Targeted α1A-Adrenergic Receptor Overexpression Induces Enhanced Cardiac Contractility but not Hypertrophy

F Lin; W A Owens; S Chen; M E Stevens; S Kesteven; J F Arthur; E A Woodcock; M P Feneley; R M Graham

doi:10.1161/hh1601.095912

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Targeted α1A-Adrenergic Receptor Overexpression Induces Enhanced Cardiac Contractility but not Hypertrophy

Journal article

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Targeted α1A-Adrenergic Receptor Overexpression Induces Enhanced Cardiac Contractility but not Hypertrophy

F Lin, W A Owens, S Chen, M E Stevens, S Kesteven, J F Arthur, E A Woodcock, M P Feneley and R M Graham

Circulation research, Vol.89(4), pp.343-350

08/17/2001

DOI: 10.1161/hh1601.095912

PMID: 11509451

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Abstract

Activation of the alpha(1A)-adrenergic receptor (alpha(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 alpha(1A)-AR (4- to 170-fold) were generated, using the rodent alpha-myosin heavy chain promoter. Heterozygous animals displayed marked enhancement of cardiac contractility, evident from increases in dP/dt(max) (80%, P<0.0001), dP/dt(max)/LVP(inst) (76%, P<0.001), dP/dt(max):dP/dt(min) (104%, P<0.0001), and fractional shortening (33%, P<0.05). Moreover, changes in the dP/dt(max)-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 alpha(1A)- but not beta-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 alpha(1A)-AR.

Gene Targeting

Receptors, Adrenergic, alpha-1 - biosynthesis

Transgenes - physiology

Blood Pressure - genetics

Myocardial Contraction - physiology

Myocardial Contraction - drug effects

Myosin Heavy Chains - genetics

Type C Phospholipases - metabolism

Adrenergic alpha-Antagonists - pharmacology

RNA, Messenger - metabolism

Cardiomegaly

Organ Specificity - genetics

Atrial Natriuretic Factor - genetics

Gene Expression - physiology

Organ Size - genetics

Adrenergic alpha-1 Receptor Antagonists

Inositol Phosphates - metabolism

Promoter Regions, Genetic

Echocardiography

Atrial Natriuretic Factor - metabolism

Heart Rate - genetics

Electrocardiography - drug effects

Mice, Transgenic

Adenylyl Cyclases - metabolism

Animals

Receptors, Adrenergic, alpha-1 - genetics

Adrenergic alpha-Agonists - pharmacology

Heterozygote

Mice

Details

Title: Subtitle: Targeted α1A-Adrenergic Receptor Overexpression Induces Enhanced Cardiac Contractility but not Hypertrophy
Creators: F Lin - Victor Chang Cardiac Research Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia
W A Owens
S Chen
M E Stevens
S Kesteven
J F Arthur
E A Woodcock
M P Feneley
R M Graham
Resource Type: Journal article
Publication Details: Circulation research, Vol.89(4), pp.343-350
DOI: 10.1161/hh1601.095912
PMID: 11509451
NLM abbreviation: Circ Res
ISSN: 0009-7330
eISSN: 1524-4571
Publisher: United States
Language: English
Date published: 08/17/2001
Academic Unit: Anatomy and Cell Biology; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040537702771

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