Role of low affinity beta1-adrenergic receptors in normal and diseased hearts


Autoria(s): Tugiono, N.; Kiriazis, H.; Gao, X.; Xu, Q.; Jennings, N.; Molenaar, P.; Du, X.
Contribuinte(s)

Jeremy, Richard

Data(s)

2010

Resumo

ROLE OF LOW AFFINITY β1-ADRENERGIC RECEPTOR IN NORMAL AND DISEASED HEARTS Background: The β1-adrenergic receptor (AR) has at least two binding sites, 1HAR and 1LAR (high and low affinity site of the 1AR respectively) which cause cardiostimulation. Some β-blockers, for example (-)-pindolol and (-)-CGP 12177 can activate β1LAR at higher concentrations than those required to block β1HAR. While β1HAR can be blocked by all clinically used β-blockers, β1LAR is relatively resistant to blockade. Thus, chronic β1LAR activation may occur in the setting of β-blocker therapy, thereby mediating persistent βAR signaling. Thus, it is important to determine the potential significance of β1LAR in vivo, particularly in disease settings. Method and result: C57Bl/6 male mice were used. Chronic (4 weeks) β1LAR activation was achieved by treatment with (-)-CGP12177 via osmotic minipump. Cardiac function was assessed by echocardiography and catheterization. (-)-CGP12177 treatment in healthy mice increased heart rate and left ventricular (LV) contractility without detectable LV remodelling or hypertrophy. In mice subjected to an 8-week period of aorta banding, (-)-CGP12177 treatment given during 4-8 weeks led to a positive inotropic effect. (-)-CGP12177 treatment exacerbated LV remodelling indicated by a worsening of LV hypertrophy by ??% (estimated by weight, wall thickness, cardiomyocyte size) and interstitial/perivascular fibrosis (by histology). Importantly, (-)-CGP12177 treatment to aorta banded mice exacerbated cardiac expression of hypertrophic, fibrogenic and inflammatory genes (all p<0.05 vs. non-treated control with aorta banding).. Conclusion: β1LAR activation provides functional support to the heart, in both normal and diseased (pressure overload) settings. Sustained β1LAR activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. Word count: 270

Identificador

http://eprints.qut.edu.au/34336/

Publicador

Heart Lung and Circulation

Relação

DOI:10.1016/j.hlc.2010.06.791

Tugiono, N., Kiriazis, H., Gao, X., Xu, Q., Jennings, N., Molenaar, P., & Du, X. (2010) Role of low affinity beta1-adrenergic receptors in normal and diseased hearts. In Jeremy, Richard (Ed.) Cardiac Society of Australia and New Zealand Annual Scientific Meeting and International Society for Heart Research Australasian Section Annual Scientific Meeting, 5-8 August 2010, Adelaide Convention Centre, Adelaide.

Fonte

Institute of Health and Biomedical Innovation

Palavras-Chave #110200 CARDIOVASCULAR MEDICINE AND HAEMATOLOGY #111500 PHARMACOLOGY AND PHARMACEUTICAL SCIENCES #(-)-CGP 12177 #hypertrophy #beta1L-adrenoceptors #heart failure
Tipo

Conference Item