Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

Kiriazis, Helen, Tugiono, Niquita, Xu, Qi, Gao, Xiao-Ming , Jennings, Nicole L., Ming, Ziqui , Su, Yidan, Klenowski, Paul, Summers, Roger J., Kaumann, Alberto, Molenaar, Peter, & Du, Xiao-Jun (2013) Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling. British Journal of Pharmacology, 170(2), pp. 352-365.

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Abstract

Background and Purpose

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.

Experimental Approach

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.

Key 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 and Implications

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.

Impact and interest:

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ID Code: 68368
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: β1L-adrenoceptor, cardiac function, pressure overload, hypertrophy, (-)-CGP12177
DOI: 10.1111/bph.12272
ISSN: 1476-5381
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > CARDIOVASCULAR MEDICINE AND HAEMATOLOGY (110200) > Cardiology (incl. Cardiovascular Diseases) (110201)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PHARMACOLOGY AND PHARMACEUTICAL SCIENCES (111500) > Basic Pharmacology (111501)
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2013 The British Pharmacological Society
Deposited On: 13 Mar 2014 01:36
Last Modified: 30 Sep 2014 14:12

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