title: Targeted alpha(1A)-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy.
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.
authors.affiliation: Victor Chang Cardiac Research Institute, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Lin
authors.forename: W A
authors.initials: WA
authors.lastname: Owens
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.forename: M E
authors.initials: ME
authors.lastname: Stevens
authors.forename: S
authors.initials: S
authors.lastname: Kesteven
authors.forename: J F
authors.initials: JF
authors.lastname: Arthur
authors.forename: E A
authors.initials: EA
authors.lastname: Woodcock
authors.forename: M P
authors.initials: MP
authors.lastname: Feneley
authors.forename: R M
authors.initials: RM
authors.lastname: Graham
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000235:genetics; D006332:Cardiomegaly; D004452:Echocardiography; D004562:Electrocardiography / Q000187:drug effects; D015870:Gene Expression / Q000502:physiology*; D018390:Gene Targeting; D006339:Heart Rate / Q000235:genetics; D006579:Heterozygote; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics; D009929:Organ Size / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis* / Q000235:genetics; D019076:Transgenes / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: C547714:Adra1a protein, mouse; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007295:Inositol Phosphates; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D009320:Atrial Natriuretic Factor; D010738:Type C Phospholipases; D018995:Myosin Heavy Chains; D000262:Adenylyl Cyclases