Targeted α1a-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy

Abstract

Activation of the α1A-adrenergic receptor (α1A-AR)/Gq pathway has been implicated as a critical trigger for me 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 α1A-AR (4- to 170-fold) were generated, using the rodent α-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 α1A- but not β-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 α1A-AR.