Published online before print August 2, 2001, doi: 10.1161/hh1601.095912
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Targeted 
1A-Adrenergic Receptor Overexpression Induces Enhanced Cardiac Contractility but not Hypertrophy
From the Victor Chang Cardiac Research Institute (F.L., W.A.O., S.C., S.K., M.P.F., R.M.G.) and Cardiology Department (S.K., M.P.F., R.M.G.), St Vincent’s Hospital, Darlinghurst, New South Wales, Australia; Faculty of Medicine (M.P.F., R.M.G.), The University of New South Wales, Kensington, New South Wales, Australia; Bayer Corp (M.E.S.), Berkeley, Calif; and Baker Medical Research Institute (J.F.A., E.A.W.), Prahran, Victoria, Australia.
Correspondence to Robert M. Graham, Molecular Cardiology Unit, Victor Chang Cardiac Research Institute, 384 Victoria St, Darlinghurst 2010, New South Wales, Australia. E-mail b.graham{at}victorchang.unsw.edu.au
Activation of the 
1A-adrenergic receptor (1A-AR)/Gq pathway has been implicated as a critical trigger for the development of cardiac hypertrophy. However, direct evidence from in vivo studies is still lacking. To address this issue, transgenic mice with cardiac-targeted overexpression of the 1A-AR (4- to 170-fold) were generated, using the rodent -myosin heavy chain promoter. Heterozygous animals displayed marked enhancement of cardiac contractility, evident from increases in dP/dtmax (80%, P<0.0001), dP/dtmax/LVPinst (76%, P<0.001), dP/dtmax:dP/dtmin (104%, P<0.0001), and fractional shortening (33%, P<0.05). Moreover, changes in the dP/dtmax–end-diastolic volume relationship provided load-independent evidence of a primary increase in contractility. Blood pressure and heart rate were largely unchanged, and there was a small increase in (-)norepinephrine-stimulated, but not basal, phospholipase C activity. Increased contractility was directly related to the level of receptor overexpression and could be completely reversed by acute 1A- but not ß-AR blockade. Despite the robust changes in contractility, transgenic animals displayed no morphological, histological, or echocardiographic evidence of left ventricular hypertrophy. In addition, apart from an increase in atrial natriuretic factor mRNA, expression of other hypertrophy-associated genes was unchanged. To our knowledge, these data provide the first in vivo evidence for an inotropic action of the 1A-AR.
Key Words: cardiac hemodynamics • phospholipase C activity • dP/dt • receptor signaling
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