditions using the perfusion model. Contractile parameters were restored by chronic treatment with the alpha-AR antagonist prazosin. In ventricular function curves, the load-dependent force increases (length-tension effects) remained intact, although the transgenic curve was shifted to lower levels. The basal level contractile deficits were paralleled by a decrease in calcium transients in isolated LV cardiomyocytes. LV function comparable to controls was restored by isoproterenol stimulation. The physiological changes occurred in the absence of cardiomyocyte hypertrophy. This transgenic model will be useful for studying the potential role of alpha1-AR in cardiac contractility and hypertrophy.
Grupp
I L
IL
Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio 45267, USA.
Lorenz
J N
JN
Walsh
R A
RA
Boivin
G P
GP
Rindt
H
H
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000503:physiopathology*; D002478:Cells, Cultured; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D011224:Prazosin / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000502:physiology*; D012044:Regression Analysis; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
C547717:Adra1b protein, mouse; D058668:Adrenergic alpha-1 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D007545:Isoproterenol; D002118:Calcium; D011224:Prazosin