title: Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling.
abstract: OBJECTIVE
  The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations.
  
  
  METHODS
  C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg(-1)·day(-1)). Cardiac function was assessed by echocardiography and micromanometry.
  
  
  RESULTS
  (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4-8 or 4-12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC.
  
  
  CONCLUSIONS
  β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure.
authors.affiliation: Experimental Cardiology Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Vic., Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.forename: Niquita
authors.initials: N
authors.lastname: Tugiono
authors.forename: Qi
authors.initials: Q
authors.lastname: Xu
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Jennings
authors.forename: Ziqui
authors.initials: Z
authors.lastname: Ming
authors.forename: Yidan
authors.initials: Y
authors.lastname: Su
authors.forename: Paul
authors.initials: P
authors.lastname: Klenowski
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Summers
authors.forename: Alberto
authors.initials: A
authors.lastname: Kaumann
authors.forename: Peter
authors.initials: P
authors.lastname: Molenaar
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D006332:Cardiomegaly / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006333:Heart Failure / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism*; D012720:Severity of Illness Index; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; C033394:CGP 12177
keywords: (-)-CGP12177; cardiac function; hypertrophy; pressure overload; β1L-adrenoceptor